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BRCA2; breast cancer 2, early onset (13q12.3)

Gene Summary

Gene:BRCA2; breast cancer 2, early onset
Aliases: FAD, FACD, FAD1, GLM3, BRCC2, FANCD, PNCA2, FANCD1, BROVCA2
Location:13q12.3
Summary:Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, Dec 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:breast cancer type 2 susceptibility protein
HPRD
Source:NCBI
Updated:12 July, 2014

Gene
Ontology:

What does this gene/protein do?
BRCA2 is implicated in:
- brain development
- BRCA2-MAGE-D1 complex
- cell aging
- cell cycle cytokinesis
- centrosome
- centrosome duplication
- cytoplasm
- DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator
- DNA repair
- double-strand break repair
- double-strand break repair via homologous recombination
- female gonad development
- gamma-tubulin binding
- H3 histone acetyltransferase activity
- H4 histone acetyltransferase activity
- hemopoiesis
- histone acetyltransferase activity
- histone H3 acetylation
- histone H4 acetylation
- homologous chromosome orientation involved in meiotic metaphase I plate congression
- inner cell mass cell proliferation
- intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator
- male meiosis I
- mammary gland development
- multicellular organism growth
- negative regulation of mammary gland epithelial cell proliferation
- nucleolus
- nucleoplasm
- nucleotide-excision repair
- nucleus
- oocyte maturation
- positive regulation of mitotic cell cycle
- positive regulation of transcription, DNA-dependent
- protease binding
- protein binding
- protein complex
- regulation of cytokinesis
- regulation of S phase of mitotic cell cycle
- replication fork protection
- response to estradiol stimulus
- response to gamma radiation
- response to nutrient
- response to UV-C
- response to X-ray
- secretory granule
- single-stranded DNA binding
- spermatogenesis
Data from Gene Ontology via CGAP

Pathways:

What pathways are this gene/protein implicaed in?
- Role of BRCA1, BRCA2 and ATR in Cancer Susceptibility BIOCARTA
Data from KEGG and BioCarta [BIOCARTA terms] via CGAP

Cancer Overview

A tumor suppressor gene located on human chromosome 13 at locus 13q12.3. Mutations in this gene predispose humans to breast and ovarian cancer. It encodes a large, nuclear protein that is an essential component of DNA repair pathways, suppressing the formation of gross chromosomal rearrangements. (from Genes Dev 2000;14(11):1400-6) [Source: MeSH, 2014]

Research Indicators

Publications Per Year (1989-2014)
Graph generated 12 July 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 12 July, 2014 using data from PubMed, MeSH and CancerIndex

Notable

BRCA2 and Breast Cancer

Related Publications (3000)

BRCA2 and Ovarian Cancer

Related Publications (1998)

BRCA2 and Outcome in Breast Cancer

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Genetic Counseling for people with BRAC1/BRCA2 mutations

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BRCA2 and Male Breast Cancer

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Prophylactic Treatments for Women with BRCA1/BRAC2 mutations Therapy

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BRCA2 mutations in Pancreatic Cancer
Germline mutations of the BRCA2 gene are estimated to be present in 5-10% of patients with pancreatic cancer.
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BRCA2 and Cancer Screening

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BRCA2 and Breast Cancer During Pregnancy

Related Publications (20)

BRCA2 mutations in Ocular Melanoma

Related Publications (10)

Fanconi Anemia - Complementation Group D1
See section below

Related Links

Fanconi Anemia - Complementation Group D1

Latest Publications

Lee JM, Hays JL, Annunziata CM, et al.
Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses.
J Natl Cancer Inst. 2014; 106(6):dju089 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
BACKGROUND: Olaparib has single-agent activity against breast/ovarian cancer (BrCa/OvCa) in germline BRCA1 or BRCA2 mutation carriers (gBRCAm). We hypothesized addition of olaparib to carboplatin can be administered safely and yield preliminary clinical activity.
METHODS: Eligible patients had measurable or evaluable disease, gBRCAm, and good end-organ function. A 3 + 3 dose escalation tested daily oral capsule olaparib (100 or 200mg every 12 hours; dose level1 or 2) with carboplatin area under the curve (AUC) on day 8 (AUC3 day 8), then every 21 days. For dose levels 3 to 6, patients were given olaparib days 1 to 7 at 200 and 400 mg every 12 hours, with carboplatin AUC3 to 5 on day 1 or 2 every 21 days; a maximum of eight combination cycles were permitted, after which daily maintenance of olaparib 400mg every12 hours continued until progression. Dose-limiting toxicity was defined in the first two cycles. Peripheral blood mononuclear cells were collected for polymorphism analysis and polyADP-ribose incorporation. Paired tumor biopsies (before/after cycle 1) were obtained for biomarker proteomics and apoptosis endpoints.
RESULTS: Forty-five women (37 OvCa/8 BrCa) were treated. Dose-limiting toxicity was not reached on the intermittent schedule. Expansion proceeded with olaparib 400mg every 12 hours on days 1 to 7/carboplatin AUC5. Grade 3/4 adverse events included neutropenia (42.2%), thrombocytopenia (20.0%), and anemia (15.6%). Responses included 1 complete response (1 BrCa; 23 months) and 21 partial responses (50.0%; 15 OvCa; 6 BrCa; median = 16 [4 to >45] in OvCa and 10 [6 to >40] months in BrCa). Proteomic analysis suggests high pretreatment pS209-eIF4E and FOXO3a correlated with duration of response (two-sided P < .001; Pearson's R (2) = 0.94).
CONCLUSIONS: Olaparib capsules 400mg every 12 hours on days 1 to 7/carboplatin AUC5 is safe and has activity in gBRCAm BrCa/OvCa patients. Exploratory translational studies indicate pretreatment tissue FOXO3a expression may be predictive for response to therapy, requiring prospective validation.

Related: Breast Cancer Carboplatin Ovarian Cancer


Friebel TM, Domchek SM, Rebbeck TR
Modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: systematic review and meta-analysis.
J Natl Cancer Inst. 2014; 106(6):dju091 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
BACKGROUND: There is substantial variability in cancer risk in women who have inherited a BRCA1 or BRCA2 (BRCA1/2) mutation. Numerous factors have been hypothesized to modify these risks, but studies are of variable quality, and it remains unclear which of these may be of value in clinical risk assessment.
METHODS: PubMed and Web of Science databases were searched for articles published through September 2013. Fixed effects meta-analysis was done using the hazard ratios and/or odds ratios to estimate the pooled effect estimates (ES) and 95% confidence intervals (CIs) to identify factors that are associated with cancer risk modification in BRCA1/2 mutation carriers.
RESULTS: We identified 44 nonoverlapping studies that met predefined quality criteria. Sufficient evidence is available to make clinically relevant inferences about a number of cancer risk modifiers. The only variable examined that produced a probable association was late age at first live birth, a meta-analysis showed a decrease in the risk of breast cancer in BRCA1 mutation carriers with women aged 30 years or older vs. women younger than 30 years (ES = 0.65; 95% CI =0.42 to 0.99). The same was shown for women aged 25 to 29 years versus those aged less than 25 years (ES = 0.69; 95% CI = 0.48 to 0.99). Breastfeeding and tubal ligation were associated with reduced ovarian cancer risk in BRCA1 mutation carriers; oral contraceptives were associated with reduced risk among BRCA1/2 mutation carriers. Smoking was associated with increased breast cancer risk in BRCA2 mutation carriers only.
CONCLUSIONS: Data assessing many potential risk modifiers are inadequate, and many have not been externally validated. Although additional studies are required to confirm some associations, sufficient information is available for some risk factors to be used in risk counseling or lifestyle modification to minimize cancer risk in BRCA1/2 mutation carriers

Related: Breast Cancer Ovarian Cancer


Rabban JT, Garg K, Crawford B, et al.
Early detection of high-grade tubal serous carcinoma in women at low risk for hereditary breast and ovarian cancer syndrome by systematic examination of fallopian tubes incidentally removed during benign surgery.
Am J Surg Pathol. 2014; 38(6):729-42 [PubMed] Related Publications
Early detection of sporadic pelvic serous carcinoma remains an elusive goal. In women at high risk for hereditary breast and ovarian cancer syndrome who undergo prophylactic salpingectomy, systematic pathologic examination of the fallopian tubes will detect occult tubal cancer, mostly in the fimbriae, of a minority of women. Such tubal cancers are the putative precursor to advanced-stage pelvic cancer. We hypothesized that early tubal cancer detection can also be accomplished in women at low risk using a similar approach. In this study, we performed complete and systematic examination of the fallopian tubes removed during surgery performed for benign indications. Among 522 women, 4 cases of serous tubal intraepithelial carcinoma (STIC) were identified. Three of these cases would have gone undetected using the current standard of care of sampling only a single random section of the tube. The fourth case was accompanied by occult ovarian carcinoma. The fimbriae contained STIC in 3 of the 4 cases and atypical mucosa in 1 case in which the STIC was in the nonfimbriated portion of the tube. The morphologic and immunohistochemical features (aberrant p53 and MIB-1) of these STICs were similar to those expected in high-risk women. All 4 patients with STIC underwent BRCA1 and BRCA2 gene testing; no germline mutations were identified in any patient. An additional 11 specimens contained atypical mucosal proliferations that fell short of morphologic and immunohistochemical criteria for STIC. Two of these 11 fulfilled criteria for a serous tubal intraepithelial lesion, and the remaining atypical proliferations exhibited normal p53 and MIB-1. For most specimens, the fimbriae could be completely submitted in 1 or 2 cassettes per tube. These results demonstrate that systematic examination of the tubal fimbriae can serve as a form of early detection of sporadic tubal cancer without incurring significant labor or cost. We propose that the tubal fimbriae should be completely examined in all patients undergoing benign surgery even if there are no clinical features to suggest risk for hereditary breast and ovarian cancer syndrome.

Related: Cancer Screening and Early Detection Fallopian Tube Cancer MKI67 TP53


Robles-Espinoza CD, Harland M, Ramsay AJ, et al.
POT1 loss-of-function variants predispose to familial melanoma.
Nat Genet. 2014; 46(5):478-81 [PubMed] Related Publications
Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases, and rare variants in CDK4, BRCA2, BAP1 and the promoter of TERT have also been linked to the disease. Here we set out to identify new high-penetrance susceptibility genes by sequencing 184 melanoma cases from 105 pedigrees recruited in the UK, The Netherlands and Australia that were negative for variants in known predisposition genes. We identified families where melanoma cosegregates with loss-of-function variants in the protection of telomeres 1 gene (POT1), with a proportion of family members presenting with an early age of onset and multiple primary tumors. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding and leading to increased telomere length. These findings suggest that POT1 variants predispose to melanoma formation via a direct effect on telomeres.

Related: Australia Melanoma


Venkitaraman AR
Cancer suppression by the chromosome custodians, BRCA1 and BRCA2.
Science. 2014; 343(6178):1470-5 [PubMed] Related Publications
Germline mutations in BRCA1 and BRCA2 predispose to common human malignancies, most notably tumors of the breast and ovaries. The proteins encoded by these genes have been implicated in a plethora of biochemical interactions and biological functions, confounding attempts to coherently explain how their inactivation promotes carcinogenesis. Here, I argue that tumor suppression by BRCA1 and BRCA2 originates from their fundamental role in controlling the assembly and activity of macromolecular complexes that monitor chromosome duplication, maintenance, and segregation across the cell cycle. A tumor-suppressive role for the BRCA proteins as "chromosome custodians" helps to explain the clinical features of cancer susceptibility after their inactivation, provides foundations for the rational therapy of BRCA-deficient cancers, and offers general insights into the mechanisms opposing early steps in human carcinogenesis.

Related: Breast Cancer


Couch FJ, Nathanson KL, Offit K
Two decades after BRCA: setting paradigms in personalized cancer care and prevention.
Science. 2014; 343(6178):1466-70 [PubMed] Article available free on PMC after 28/09/2014 Related Publications
The cloning of the breast cancer susceptibility genes BRCA1 and BRCA2 nearly two decades ago helped set in motion an avalanche of research exploring how genomic information can be optimally applied to identify and clinically care for individuals with a high risk of developing cancer. Genetic testing for mutations in BRCA1, BRCA2, and other breast cancer susceptibility genes has since proved to be a valuable tool for determining eligibility for enhanced screening and prevention strategies, as well as for identifying patients most likely to benefit from a targeted therapy. Here, we discuss the landscape of inherited mutations and sequence variants in BRCA1 and BRCA2, the complexities of determining disease risk when the pathogenicity of sequence variants is uncertain, and current strategies for clinical management of women who carry BRCA1/2 mutations.

Related: Breast Cancer


Bookman MA, Gilks CB, Kohn EC, et al.
Better therapeutic trials in ovarian cancer.
J Natl Cancer Inst. 2014; 106(4):dju029 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
The Ovarian Task Force of the Gynecologic Cancer Steering Committee convened a clinical trials planning meeting on October 28-29, 2011, with the goals to identify key tumor types, associated molecular pathways, and biomarkers for targeted drug intervention; review strategies to improve early-phase screening, therapeutic evaluation, and comparison of new agents; and optimize design of randomized trials in response to an evolving landscape of scientific, regulatory, and funding priorities. The meeting was attended by international clinical and translational investigators, pharmaceutical industry representatives, government regulators, and patient advocates. Panel discussions focused on disease types, early-phase trials, and randomized trials. A manuscript team summarized the discussions and assisted with formulating key recommendations. A more integrated and efficient approach for screening new agents using smaller selective randomized trials in specific disease-type settings was endorsed, together with collaborative funding models between industry and the evolving national clinical trials network, as well as efforts to enhance public awareness and study enrollment through advocacy.

Related: Ovarian Cancer USA


Melchor L, Molyneux G, Mackay A, et al.
Identification of cellular and genetic drivers of breast cancer heterogeneity in genetically engineered mouse tumour models.
J Pathol. 2014; 233(2):124-37 [PubMed] Related Publications
The heterogeneous nature of mammary tumours may arise from different initiating genetic lesions occurring in distinct cells of origin. Here, we generated mice in which Brca2, Pten and p53 were depleted in either basal mammary epithelial cells or luminal oestrogen receptor (ER)-negative cells. Basal cell-origin tumours displayed similar histological phenotypes, regardless of the depleted gene. In contrast, luminal ER-negative cells gave rise to diverse phenotypes, depending on the initiating lesions, including both ER-negative and, strikingly, ER-positive invasive ductal carcinomas. Molecular profiling demonstrated that luminal ER-negative cell-origin tumours resembled a range of the molecular subtypes of human breast cancer, including basal-like, luminal B and 'normal-like'. Furthermore, a subset of these tumours resembled the 'claudin-low' tumour subtype. These findings demonstrate that not only do mammary tumour phenotypes depend on the interactions between cell of origin and driver genetic aberrations, but also multiple mammary tumour subtypes, including both ER-positive and -negative disease, can originate from a single epithelial cell type. This is a fundamental advance in our understanding of tumour aetiology.

Related: Breast Cancer PTEN TP53


Finch AP, Lubinski J, Møller P, et al.
Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation.
J Clin Oncol. 2014; 32(15):1547-53 [PubMed] Article available free on PMC after 20/05/2015 Related Publications
PURPOSE: The purposes of this study were to estimate the reduction in risk of ovarian, fallopian tube, or peritoneal cancer in women with a BRCA1 or BRCA2 mutation after oophorectomy, by age of oophorectomy; to estimate the impact of prophylactic oophorectomy on all-cause mortality; and to estimate 5-year survival associated with clinically detected ovarian, occult, and peritoneal cancers diagnosed in the cohort.
PATIENTS AND METHODS: Women with a BRCA1 or BRCA2 mutation were identified from an international registry; 5,783 women completed a baseline questionnaire and ≥ one follow-up questionnaires. Women were observed until either diagnosis of ovarian, fallopian tube, or peritoneal cancer, death, or date of most recent follow-up. Hazard ratios (HRs) for cancer incidence and all-cause mortality associated with oophorectomy were evaluated using time-dependent survival analyses.
RESULTS: After an average follow-up period of 5.6 years, 186 women developed either ovarian (n = 132), fallopian (n = 22), or peritoneal (n = 32) cancer, of whom 68 have died. HR for ovarian, fallopian, or peritoneal cancer associated with bilateral oophorectomy was 0.20 (95% CI, 0.13 to 0.30; P < .001). Among women who had no history of cancer at baseline, HR for all-cause mortality to age 70 years associated with an oophorectomy was 0.23 (95% CI, 0.13 to 0.39; P < .001).
CONCLUSION: Preventive oophorectomy was associated with an 80% reduction in the risk of ovarian, fallopian tube, or peritoneal cancer in BRCA1 or BRCA2 carriers and a 77% reduction in all-cause mortality.

Related: Fallopian Tube Cancer Ovarian Cancer


Davis L, Maizels N
Homology-directed repair of DNA nicks via pathways distinct from canonical double-strand break repair.
Proc Natl Acad Sci U S A. 2014; 111(10):E924-32 [PubMed] Article available free on PMC after 11/09/2014 Related Publications
DNA nicks are the most common form of DNA damage, and if unrepaired can give rise to genomic instability. In human cells, nicks are efficiently repaired via the single-strand break repair pathway, but relatively little is known about the fate of nicks not processed by that pathway. Here we show that homology-directed repair (HDR) at nicks occurs via a mechanism distinct from HDR at double-strand breaks (DSBs). HDR at nicks, but not DSBs, is associated with transcription and is eightfold more efficient at a nick on the transcribed strand than at a nick on the nontranscribed strand. HDR at nicks can proceed by a pathway dependent upon canonical HDR factors RAD51 and BRCA2; or by an efficient alternative pathway that uses either ssDNA or nicked dsDNA donors and that is strongly inhibited by RAD51 and BRCA2. Nicks generated by either I-AniI or the CRISPR/Cas9(D10A) nickase are repaired by the alternative HDR pathway with little accompanying mutagenic end-joining, so this pathway may be usefully applied to genome engineering. These results suggest that alternative HDR at nicks may be stimulated in physiological contexts in which canonical RAD51/BRCA2-dependent HDR is compromised or down-regulated, which occurs frequently in tumors.


Latest Publications: BRCA2 (cancer-related)

Kirby R
Optimising the management of early prostate cancer.
Practitioner. 2014; 258(1770):15-8, 2 [PubMed] Related Publications
One in eight men in the UK will be diagnosed with prostate cancer during their lifetime. The risk of prostate cancer is strongly age-related and is also linked with a Western lifestyle. Other risk factors include Afro-Caribbean ethnic origin and a positive family history. The more first-degree relatives affected the greater the risk of developing the disease. More than 70 familial prostate cancer susceptibility genes, including the important breast cancer gene BRCA2, have now been identified. A suspicion of a diagnosis of prostate cancer is usually based on either induration or nodularity of the prostate on digital rectal examination or, more commonly, a rise in serum prostate specific antigen (PSA) level. The usual cut-off point for PSA is taken as 4 ng/ml, but in men below 65 a value of more than 2.5 ng/ml should raise suspicion. A progressive rise in PSA over time may also indicate the possibility of the presence of a cancer within the prostate. When prostate cancer is suspected, increasingly urologists are requesting multiparametric magnetic resonance imaging of the gland before deciding whether or not a biopsy is indicated. The Gleason grading of any cancer identified is an important part of the decision-making process concerning the need for active treatment, as opposed to surveillance alone. Gleason pattern 6 cancers are regarded as low risk, Gleason 7 intermediate risk and 8-10 high risk. In patients diagnosed with intermediate- or high-risk prostate cancer further investigations are required to determine the local extent of the disease and to exclude the presence of metastases.

Related: Prostate Cancer


Lee JM, Hays JL, Annunziata CM, et al.
Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses.
J Natl Cancer Inst. 2014; 106(6):dju089 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
BACKGROUND: Olaparib has single-agent activity against breast/ovarian cancer (BrCa/OvCa) in germline BRCA1 or BRCA2 mutation carriers (gBRCAm). We hypothesized addition of olaparib to carboplatin can be administered safely and yield preliminary clinical activity.
METHODS: Eligible patients had measurable or evaluable disease, gBRCAm, and good end-organ function. A 3 + 3 dose escalation tested daily oral capsule olaparib (100 or 200mg every 12 hours; dose level1 or 2) with carboplatin area under the curve (AUC) on day 8 (AUC3 day 8), then every 21 days. For dose levels 3 to 6, patients were given olaparib days 1 to 7 at 200 and 400 mg every 12 hours, with carboplatin AUC3 to 5 on day 1 or 2 every 21 days; a maximum of eight combination cycles were permitted, after which daily maintenance of olaparib 400mg every12 hours continued until progression. Dose-limiting toxicity was defined in the first two cycles. Peripheral blood mononuclear cells were collected for polymorphism analysis and polyADP-ribose incorporation. Paired tumor biopsies (before/after cycle 1) were obtained for biomarker proteomics and apoptosis endpoints.
RESULTS: Forty-five women (37 OvCa/8 BrCa) were treated. Dose-limiting toxicity was not reached on the intermittent schedule. Expansion proceeded with olaparib 400mg every 12 hours on days 1 to 7/carboplatin AUC5. Grade 3/4 adverse events included neutropenia (42.2%), thrombocytopenia (20.0%), and anemia (15.6%). Responses included 1 complete response (1 BrCa; 23 months) and 21 partial responses (50.0%; 15 OvCa; 6 BrCa; median = 16 [4 to >45] in OvCa and 10 [6 to >40] months in BrCa). Proteomic analysis suggests high pretreatment pS209-eIF4E and FOXO3a correlated with duration of response (two-sided P < .001; Pearson's R (2) = 0.94).
CONCLUSIONS: Olaparib capsules 400mg every 12 hours on days 1 to 7/carboplatin AUC5 is safe and has activity in gBRCAm BrCa/OvCa patients. Exploratory translational studies indicate pretreatment tissue FOXO3a expression may be predictive for response to therapy, requiring prospective validation.

Related: Breast Cancer Carboplatin Ovarian Cancer


Friebel TM, Domchek SM, Rebbeck TR
Modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: systematic review and meta-analysis.
J Natl Cancer Inst. 2014; 106(6):dju091 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
BACKGROUND: There is substantial variability in cancer risk in women who have inherited a BRCA1 or BRCA2 (BRCA1/2) mutation. Numerous factors have been hypothesized to modify these risks, but studies are of variable quality, and it remains unclear which of these may be of value in clinical risk assessment.
METHODS: PubMed and Web of Science databases were searched for articles published through September 2013. Fixed effects meta-analysis was done using the hazard ratios and/or odds ratios to estimate the pooled effect estimates (ES) and 95% confidence intervals (CIs) to identify factors that are associated with cancer risk modification in BRCA1/2 mutation carriers.
RESULTS: We identified 44 nonoverlapping studies that met predefined quality criteria. Sufficient evidence is available to make clinically relevant inferences about a number of cancer risk modifiers. The only variable examined that produced a probable association was late age at first live birth, a meta-analysis showed a decrease in the risk of breast cancer in BRCA1 mutation carriers with women aged 30 years or older vs. women younger than 30 years (ES = 0.65; 95% CI =0.42 to 0.99). The same was shown for women aged 25 to 29 years versus those aged less than 25 years (ES = 0.69; 95% CI = 0.48 to 0.99). Breastfeeding and tubal ligation were associated with reduced ovarian cancer risk in BRCA1 mutation carriers; oral contraceptives were associated with reduced risk among BRCA1/2 mutation carriers. Smoking was associated with increased breast cancer risk in BRCA2 mutation carriers only.
CONCLUSIONS: Data assessing many potential risk modifiers are inadequate, and many have not been externally validated. Although additional studies are required to confirm some associations, sufficient information is available for some risk factors to be used in risk counseling or lifestyle modification to minimize cancer risk in BRCA1/2 mutation carriers

Related: Breast Cancer Ovarian Cancer


Robles-Espinoza CD, Harland M, Ramsay AJ, et al.
POT1 loss-of-function variants predispose to familial melanoma.
Nat Genet. 2014; 46(5):478-81 [PubMed] Related Publications
Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases, and rare variants in CDK4, BRCA2, BAP1 and the promoter of TERT have also been linked to the disease. Here we set out to identify new high-penetrance susceptibility genes by sequencing 184 melanoma cases from 105 pedigrees recruited in the UK, The Netherlands and Australia that were negative for variants in known predisposition genes. We identified families where melanoma cosegregates with loss-of-function variants in the protection of telomeres 1 gene (POT1), with a proportion of family members presenting with an early age of onset and multiple primary tumors. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding and leading to increased telomere length. These findings suggest that POT1 variants predispose to melanoma formation via a direct effect on telomeres.

Related: Australia Melanoma


Venkitaraman AR
Cancer suppression by the chromosome custodians, BRCA1 and BRCA2.
Science. 2014; 343(6178):1470-5 [PubMed] Related Publications
Germline mutations in BRCA1 and BRCA2 predispose to common human malignancies, most notably tumors of the breast and ovaries. The proteins encoded by these genes have been implicated in a plethora of biochemical interactions and biological functions, confounding attempts to coherently explain how their inactivation promotes carcinogenesis. Here, I argue that tumor suppression by BRCA1 and BRCA2 originates from their fundamental role in controlling the assembly and activity of macromolecular complexes that monitor chromosome duplication, maintenance, and segregation across the cell cycle. A tumor-suppressive role for the BRCA proteins as "chromosome custodians" helps to explain the clinical features of cancer susceptibility after their inactivation, provides foundations for the rational therapy of BRCA-deficient cancers, and offers general insights into the mechanisms opposing early steps in human carcinogenesis.

Related: Breast Cancer


Couch FJ, Nathanson KL, Offit K
Two decades after BRCA: setting paradigms in personalized cancer care and prevention.
Science. 2014; 343(6178):1466-70 [PubMed] Article available free on PMC after 28/09/2014 Related Publications
The cloning of the breast cancer susceptibility genes BRCA1 and BRCA2 nearly two decades ago helped set in motion an avalanche of research exploring how genomic information can be optimally applied to identify and clinically care for individuals with a high risk of developing cancer. Genetic testing for mutations in BRCA1, BRCA2, and other breast cancer susceptibility genes has since proved to be a valuable tool for determining eligibility for enhanced screening and prevention strategies, as well as for identifying patients most likely to benefit from a targeted therapy. Here, we discuss the landscape of inherited mutations and sequence variants in BRCA1 and BRCA2, the complexities of determining disease risk when the pathogenicity of sequence variants is uncertain, and current strategies for clinical management of women who carry BRCA1/2 mutations.

Related: Breast Cancer


Liu JF, Konstantinopoulos PA, Matulonis UA
PARP inhibitors in ovarian cancer: current status and future promise.
Gynecol Oncol. 2014; 133(2):362-9 [PubMed] Related Publications
Clinical investigation of poly(ADP-ribose) polymerase (PARP) inhibitors for ovarian cancer treatment has rapidly evolved from observations of single-agent in vitro activity of these agents in BRCA-deficient cancer cells in 2005 to the initiation of multiple phase III studies in 2013. With clinical trial design and treatment of ovarian cancer increasingly based on histological and molecular characteristics, PARP inhibitors are on the horizon of becoming the first biologic agents to be used to treat ovarian cancer based upon pre-selection characteristics of the patient's cancer. PARP inhibitors are most active in ovarian cancers that have defects or aberrations in DNA repair; use of these agents has been of particular interest in high grade serous cancers (HGSC), where studies have shown that ~50% of HGSC have abnormalities of DNA repair through BRCA germline and somatic mutation, post-translational changes of BRCA, and abnormalities of other DNA repair molecules. In addition, as aberrant DNA pathways in other histological subtypes of ovarian cancer are identified, and through the combination of PARP inhibitors with other biologic agents, the pool of eligible patients who may benefit from PARP inhibitors will likely expand. Pending review by the Food and Drug Administration (FDA) and the outcome of confirmatory phase III studies, PARP inhibitors could become the first FDA-approved biologic agent for ovarian cancer and also the first new FDA-approval in ovarian cancer since carboplatin and gemcitabine were approved for platinum sensitive ovarian cancer in 2006. This review discusses the PARP inhibitors that are currently in testing for ovarian cancer treatment and the future of this class of anti-cancer agents.

Related: BRCA1 Ovarian Cancer


Pei R, Wang P, Zhou Y, et al.
Association of BRCA1 K1183R polymorphism with survival in BRCA1/2-negative chinese familial breast cancer.
Clin Lab. 2014; 60(1):47-53 [PubMed] Related Publications
BACKGROUND: To determine whether a common BRCA1 K1183R polymorphism (3667A > G) affects survival in BRCA1/2-negative Chinese familial breast cancer. We investigated the associations between the BRCA1 E1183R polymorphism and disease-free survival and clinicopathological characteristics in a cohort of 325 Chinese familial breast cancer patients without BRCA1/2 germline mutations.
METHODS: K1183R polymorphism was detected by polymerase chain reaction (PCR)-sequencing assay.
RESULTS: Among the 325 Chinese familial breast cancer patients, the frequencies of the genotypes of E1183R polymorphism were 81.5% for wild-type (AA), 14.5% for heterozygote (AG), and 4.0% for variant (GG). No significant association between the genotypes and clinicopathological characteristics was found. There was a trend association that patients with the AA genotype had a better disease-free survival than those with the AG/GG genotype in univariate analysis (p = 0.111), but patients with AA genotype had a significantly better disease-free survival than did patients with AG or GG genotype in the HER2 positive subgroup (p = 0.012).
CONCLUSIONS: The present study suggests that the AA genotype of BRCA1 K1183R polymorphism is associated with a favorable survival in HER2 positive familial breast cancer patients.

Related: Breast Cancer BRCA1 Polymorphisms


Holman LL, Friedman S, Daniels MS, et al.
Acceptability of prophylactic salpingectomy with delayed oophorectomy as risk-reducing surgery among BRCA mutation carriers.
Gynecol Oncol. 2014; 133(2):283-6 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
OBJECTIVE: Given the emerging evidence for the fimbria as the site of origin for many serous carcinomas in BRCA mutation carriers, consideration is being given in studying prophylactic salpingectomy with delayed oophorectomy (PSDO) as a risk-reducing surgery. We aimed to determine the interest in a study of PSDO among these women.
METHODS: We evaluated the results of an online survey conducted by Facing Our Risk of Cancer Empowered (FORCE), a patient advocacy group, from October 2010 to August 2012. Premenopausal BRCA mutation carriers with no history of ovarian cancer or prior bilateral salpingo-oophorectomy (BSO) were included.
RESULTS: Of the 204 women meeting inclusion criteria, median age was 35 years, 92.5% were white, 25.7% were Jewish, and 16.7% had a history of breast cancer. Overall, 34.3% reported interest in a study of salpingectomy, 35.3% were unsure, and 30.4% were not interested in the study. Women noted the possibility of lowering ovarian cancer risk without menopause as a compelling reason to participate (83.8%). Reasons for not participating in a salpingectomy study included surgical complications (46.6%), potential ovarian damage (42.2%), planning BSO soon (32.4%), and surgical costs (32.8%). Acceptable study risks included the need for two surgeries (77.2%), possibility of not lowering ovarian cancer risk (68%), and disruption of ovarian blood supply (66.5%).
CONCLUSIONS: One-third of BRCA mutation carriers indicated definite interest in a PSDO study. Potential study risks were acceptable to most women. These findings suggest that patient accrual for a clinical trial of prophylactic salpingectomy with delayed oophorectomy is possible.

Related: BRCA1 Ovarian Cancer


Finch AP, Lubinski J, Møller P, et al.
Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation.
J Clin Oncol. 2014; 32(15):1547-53 [PubMed] Article available free on PMC after 20/05/2015 Related Publications
PURPOSE: The purposes of this study were to estimate the reduction in risk of ovarian, fallopian tube, or peritoneal cancer in women with a BRCA1 or BRCA2 mutation after oophorectomy, by age of oophorectomy; to estimate the impact of prophylactic oophorectomy on all-cause mortality; and to estimate 5-year survival associated with clinically detected ovarian, occult, and peritoneal cancers diagnosed in the cohort.
PATIENTS AND METHODS: Women with a BRCA1 or BRCA2 mutation were identified from an international registry; 5,783 women completed a baseline questionnaire and ≥ one follow-up questionnaires. Women were observed until either diagnosis of ovarian, fallopian tube, or peritoneal cancer, death, or date of most recent follow-up. Hazard ratios (HRs) for cancer incidence and all-cause mortality associated with oophorectomy were evaluated using time-dependent survival analyses.
RESULTS: After an average follow-up period of 5.6 years, 186 women developed either ovarian (n = 132), fallopian (n = 22), or peritoneal (n = 32) cancer, of whom 68 have died. HR for ovarian, fallopian, or peritoneal cancer associated with bilateral oophorectomy was 0.20 (95% CI, 0.13 to 0.30; P < .001). Among women who had no history of cancer at baseline, HR for all-cause mortality to age 70 years associated with an oophorectomy was 0.23 (95% CI, 0.13 to 0.39; P < .001).
CONCLUSION: Preventive oophorectomy was associated with an 80% reduction in the risk of ovarian, fallopian tube, or peritoneal cancer in BRCA1 or BRCA2 carriers and a 77% reduction in all-cause mortality.

Related: Fallopian Tube Cancer Ovarian Cancer


Joshi PM, Sutor SL, Huntoon CJ, Karnitz LM
Ovarian cancer-associated mutations disable catalytic activity of CDK12, a kinase that promotes homologous recombination repair and resistance to cisplatin and poly(ADP-ribose) polymerase inhibitors.
J Biol Chem. 2014; 289(13):9247-53 [PubMed] Article available free on PMC after 28/03/2015 Related Publications
Mutations in the tumor suppressors BRCA1 and BRCA2, which encode proteins that are key participants in homologous recombination (HR) repair, occur in ∼20% of high grade serous ovarian cancers. Although only 20% of these tumors have mutations in BRCA1 and BRCA2, nearly 50% of these tumors have defects in HR. Notably, however, the underlying genetic defects that give rise to HR defects in the absence of BRCA1 and BRCA2 mutations have not been fully elucidated. Here we show that the recurrent somatic CDK12 mutations identified in ovarian cancers impair the catalytic activity of this kinase, which is involved in the transcription of a subset of genes, including BRCA1 and other DNA repair genes. Furthermore, we show that disabling CDK12 function in ovarian cancer cells reduces BRCA1 levels, disrupts HR repair, and sensitizes these cells to the cross-linking agents melphalan and cisplatin and to the poly(ADP-ribose) polymerase (PARP) inhibitor veliparib (ABT-888). Taken together, these findings suggest that many CDK12 mutations are an unrecognized cause of HR defects in ovarian cancers.

Related: Cisplatin Ovarian Cancer CDK12 gene


Jackson SA, Davis AA, Li J, et al.
Characteristics of individuals with breast cancer rearrangements in BRCA1 and BRCA2.
Cancer. 2014; 120(10):1557-64 [PubMed] Related Publications
BACKGROUND: Large rearrangements in BRCA1 and BRCA2 occur in a small percentage (< 1%) of patients tested for hereditary breast (BC) and ovarian cancer. It is unclear what factors predict BRACAnalysis Large Rearrangement Test (BART) positivity.
METHODS: Data from 6 centers were included in this analysis. Individuals with negative Comprehensive BRACAnalysis tested for BART were included.
RESULTS: From 1300 individuals, 42 (3.2%) were BART positivity. Factors positively associated with BART positivity were Myriad score, first-degree relatives with BC, infiltrating BC with ductal carcinoma in situ, younger age at BC diagnosis, estrogen receptor-negative BC for both the first and second BC, and Latin American/Caribbean ethnicity. Presence of unilateral BC was inversely associated with BART positivity. Several analyses were performed on the variables available to find the model that best predicts for BART positivity. The BART predictive model, including first BC, ovarian cancer, primary maternal ancestry being Latin America/Caribbean, number of first-degree relatives with BC of 1 or more versus 0, and family history of prostate and pancreatic cancer, had good predictive ability with an area under the curve of 0.77.
CONCLUSIONS: Several factors are significantly associated with BART positivity. Among them we have found that Latin American/Caribbean ancestry, Myriad score, first degree relatives with BC, younger age at BC diagnosis, estrogen receptor-negative status of BC, and infiltrating ductal carcinoma with ductal carcinoma in situ features are significantly associated with BART positivity. A BART predictive model may help in a clinical setting.

Related: Breast Cancer BRCA1 Ovarian Cancer USA


Metcalfe K, Gershman S, Ghadirian P, et al.
Contralateral mastectomy and survival after breast cancer in carriers of BRCA1 and BRCA2 mutations: retrospective analysis.
BMJ. 2014; 348:g226 [PubMed] Article available free on PMC after 28/03/2015 Related Publications
OBJECTIVE: To compare the survival rates of women with BRCA associated breast cancer who did and did not undergo mastectomy of the contralateral breast.
DESIGN: Retrospective analysis.
SETTING: 12 cancer genetics clinics.
PARTICIPANTS: 390 women with a family history of stage I or II breast cancer who were carriers of BRCA1 and BRCA2 mutations and initially treated with unilateral or bilateral mastectomy. 181 patients had mastectomy of the contralateral breast. Patients were followed for up to 20 years from diagnosis.
MAIN OUTCOME MEASURE: Death from breast cancer.
RESULTS: 79 women died of breast cancer in the follow-up period (18 in the bilateral mastectomy group and 61 in the unilateral mastectomy group). The median follow-up time was 14.3 years (range 0.1-20.0 years). At 20 years the survival rate for women who had mastectomy of the contralateral breast was 88% (95% confidence interval 83% to 93%) and for those who did not was 66% (59% to 73%). In a multivariable analysis, controlling for age at diagnosis, year of diagnosis, treatment, and other prognostic features, contralateral mastectomy was associated with a 48% reduction in death from breast cancer (hazard ratio 0.52, 95% confidence interval 0.29 to 0.93; P=0.03). In a propensity score adjusted analysis of 79 matched pairs, the association was not significant (0.60, 0.34 to 1.06; P=0.08). Based on these results, we predict that of 100 women treated with contralateral mastectomy, 87 will be alive at 20 years compared with 66 of 100 women treated with unilateral mastectomy.
CONCLUSIONS: This study suggests that women who are positive for BRCA mutations and who are treated for stage I or II breast cancer with bilateral mastectomy are less likely to die from breast cancer than women who are treated with unilateral mastectomy. Given the small number of events in this cohort, further research is required to confirm these findings.

Related: Breast Cancer Canada USA


Reade CJ, McVey RM, Tone AA, et al.
The fallopian tube as the origin of high grade serous ovarian cancer: review of a paradigm shift.
J Obstet Gynaecol Can. 2014; 36(2):133-40 [PubMed] Related Publications
Research published over the past 10 years has suggested that most "ovarian cancer," and specifically the high-grade serous carcinoma (HGSC) subtype of ovarian cancer, actually originates in the fallopian tube. In this review, we examine the evidence supporting the tubal origin hypothesis for HGSC, and discuss the clinical implications of our improved understanding of the pathogenesis of ovarian cancer. We searched Medline R and Medline in-process and non-indexed citations from inception to December 15, 2012, to identify all English or French language articles discussing the origins of HGSC. Articles and findings were summarized descriptively. A step-wise transformation from normal epithelium to a lesion with the ability to invade and metastasize has been demonstrated within the fallopian tube. Intraepithelial or early invasive carcinoma of the fallopian tube is frequently identified in BRCA mutation carriers who undergo prophylactic risk-reducing salpingo-oophorectomy. In both BRCA mutation carriers and women from the general population, pre-invasive changes within the fimbriated end of the fallopian tube appear in association with early HGSC. Molecular and genetic studies, as well as in vitro and animal models, have also supported a tubal origin for HGSC. Whether the removal of fallopian tubes (salpingectomy) at the time of pelvic surgery for other reasons will lead to reductions in mortality from ovarian cancer is currently unknown, but it is an important area for future clinical research.

Related: Fallopian Tube Cancer BRCA1 Ovarian Cancer


Muggia F, Safra T
'BRCAness' and its implications for platinum action in gynecologic cancer.
Anticancer Res. 2014; 34(2):551-6 [PubMed] Related Publications
Gynecological carcinomas are major therapeutic targets of platinum-containing regimens. They may be particularly susceptible to these agents if their origins are related to hereditary breast cancer (BRCA) mutations; this implicates defective DNA repair secondary to inherited alterations in BRCA function. The concept of 'BRCAness' was introduced by Ashworth and colleagues in order to identify phenotypic changes in sporadic cancer that would lead to analogous treatment susceptibility. In fact, recent analyses of genetic alterations in ovarian cancer have led to further extending this concept to all women with high-grade serous cancer, the predominant form of ovarian cancer arising in association with hereditary mutations in BRCA genes. Presumably, most serous types of cancer of gynecological origin share BRCA dysfunction to some extent. This renders these types of cancer susceptible to platinum and to other DNA-damaging agents, justifying the general inclusion of this histology in trials of new drugs and therapeutic strategies that have shown activity against hereditary cancer. More recently, however, differences in outcome between BRCA mutation carriers vis-à-vis those with no mutations or those with epigenetic or acquired forms of BRCA genes (somatic mutations) in their respective tumors have been identified. These findings raise additional questions on modifiers of 'BRCAness' and other pathways that appear to contribute to the effects of platinum and other DNA-damaging agents in ovarian cancer. The Cancer Genome Atlas analyses delineate the complexity of genomic alterations in ovarian cancer and other malignancies of Mullerian epithelial origin promising further refinements of the 'BRCAness' concept.

Related: BRCA1 Gynacological Cancers


Prensner JR, Chen W, Iyer MK, et al.
PCAT-1, a long noncoding RNA, regulates BRCA2 and controls homologous recombination in cancer.
Cancer Res. 2014; 74(6):1651-60 [PubMed] Article available free on PMC after 15/03/2015 Related Publications
Impairment of double-stranded DNA break (DSB) repair is essential to many cancers. However, although mutations in DSB repair proteins are common in hereditary cancers, mechanisms of impaired DSB repair in sporadic cancers remain incompletely understood. Here, we describe the first role for a long noncoding RNA (lncRNA) in DSB repair in prostate cancer. We identify PCAT-1, a prostate cancer outlier lncRNA, which regulates cell response to genotoxic stress. PCAT-1 expression produces a functional deficiency in homologous recombination through its repression of the BRCA2 tumor suppressor, which, in turn, imparts a high sensitivity to small-molecule inhibitors of PARP1. These effects reflected a posttranscriptional repression of the BRCA2 3'UTR by PCAT-1. Our observations thus offer a novel mechanism of "BRCAness" in sporadic cancers.

Related: Prostate Cancer PARP1


Schwartz MD, Valdimarsdottir HB, Peshkin BN, et al.
Randomized noninferiority trial of telephone versus in-person genetic counseling for hereditary breast and ovarian cancer.
J Clin Oncol. 2014; 32(7):618-26 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
PURPOSE: Although guidelines recommend in-person counseling before BRCA1/BRCA2 gene testing, genetic counseling is increasingly offered by telephone. As genomic testing becomes more common, evaluating alternative delivery approaches becomes increasingly salient. We tested whether telephone delivery of BRCA1/2 genetic counseling was noninferior to in-person delivery.
PATIENTS AND METHODS: Participants (women age 21 to 85 years who did not have newly diagnosed or metastatic cancer and lived within a study site catchment area) were randomly assigned to usual care (UC; n = 334) or telephone counseling (TC; n = 335). UC participants received in-person pre- and post-test counseling; TC participants completed all counseling by telephone. Primary outcomes were knowledge, satisfaction, decision conflict, distress, and quality of life; secondary outcomes were equivalence of BRCA1/2 test uptake and costs of delivering TC versus UC.
RESULTS: TC was noninferior to UC on all primary outcomes. At 2 weeks after pretest counseling, knowledge (d = 0.03; lower bound of 97.5% CI, -0.61), perceived stress (d = -0.12; upper bound of 97.5% CI, 0.21), and satisfaction (d = -0.16; lower bound of 97.5% CI, -0.70) had group differences and confidence intervals that did not cross their 1-point noninferiority limits. Decision conflict (d = 1.1; upper bound of 97.5% CI, 3.3) and cancer distress (d = -1.6; upper bound of 97.5% CI, 0.27) did not cross their 4-point noninferiority limit. Results were comparable at 3 months. TC was not equivalent to UC on BRCA1/2 test uptake (UC, 90.1%; TC, 84.2%). TC yielded cost savings of $114 per patient.
CONCLUSION: Genetic counseling can be effectively and efficiently delivered via telephone to increase access and decrease costs.

Related: Breast Cancer BRCA1 Ovarian Cancer


Rustgi AK
Familial pancreatic cancer: genetic advances.
Genes Dev. 2014; 28(1):1-7 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Beset by poor prognosis, pancreatic ductal adenocarcinoma is classified as familial or sporadic. This review elaborates on the known genetic syndromes that underlie familial pancreatic cancer, where there are opportunities for genetic counseling and testing as well as clinical monitoring of at-risk patients. Such subsets of familial pancreatic cancer involve germline cationic trypsinogen or PRSS1 mutations (hereditary pancreatitis), BRCA2 mutations (usually in association with hereditary breast-ovarian cancer syndrome), CDKN2 mutations (familial atypical mole and multiple melanoma), or DNA repair gene mutations (e.g., ATM and PALB2, apart from those in BRCA2). However, the vast majority of familial pancreatic cancer cases have yet to have their genetic underpinnings elucidated, waiting in part for the results of deep sequencing efforts.

Related: Melanoma Cancer of the Pancreas Pancreatic Cancer


Garcia C, Wendt J, Lyon L, et al.
Risk management options elected by women after testing positive for a BRCA mutation.
Gynecol Oncol. 2014; 132(2):428-33 [PubMed] Related Publications
OBJECTIVE: To assess the uptake of risk-reducing options for the management of ovarian and breast cancer risk in BRCA mutation carriers in a large community based integrated health system in Northern California.
METHODS: A retrospective cohort of deleterious BRCA mutation carriers (1995-2012) was evaluated for consistency with NCCN guidelines for risk reducing salpingo-oophorectomy (RRSO) by age of 35-40, risk reducing mastectomy (RRM), as well as surveillance practices, including pelvic ultrasound, CA 125, mammogram, and breast MRI. Secondary outcomes included the use of chemoprevention and hormone replacement.
RESULTS: Of the 305 eligible women, 170 were BRCA1 positive, and 135 were BRCA2 positive. Seventy four percent underwent RRSO with only 17% under age 40, while 44% underwent RRM. The median time from the test to both RRSO and RRM was 6 months. In the first year after BRCA diagnosis, 45% underwent a pelvic ultrasound, dropping to 2.3% by year 5. In year 1, 47% had a CA 125, dropping to 2% by year 5. The number of women undergoing annual MRI and mammogram fell similarly over time. Sixteen percent of BRCA carriers used oral contraceptives (OCPs) and only one patient used tamoxifen for chemoprevention.
CONCLUSION: Uptake of RRSO in BRCA carriers in a population based health system is high, however the majority of women do not have RRSO by the NCCN recommended age. Compliance with surveillance is low and rapidly declines even 1 year out from testing. Attention needs to be focused on the earlier identification of BRCA mutation carriers with consolidated and standardized care to improve risk reduction.

Related: Breast Cancer BRCA1 Ovarian Cancer


Lee AJ, Cunningham AP, Kuchenbaecker KB, et al.
BOADICEA breast cancer risk prediction model: updates to cancer incidences, tumour pathology and web interface.
Br J Cancer. 2014; 110(2):535-45 [PubMed] Article available free on PMC after 21/01/2015 Related Publications
BACKGROUND: The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) is a risk prediction model that is used to compute probabilities of carrying mutations in the high-risk breast and ovarian cancer susceptibility genes BRCA1 and BRCA2, and to estimate the future risks of developing breast or ovarian cancer. In this paper, we describe updates to the BOADICEA model that extend its capabilities, make it easier to use in a clinical setting and yield more accurate predictions.
METHODS: We describe: (1) updates to the statistical model to include cancer incidences from multiple populations; (2) updates to the distributions of tumour pathology characteristics using new data on BRCA1 and BRCA2 mutation carriers and women with breast cancer from the general population; (3) improvements to the computational efficiency of the algorithm so that risk calculations now run substantially faster; and (4) updates to the model's web interface to accommodate these new features and to make it easier to use in a clinical setting.
RESULTS: We present results derived using the updated model, and demonstrate that the changes have a significant impact on risk predictions.
CONCLUSION: All updates have been implemented in a new version of the BOADICEA web interface that is now available for general use: http://ccge.medschl.cam.ac.uk/boadicea/.

Related: Breast Cancer Male Breast Cancer


Cai F, Ge I, Wang M, et al.
Pyrosequencing analysis of BRCA1 methylation level in breast cancer cells.
Tumour Biol. 2014; 35(4):3839-44 [PubMed] Related Publications
BRCA1 and BRCA2 genes are crucial for double-strand break repair by homologous recombination, and mutations in these genes are responsible for most familial breast carcinomas. Cells with inactivating mutations of the BRCA1 or BRCA2 tumor suppressor genes are sensitive to poly (ADP-ribose) polymerase-1 (PARP1) inhibitors. Already in 2010, it has been predicted, that BRCA1 hypermethylation might be sensitive to PARP1 inhibitor. However, till today, a statistically significant proof has been missing, and the effectiveness of PARP1 inhibitors for breast cancer caused by BRCA1 promoter hypermethylation remained elusive. Pyrosequencing has been proposed as an optimal method to investigate the methylation status of the BRCA1 genes. Here, we show for the first time that BRCA1 CpG island hypermethylation is sensitive to PARP1 inhibitors. In clinical settings, this might improve treatment response and provide a more personalized therapy for breast cancer patients. Furthermore, the determination of methylation status of BRCA1 and other genes of the BRCA/homologous recombination (HR) pathway may be an important predictive classifier of response to PARP inhibitor therapy.

Related: Breast Cancer BRCA1 PARP1


Conner JR, Meserve E, Pizer E, et al.
Outcome of unexpected adnexal neoplasia discovered during risk reduction salpingo-oophorectomy in women with germ-line BRCA1 or BRCA2 mutations.
Gynecol Oncol. 2014; 132(2):280-6 [PubMed] Article available free on PMC after 01/02/2015 Related Publications
OBJECTIVE: This study computed the risk of clinically silent adnexal neoplasia in women with germ-line BRCA1 or BRCA2 mutations (BRCA(m+)) and determined recurrence risk.
METHODS: We analyzed risk reduction salpingo-oophorectomies (RRSOs) from 349 BRCA(m+) women processed by the SEE-FIM protocol and addressed recurrence rates for 29 neoplasms from three institutions.
RESULTS: Nineteen neoplasms (5.4%) were identified at one institution, 9.2% of BRCA1 and 3.4% of BRCA2 mutation-positive women. Fourteen had a high-grade tubal intraepithelial neoplasm (HGTIN, 74%). Mean age (54.4) was higher than the BRCA(m+) cohort without neoplasia (47.8) and frequency increased with age (p < 0.001). Twenty-nine BRCA(m+) patients with neoplasia from three institutions were followed for a median of 5 years (1-8 years.). One of 11 with HGTIN alone (9%) recurred at 4 years, in contrast to 3 of 18 with invasion or involvement of other sites (16.7%). All but two are currently alive. Among the 29 patients in the three institution cohort, mean ages for HGTIN and advanced disease were 49.2 and 57.7 (p = 0.027).
CONCLUSIONS: Adnexal neoplasia is present in 5-6% of RRSOs, is more common in women with BRCA1 mutations, and recurs in 9% of women with HGTIN alone. The lag in time from diagnosis of the HGTIN to pelvic recurrence (4 years) and differences in mean age between HGTIN and advanced disease (8.5 years) suggest an interval of several years from the onset of HGTIN until pelvic cancer develops. However, some neoplasms occur in the absence of HGTIN.

Related: BRCA1 Ovarian Cancer


Xiao X, Melton DW, Gourley C
Mismatch repair deficiency in ovarian cancer -- molecular characteristics and clinical implications.
Gynecol Oncol. 2014; 132(2):506-12 [PubMed] Related Publications
DNA mismatch repair (MMR) deficiency is associated with increased risk of developing several types of cancer and is the most common cause of hereditary ovarian cancer after BRCA1 and BRCA2 mutations. While there has been extensive investigation of MMR deficiency in colorectal cancer, MMR in ovarian cancer is relatively under-investigated. This review summarizes the mechanism of MMR, the ways in which MMR deficiency can promote carcinogenesis in general and then assesses the available studies regarding MMR deficiency in ovarian cancers with specific emphasis on implications for disease incidence and therapy. The incidence of germline MMR gene mutations in ovarian cancer is only 2% but other mechanisms of gene inactivation mean that loss of expression of one of the seven main genes (MSH2, MSH3, MSH6, MLH1, MLH3, PMS1 and PMS2) occurs in up to 29% of cases. Both mutational and expression data suggest that MMR deficiency is more common in non-serous ovarian cancer. Some studies suggest an improved survival for patients with MMR deficiency compared to historical controls but these do not account for the preponderance of non-serous tumors. A number of in vitro studies have suggested that MMR deficiency is a cause of platinum resistance. To date this has not been categorically demonstrated in the clinic. Larger studies that account for stage of presentation and immunohistochemical subtype are required to assess the effect of MMR deficiency on survival and chemosensitivity. Investigation of MMR related synthetic lethality in colorectal cancer has identified dihydrofolate reductase, DNA polymerase β and DNA polymerase γ and PTEN-induced putative kinase 1 as synthetic lethal to certain MMR defects by causing accumulation of oxidative DNA damage. These synthetic lethal targets require tested and others should be sought within the context of MMR deficient ovarian cancer in an attempt to provide novel therapeutic strategies for these patients.

Related: Ovarian Cancer


Karami F, Mehdipour P
A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer.
Biomed Res Int. 2013; 2013:928562 [PubMed] Article available free on PMC after 01/02/2015 Related Publications
Breast cancer (BC) is the most common cancer of women all over the world. BRCA1 and BRCA2 gene mutations comprise the most important genetic susceptibility of BC. Except for few common mutations, the spectrum of BRCA1 and BRCA2 mutations is heterogeneous in diverse populations. 185AGdel and 5382insC are the most important BRCA1 and BRCA2 alterations which have been encountered in most of the populations. After those Ashkenazi founder mutations, 300T>G also demonstrated sparse frequency in African American and European populations. This review affords quick access to the most frequent alterations among various populations which could be helpful in BRCA screening programs.

Related: Breast Cancer BRCA1 Polymorphisms


Jiao Y, Yonescu R, Offerhaus GJ, et al.
Whole-exome sequencing of pancreatic neoplasms with acinar differentiation.
J Pathol. 2014; 232(4):428-35 [PubMed] Article available free on PMC after 01/02/2015 Related Publications
Pancreatic carcinomas with acinar differentiation, including acinar cell carcinoma, pancreatoblastoma and carcinomas with mixed differentiation, are distinct pancreatic neoplasms with poor prognosis. Although recent whole-exome sequencing analyses have defined the somatic mutations that characterize the other major neoplasms of the pancreas, the molecular alterations underlying pancreatic carcinomas with acinar differentiation remain largely unknown. In the current study, we sequenced the exomes of 23 surgically resected pancreatic carcinomas with acinar differentiation. These analyses revealed a relatively large number of genetic alterations at both the individual base pair and chromosomal levels. There was an average of 119 somatic mutations/carcinoma. When three outliers were excluded, there was an average of 64 somatic mutations/tumour (range 12-189). The mean fractional allelic loss (FAL) was 0.27 (range 0-0.89) and heterogeneity at the chromosome level was confirmed in selected cases using fluorescence in situ hybridization (FISH). No gene was mutated in >30% of the cancers. Genes altered in other neoplasms of the pancreas were occasionally targeted in carcinomas with acinar differentiation; SMAD4 was mutated in six tumours (26%), TP53 in three (13%), GNAS in two (9%), RNF43 in one (4%) and MEN1 in one (4%). Somatic mutations were identified in genes in which constitutional alterations are associated with familial pancreatic ductal adenocarcinoma, such as ATM, BRCA2 and PALB2 (one tumour each), as well as in genes altered in extra-pancreatic neoplasms, such as JAK1 in four tumours (17%), BRAF in three (13%), RB1 in three (13%), APC in two (9%), PTEN in two (9%), ARID1A in two (9%), MLL3 in two (9%) and BAP1 in one (4%). Perhaps most importantly, we found that more than one-third of these carcinomas have potentially targetable genetic alterations, including mutations in BRCA2, PALB2, ATM, BAP1, BRAF and JAK1.

Related: FISH Cancer of the Pancreas Pancreatic Cancer


Phelan CM, Iqbal J, Lynch HT, et al.
Incidence of colorectal cancer in BRCA1 and BRCA2 mutation carriers: results from a follow-up study.
Br J Cancer. 2014; 110(2):530-4 [PubMed] Article available free on PMC after 21/01/2015 Related Publications
BACKGROUND: The BRCA1 and BRCA2 genes confer increased susceptibility to breast and ovarian cancer and to a spectrum of other cancers. There is controversy regarding the risk of colorectal cancer conferred by germline mutations in these two genes.
METHODS: We followed 7015 women with a BRCA mutation for new cases of colorectal cancer. Incidence rates in carriers were compared with population-specific incidence rates, and standardised incidence ratios (SIRs) were estimated. The expected numbers of cancers were computed by multiplying person-years at risk by the appropriate age-, sex- and country-specific incidence rates from the five countries.
RESULTS: Twenty-one incident colorectal cancer cases were observed among all mutation carriers, compared with 23.6 cases expected. The SIR for BRCA1 carriers was 0.92 (95% confidence interval (CI), 0.54-1.40, P=0.7) and for BRCA2 carriers was 0.82 (95% CI, 0.30-1.81, P=0.7). The SIR for colon cancer was 3.81 (95% CI 1.77-7.23) for women below the age of 50 years (both genes combined) and was 0.60 (95% CI 0.33-1.00) for women aged 50 years and above.
CONCLUSION: The risk of colorectal cancer is increased in female carriers of BRCA1 mutations below the age of 50 years but not in women with BRCA2 mutations or in older women.

Related: Canada Colorectal (Bowel) Cancer BRCA1 USA


Rezano A, Kuwahara K, Yamamoto-Ibusuki M, et al.
Breast cancers with high DSS1 expression that potentially maintains BRCA2 stability have poor prognosis in the relapse-free survival.
BMC Cancer. 2013; 13:562 [PubMed] Related Publications
BACKGROUND: Genetic BRCA2 insufficiency is associated with breast cancer development; however, in sporadic breast cancer cases, high BRCA2 expression is paradoxically correlated with poor prognosis. Because DSS1, a mammalian component of the transcription/RNA export complex, is known to stabilize BRCA2, we investigated how the expression of DSS1 is associated with clinical parameters in breast cancers.
METHODS: DSS1 mRNA and p53 protein were examined by RT-PCR and immunohistochemical staining of breast cancer specimens to classify DSS1(high) and DSS1(low) or p53(high) and p53(low) groups. Patient survival was compared using Kaplan-Meier method. DSS1(high) or DSS1(low) breast cancer cells were prepared by retroviral cDNA transfection or DSS1 siRNA on proliferation, cell cycle progression, and survival by flow cytometric analyses with or without anti-cancer drugs.
RESULTS: In comparison to patients with low levels of DSS1, high-DSS1 patients showed a poorer prognosis, with respect to relapse-free survival period. The effect of DSS1 was examined in breast cancer cells in vitro. DSS1 high-expression reduces the susceptibility of MCF7 cells to DNA-damaging drugs, as observed in cell cycle and apoptosis analyses. DSS1 knockdown, however, increased the susceptibility to the DNA-damaging drugs camptothecin and etoposide and caused early apoptosis in p53 wild type MCF7 and p53-insufficient MDA-MB-231 cells. DSS1 knockdown suppresses the proliferation of drug-resistant MDA-MB-231 breast cancer cells, particularly effectively in combination with DNA-damaging agents.
CONCLUSION: Breast cancers with high DSS1 expression have worse prognosis and shorter relapse-free survival times. DSS1 is necessary to rescue cells from DNA damage, but high DSS1 expression increases drug resistance. We suggest that DSS1 expression could be a useful marker for drug resistance in breast cancers, and DSS1 knockdown can induce tumor apoptosis when used in combination with DNA-damaging drugs.

Related: Apoptosis Breast Cancer TP53


Stout NK, Nekhlyudov L, Li L, et al.
Rapid increase in breast magnetic resonance imaging use: trends from 2000 to 2011.
JAMA Intern Med. 2014; 174(1):114-21 [PubMed] Related Publications
IMPORTANCE: Breast magnetic resonance imaging (MRI) is highly sensitive for detecting breast cancer. Low specificity, cost, and little evidence regarding mortality benefits, however, limit recommendations for its use to high-risk women. How breast MRI is actually used in community settings is unknown.
OBJECTIVE: To describe breast MRI trends and indications in a community setting.
DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study at a not-for-profit health plan and multispecialty group medical practice in New England of 10,518 women aged 20 years and older enrolled in the health plan for at least 1 year who had at least 1 breast MRI between January 1, 2000, and December 31, 2011.
MAIN OUTCOMES AND MEASURES: Breast MRI counts were obtained from claims data. Clinical indication (screening, diagnostic evaluation, staging or treatment, or surveillance) was determined using a prediction model developed from electronic medical records on a subset of participants. Breast cancer risk status was assessed using claims data and, for the subset, also through electronic medical record review. RESULTS; Breast MRI use increased more than 20-fold from 6.5 per 10,000 women in 2000 to 130.7 per 10,000 in 2009. Use then declined and stabilized to 104.8 per 10,000 by 2011. Screening and surveillance, rare indications in 2000, together accounted for 57.6% of MRI use by 2011; 30.1% had a claims-documented personal history and 51.7% a family history of breast cancer, whereas 3.5% of women had a documented genetic mutation. In the subset of women with electronic medical records who received screening or surveillance MRIs, only 21.0% had evidence of meeting American Cancer Society (ACS) criteria for breast MRI. Conversely, only 48.4% of women with documented deleterious genetic mutations received breast MRI screening.
CONCLUSIONS AND RELEVANCE: Breast MRI use increased steeply over 10 years and then stabilized, especially for screening and surveillance among women with family or personal history of breast cancer; most women receiving screening and surveillance breast MRIs lacked documented evidence of meeting ACS criteria, and many women with mutations were not screened. Efforts are needed to ensure that breast MRI use and documentation are focused on those women who will benefit most.

Related: Breast Cancer Cancer Screening and Early Detection BRCA1


Bajrami I, Frankum JR, Konde A, et al.
Genome-wide profiling of genetic synthetic lethality identifies CDK12 as a novel determinant of PARP1/2 inhibitor sensitivity.
Cancer Res. 2014; 74(1):287-97 [PubMed] Related Publications
Small-molecule inhibitors of PARP1/2, such as olaparib, have been proposed to serve as a synthetic lethal therapy for cancers that harbor BRCA1 or BRCA2 mutations. Indeed, in clinical trials, PARP1/2 inhibitors elicit sustained antitumor responses in patients with germline BRCA gene mutations. In hypothesizing that additional genetic determinants might direct use of these drugs, we conducted a genome-wide synthetic lethal screen for candidate olaparib sensitivity genes. In support of this hypothesis, the set of identified genes included known determinants of olaparib sensitivity, such as BRCA1, RAD51, and Fanconi's anemia susceptibility genes. In addition, the set included genes implicated in established networks of DNA repair, DNA cohesion, and chromatin remodeling, none of which were known previously to confer sensitivity to PARP1/2 inhibition. Notably, integration of the list of candidate sensitivity genes with data from tumor DNA sequencing studies identified CDK12 deficiency as a clinically relevant biomarker of PARP1/2 inhibitor sensitivity. In models of high-grade serous ovarian cancer (HGS-OVCa), CDK12 attenuation was sufficient to confer sensitivity to PARP1/2 inhibition, suppression of DNA repair via homologous recombination, and reduced expression of BRCA1. As one of only nine genes known to be significantly mutated in HGS-OVCa, CDK12 has properties that should confirm interest in its use as a biomarker, particularly in ongoing clinical trials of PARP1/2 inhibitors and other agents that trigger replication fork arrest.

Related: Ovarian Cancer PARP1 CDK12 gene


Collins IM, Milne RL, Weideman PC, et al.
Preventing breast and ovarian cancers in high-risk BRCA1 and BRCA2 mutation carriers.
Med J Aust. 2013; 199(10):680-3 [PubMed] Related Publications
OBJECTIVE: To estimate the prevalence of the use of cancer risk-reducing measures among Australian BRCA1 and BRCA2 mutation carriers.
DESIGN, SETTING AND PARTICIPANTS: Prospective follow-up of female carriers of BRCA1 or BRCA2 mutations who had no personal history of cancer and were enrolled in a multiple-case breast cancer family cohort study (kConFab). Data, including cancer events and uptake of risk-reducing surgery and medication were collected by self-report at cohort entry and 3 yearly thereafter. Surgery was confirmed from pathology and medical records. Women were followed up from enrolment until cancer diagnosis, date of last follow-up, or death. Data were collected from 3 November 1997 to 21 May 2012.
MAIN OUTCOME MEASURES: Uptake of risk-reducing surgery and/or medication.
RESULTS: Of 175 BRCA1 and 150 BRCA2 mutation carriers (median age, 37 years at cohort enrolment), 69 (21%) underwent risk-reducing mastectomy, 125 (38%) underwent risk-reducing bilateral salpingo-oophorectomy and nine (3%) participated in a clinical trial of risk-reducing medication, during 2447 person-years of follow-up (median follow-up, 9 years). Sixty-eight women (21%) reported incident cancers, including 52 breast cancers and nine ovarian cancers (defined in this article as high-grade serous cancers of the ovary, fallopian tube or peritoneum).
CONCLUSIONS: There is considerable scope to increase the uptake of cancer risk-reducing measures in Australian BRCA1 and BRCA2 mutation carriers. These findings should drive (i) future research into the factors contributing to low uptake in Australia and (ii) changes to policy and practice to help better translate genetic knowledge into reductions in cancer incidence.

Related: Australia BRCA1


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