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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:08 March, 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 08 March 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 08 March, 2014 using data from PubMed, MeSH and CancerIndex

Notable

BRCA2 and Breast Cancer

Related Publications (3000)

BRCA2 and Ovarian Cancer

Related Publications (1930)

BRCA2 and Cancer Screening

Related Publications (68)

BRCA2 mutations in Pancreatic Cancer
Germline mutations of the BRCA2 gene are estimated to be present in 5-10% of patients with pancreatic cancer.
Related Publications (178)

BRCA2 and Male Breast Cancer

Related Publications (277)

BRCA2 mutations in Ocular Melanoma

Related Publications (10)

Prophylactic Treatments for Women with BRCA1/BRAC2 mutations Therapy

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BRCA2 and Breast Cancer During Pregnancy

Related Publications (20)

BRCA2 and Outcome in Breast Cancer

Related Publications (499)

Genetic Counseling for people with BRAC1/BRCA2 mutations

Related Publications (270)

Fanconi Anemia - Complementation Group D1
See section below

Related Links

Fanconi Anemia - Complementation Group D1

Latest Publications

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] Free Access to Full Article 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


Akbari MR, Lepage P, Rosen B, et al.
PPM1D mutations in circulating white blood cells and the risk for ovarian cancer.
J Natl Cancer Inst. 2014; 106(1):djt323 [PubMed] Related Publications
We compared the frequency of PPM1D mutation in the white blood cells from 1295 ovarian cancer case patients and 834 control subjects. We found a truncating mutation in 20 case patients vs 1 control subject (odds ratio [OR] = 13.07; 95% confidence interval [CI] = 1.75 to 97.55; P < .001). The 12-year mortality of the PPM1D-positive case patients was higher than that of the PPM1D-negative case patients (hazard ratio = 2.02; 95% CI = 1.21 to 3.39; P = .007). Three of the 20 PPM1D carrier case patients had a past history of breast cancer compared with 29 of 1129 noncarriers (OR = 6.69; 95% CI = 1.86 to 24.11; P = .007). The lifetime risks for breast or ovarian cancer among female first-degree relatives of PPM1D mutation carriers were not increased compared with that of case patients without mutations. These observations suggest PPM1D mutations in the mosaic state predispose women to breast and ovarian cancer in the absence of a family history of cancer.

Related: Breast Cancer Canada Ovarian Cancer


Hirasawa A, Masuda K, Akahane T, et al.
Family history and BRCA1/BRCA2 status among Japanese ovarian cancer patients and occult cancer in a BRCA1 mutant case.
Jpn J Clin Oncol. 2014; 44(1):49-56 [PubMed] Related Publications
BACKGROUND: This study aimed to examine family history among Japanese ovarian cancer patients and to investigate the TP53 status of fallopian tube epithelial and ovarian cancer cells in a Japanese BRCA1 mutant case that may be associated with the transformed state in hereditary ovarian cancer.
METHODS: One hundred and two primary ovarian cancer patients were retrospectively evaluated in this cross-sectional study. The family history of cancer was determined in probands. In a BRCA1 mutant case, p53 immunostaining and direct sequencing, followed by laser-capture microdissection, were performed for the fallopian tube, considered the origin of ovarian cancer.
RESULTS: Nine of 102 (8.8%) families were regarded as having hereditary breast-ovarian cancer syndrome, two families (2.0%) were diagnosed with Lynch syndrome and six patients harbored BRCA1 or BRCA2 mutations. One case underwent risk-reductive salpingo-oophorectomy as a BRCA1 mutant carrier was retrospectively diagnosed as occult cancer. Common TP53 mutations were detected in cancer and fallopian tube epithelial cells in the case.
CONCLUSIONS: Here, we integrate family cancer history and histology in ovarian cancer cases as well as TP53 status in a BRCA1 mutant case into a discussion regarding carcinogenesis in a Japanese population. The TP53 status for the BRCA1 mutant case examined here supports the recently proposed theory that ovarian cancer develops because of BRCA1 or BRCA2 inactivation and/or TP53 mutations.

Related: Breast Cancer Cancer of Unknown Primary Ovarian Cancer TP53


Huszno J, Budryk M, Kołosza Z, Nowara E
The influence of BRCA1/BRCA2 mutations on toxicity related to chemotherapy and radiotherapy in early breast cancer patients.
Oncology. 2013; 85(5):278-82 [PubMed] Related Publications
OBJECTIVE: The presence of BRCA gene mutation and low expressions of BRCA proteins are associated with a greater sensitivity of tumor cells to ionizing radiation and to cytostatics damaging the DNA of the cells. The purpose of this study was to estimate the rate of adverse events in BRCA1/2-associated breast cancer patients receiving anthracycline-based chemotherapy compared to patients without mutation. The authors also compared radiotherapy toxicity in these 2 groups.
METHODS: The analysis included 270 early-stage breast cancer patients treated between 2006 and 2012. All patients were examined for the presence of BRCA1/2 mutations.
RESULTS: BRCA mutation was detected in 41 (15%) patients. Toxicity grade 3, especially nausea and vomiting, was observed more often in noncarriers (7 vs. 13%, p = 0.0008). Neutropenia was detected more frequently in patients with BRCA1/2 mutation (32 vs. 10%), but only after 1 cycle of chemotherapy (p = 0.0007). There was increased radiation toxicity in BRCA1/2 patients who underwent mastectomy and neoadjuvant chemotherapy (p = 0.016).
CONCLUSIONS: BRCA1/2 mutation carriers seemed to be more at risk of neutropenia after the first cycle of the treatment. In terms of other side effects, there was a lack of increased toxicity in this group. Mastectomy and neoadjuvant chemotherapy were risk factors for radiation toxicity in mutation carriers.

Related: Breast Cancer


Lord CJ, Ashworth A
Mechanisms of resistance to therapies targeting BRCA-mutant cancers.
Nat Med. 2013; 19(11):1381-8 [PubMed] Related Publications
Synthetic lethality provides a potential mechanistic framework for the therapeutic targeting of genetic and functional deficiencies in cancers and is now being explored widely. The first clinical exemplification of synthetic lethality in cancer has been the exploitation of inhibitors of poly-(ADP-ribose) polymerase (PARP) for the treatment of cancers with defects in the BRCA1 or BRCA2 tumor suppressor proteins, which are involved in the repair of DNA damage. Although this approach has shown promise, multiple potential resistance mechanisms have been identified. In this Perspective, we discuss these mechanisms and their relevance to the development of selective therapies for BRCA-deficient cancers.

Related: BRCA1 Cancer Prevention and Risk Reduction


Moorman PG, Havrilesky LJ, Gierisch JM, et al.
Oral contraceptives and risk of ovarian cancer and breast cancer among high-risk women: a systematic review and meta-analysis.
J Clin Oncol. 2013; 31(33):4188-98 [PubMed] Related Publications
PURPOSE: To estimate the risks of ovarian cancer and breast cancer associated with oral contraceptive (OC) use among women at elevated risk owing to mutations in BRCA1/2 or a strong family history.
METHODS: We searched PubMed, Embase, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov for studies published 2000 to 2012 that evaluated associations between OC use and breast or ovarian cancer among women who are carriers of a BRCA1/2 mutation or have a family history of breast or ovarian cancer.
RESULTS: From 6,476 unique citations, we identified six studies examining ovarian cancer risk in BRCA1/2 mutation carriers and eight studies examining breast cancer risk in BRCA1/2 mutation carriers. For BRCA1/2 mutation carriers combined, meta-analysis showed an inverse association between OC use and ovarian cancer (odds ratio [OR], 0.58; 95% CI, 0.46 to 0.73) and a nonstatistically significant association with breast cancer (OR, 1.21; 95% CI, 0.93 to 1.58). Findings were similar when examining BRCA1 and BRCA2 mutation carriers separately. Data were inadequate to perform meta-analyses examining duration or timing of use. For women with a family history of ovarian or breast cancer, we identified four studies examining risk for ovarian cancer and three for breast cancer, but differences between studies precluded combining the data for meta-analyses, and no overall pattern could be discerned.
CONCLUSION: Our analyses suggest that associations between ever use of OCs and ovarian and breast cancer among women who are BRCA1 or BRCA2 mutation carriers are similar to those reported for the general population.

Related: Breast Cancer Ovarian Cancer


Widschwendter M, Rosenthal AN, Philpott S, et al.
The sex hormone system in carriers of BRCA1/2 mutations: a case-control study.
Lancet Oncol. 2013; 14(12):1226-32 [PubMed] Related Publications
BACKGROUND: Penetrance for breast cancer, ovarian cancer, or both in carriers of BRCA1/BRCA2 mutations is disproportionately high. Sex hormone dysregulation and altered end-organ hormone sensitivity might explain this organ-specific penetrance. We sought to identify differences in hormone regulation between carriers of BRCA1/2 and women who are negative for BRCA1/2 mutations.
METHODS: We assessed endometrial thickness for each menstrual cycle day (as an index of hormone regulation) in 393 scans from 228 women in the UK Familial Ovarian Cancer Screening Study (UK FOCSS) known to carry either mutation and 1573 scans from 754 women known to be negative for the mutations. To quantify differences in endometrial thickness we focused on days 10-14 and days 21-26, and calculated the area under the curve. We then compared serum oestradiol and progesterone titres during these days of the menstrual cycle in the same groups. Follicular and luteal oestradiol and progesterone serum titres were grouped into quartiles and odds ratios were calculated with logistic regression.
FINDINGS: Follicular phase endometrial thickness of carriers of the mutations adjusted for age and day of the menstrual cycle was higher (odds ratio [OR] 1·11, 95% CI 1·03-1·20; p=0·0063) and luteal phase endometrial thickness lower (0·90, 0·83-0·98; p=0·027) than for women negative for the mutations. Median luteal phase titres of progesterone were 121% higher (p=0·00037) in carriers than in women negative for the mutations, and for oestradiol were 33% higher (p=0·007)-ie, 59% of carriers had concentrations of serum progesterone that would have been in the top quartile of concentrations in the control group (OR 8·0, 95% CI 2·1-52·57; p=0·008).
INTERPRETATION: Carriers of BRCA1/BRCA2 mutations are exposed to higher titres of oestradiol and progesterone-known risk-factors for breast cancer. Higher titres of oestradiol in carriers are compatible with this hormone having a role in ovarian carcinogenesis in such women. Our findings could not be explained by differential contraceptive pill use.

Related: Breast Cancer Ovarian Cancer


Antczak A, Kluźniak W, Wokołorczyk D, et al.
A common nonsense mutation of the BLM gene and prostate cancer risk and survival.
Gene. 2013; 532(2):173-6 [PubMed] Related Publications
BACKGROUND: Germline mutations of BRCA2 and NBS1 genes cause inherited recessive chromosomal instability syndromes and predispose to prostate cancer of poor prognosis. Mutations of the BLM gene cause another chromosomal instability clinical syndrome, called Bloom syndrome. Recently, a recurrent truncating mutation of BLM (Q548X) has been associated with a 6-fold increased risk of breast cancer in Russia, Belarus and Ukraine, but its role in prostate cancer etiology and survival has not been investigated yet.
METHODS: To establish whether the Q548X allele of the BLM gene is present in Poland, and whether this allele predisposes to poor prognosis prostate cancer, we genotyped 3337 men with prostate cancer and 2604 controls.
RESULTS: Q548X was detected in 13 of 3337 (0.4%) men with prostate cancer compared to 15 of 2604 (0.6%) controls (OR=0.7; 95% CI 0.3-1.4). A positive family history of any cancer in a first- or second-degree relative was seen only in 4 of the 13 (30%) mutation positive families, compared to 49% (1485/3001) of the non-carrier families (p=0.3). The mean follow-up was 49months. Survival was similar among carriers of Q548X and non-carriers (HR=1.1; p=0.9). The 5-year survival for men with a BLM mutation was 83%, compared to 72% for mutation-negative cases.
CONCLUSIONS: BLM Q548X is a common founder mutation in Poland. We found no evidence that this mutation predisposes one to prostate cancer or affect prostate cancer survival. However, based on the observed 0.6% population frequency of the Q548X allele, we estimate that one in 100,000 children should be affected by Bloom syndrome in Poland.

Related: Prostate Cancer


Johnson N, Johnson SF, Yao W, et al.
Stabilization of mutant BRCA1 protein confers PARP inhibitor and platinum resistance.
Proc Natl Acad Sci U S A. 2013; 110(42):17041-6 [PubMed] Article available free on PMC after 15/04/2014 Related Publications
Breast Cancer Type 1 Susceptibility Protein (BRCA1)-deficient cells have compromised DNA repair and are sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. Despite initial responses, the development of resistance limits clinical efficacy. Mutations in the BRCA C-terminal (BRCT) domain of BRCA1 frequently create protein products unable to fold that are subject to protease-mediated degradation. Here, we show HSP90-mediated stabilization of a BRCT domain mutant BRCA1 protein under PARP inhibitor selection pressure. The stabilized mutant BRCA1 protein interacted with PALB2-BRCA2-RAD51, was essential for RAD51 focus formation, and conferred PARP inhibitor as well as cisplatin resistance. Treatment of resistant cells with the HSP90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin reduced mutant BRCA1 protein levels and restored their sensitivity to PARP inhibition. Resistant cells also acquired a TP53BP1 mutation that facilitated DNA end resection in the absence of a BRCA1 protein capable of binding CtIP. Finally, concomitant increased mutant BRCA1 and decreased 53BP1 protein expression occur in clinical samples of BRCA1-mutated recurrent ovarian carcinomas that have developed resistance to platinum. These results provide evidence for a two-event mechanism by which BRCA1-mutant tumors acquire anticancer therapy resistance.

Related: Cisplatin Ovarian Cancer PALB2


Jeyasekharan AD, Liu Y, Hattori H, et al.
A cancer-associated BRCA2 mutation reveals masked nuclear export signals controlling localization.
Nat Struct Mol Biol. 2013; 20(10):1191-8 [PubMed] Article available free on PMC after 01/04/2014 Related Publications
Germline missense mutations affecting a single BRCA2 allele predispose humans to cancer. Here we identify a protein-targeting mechanism that is disrupted by the cancer-associated mutation, BRCA2(D2723H), and that controls the nuclear localization of BRCA2 and its cargo, the recombination enzyme RAD51. A nuclear export signal (NES) in BRCA2 is masked by its interaction with a partner protein, DSS1, such that point mutations impairing BRCA2-DSS1 binding render BRCA2 cytoplasmic. In turn, cytoplasmic mislocalization of mutant BRCA2 inhibits the nuclear retention of RAD51 by exposing a similar NES in RAD51 that is usually obscured by the BRCA2-RAD51 interaction. Thus, a series of NES-masking interactions localizes BRCA2 and RAD51 in the nucleus. Notably, BRCA2(D2723H) decreases RAD51 nuclear retention even when wild-type BRCA2 is also present. Our findings suggest a mechanism for the regulation of the nucleocytoplasmic distribution of BRCA2 and RAD51 and its impairment by a heterozygous disease-associated mutation.


Latest Publications: BRCA2 (cancer-related)

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] Free Access to Full Article 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


Rustgi AK
Familial pancreatic cancer: genetic advances.
Genes Dev. 2014; 28(1):1-7 [PubMed] Article available free on PMC after 01/07/2014 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


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


Hirasawa A, Masuda K, Akahane T, et al.
Family history and BRCA1/BRCA2 status among Japanese ovarian cancer patients and occult cancer in a BRCA1 mutant case.
Jpn J Clin Oncol. 2014; 44(1):49-56 [PubMed] Related Publications
BACKGROUND: This study aimed to examine family history among Japanese ovarian cancer patients and to investigate the TP53 status of fallopian tube epithelial and ovarian cancer cells in a Japanese BRCA1 mutant case that may be associated with the transformed state in hereditary ovarian cancer.
METHODS: One hundred and two primary ovarian cancer patients were retrospectively evaluated in this cross-sectional study. The family history of cancer was determined in probands. In a BRCA1 mutant case, p53 immunostaining and direct sequencing, followed by laser-capture microdissection, were performed for the fallopian tube, considered the origin of ovarian cancer.
RESULTS: Nine of 102 (8.8%) families were regarded as having hereditary breast-ovarian cancer syndrome, two families (2.0%) were diagnosed with Lynch syndrome and six patients harbored BRCA1 or BRCA2 mutations. One case underwent risk-reductive salpingo-oophorectomy as a BRCA1 mutant carrier was retrospectively diagnosed as occult cancer. Common TP53 mutations were detected in cancer and fallopian tube epithelial cells in the case.
CONCLUSIONS: Here, we integrate family cancer history and histology in ovarian cancer cases as well as TP53 status in a BRCA1 mutant case into a discussion regarding carcinogenesis in a Japanese population. The TP53 status for the BRCA1 mutant case examined here supports the recently proposed theory that ovarian cancer develops because of BRCA1 or BRCA2 inactivation and/or TP53 mutations.

Related: Breast Cancer Cancer of Unknown Primary Ovarian Cancer TP53


Huszno J, Budryk M, Kołosza Z, Nowara E
The influence of BRCA1/BRCA2 mutations on toxicity related to chemotherapy and radiotherapy in early breast cancer patients.
Oncology. 2013; 85(5):278-82 [PubMed] Related Publications
OBJECTIVE: The presence of BRCA gene mutation and low expressions of BRCA proteins are associated with a greater sensitivity of tumor cells to ionizing radiation and to cytostatics damaging the DNA of the cells. The purpose of this study was to estimate the rate of adverse events in BRCA1/2-associated breast cancer patients receiving anthracycline-based chemotherapy compared to patients without mutation. The authors also compared radiotherapy toxicity in these 2 groups.
METHODS: The analysis included 270 early-stage breast cancer patients treated between 2006 and 2012. All patients were examined for the presence of BRCA1/2 mutations.
RESULTS: BRCA mutation was detected in 41 (15%) patients. Toxicity grade 3, especially nausea and vomiting, was observed more often in noncarriers (7 vs. 13%, p = 0.0008). Neutropenia was detected more frequently in patients with BRCA1/2 mutation (32 vs. 10%), but only after 1 cycle of chemotherapy (p = 0.0007). There was increased radiation toxicity in BRCA1/2 patients who underwent mastectomy and neoadjuvant chemotherapy (p = 0.016).
CONCLUSIONS: BRCA1/2 mutation carriers seemed to be more at risk of neutropenia after the first cycle of the treatment. In terms of other side effects, there was a lack of increased toxicity in this group. Mastectomy and neoadjuvant chemotherapy were risk factors for radiation toxicity in mutation carriers.

Related: Breast Cancer


Lord CJ, Ashworth A
Mechanisms of resistance to therapies targeting BRCA-mutant cancers.
Nat Med. 2013; 19(11):1381-8 [PubMed] Related Publications
Synthetic lethality provides a potential mechanistic framework for the therapeutic targeting of genetic and functional deficiencies in cancers and is now being explored widely. The first clinical exemplification of synthetic lethality in cancer has been the exploitation of inhibitors of poly-(ADP-ribose) polymerase (PARP) for the treatment of cancers with defects in the BRCA1 or BRCA2 tumor suppressor proteins, which are involved in the repair of DNA damage. Although this approach has shown promise, multiple potential resistance mechanisms have been identified. In this Perspective, we discuss these mechanisms and their relevance to the development of selective therapies for BRCA-deficient cancers.

Related: BRCA1 Cancer Prevention and Risk Reduction


Khadim MF, Eastwood P, Price J, et al.
Multidisciplinary one-stage risk-reducing gynaecological and breast surgery with immediate reconstruction in BRCA-gene carrier women.
Eur J Surg Oncol. 2013; 39(12):1346-50 [PubMed] Related Publications
Familial breast cancer accounts for 5-10% of all breast cancers. Due to BRCA1/2 tumour suppressor gene mutation, hereditary breast and ovarian syndrome is the most common form. Risk-reducing gynaecological and breast surgery is offered to such patients in ever-increasing numbers. Hence, the development of a multi-specialty combined treatment approach is called for. Twenty-two BRCA gene-mutation carrier women underwent one-stage gynaecological and breast risk-reducing surgery and immediate reconstruction between January 2005 and December 2011 at the Belfast City Hospital. Their mean age was 41.2 years (median 41 years). Nearly half of the patients were BRCA2 and a quarter were BRCA1 carriers. The rest were positive for both genes. Hormone-replacement therapy was initiated in 14 women. Average theatre time and stay in the hospital were three hours and two and a half days, respectively. Two patients developed complications unrelated to combining the procedures. Both were treated conservatively and recovered. The one-stage approach logically proves economical by limiting the time the patients are in the hospital and away from work. We describe our multidisciplinary team service that is offering safe and economical one-stage risk-reducing surgery and reconstruction to young BRCA gene-mutation carrier women in Northern Ireland.

Related: Breast Cancer BRCA1 Ovarian Cancer


Tanic M, Andrés E, Rodriguez-Pinilla SM, et al.
MicroRNA-based molecular classification of non-BRCA1/2 hereditary breast tumours.
Br J Cancer. 2013; 109(10):2724-34 [PubMed] Article available free on PMC after 12/11/2014 Related Publications
BACKGROUND: Hereditary breast cancer comprises 5-10% of all breast cancers. Mutations in two high-risk susceptibility genes, BRCA1 and BRCA2, along with rare intermediate-risk genes and common low-penetrance alleles identified, altogether explain no more than 45% of the high-risk breast cancer families, although the majority of cases are unaccounted for and are designated as BRCAX tumours. Micro RNAs have called great attention for classification of different cancer types and have been implicated in a range of important biological processes and are deregulated in cancer pathogenesis.
METHODS: Here we have performed an exploratory hypothesis-generating study of miRNA expression profiles in a large series of 66 primary hereditary breast tumours by microarray analysis.
RESULTS: Unsupervised clustering analysis of miRNA molecular profiles revealed distinct subgroups of BRCAX tumours, 'normal-like' BRCAX-A, 'proliferative' BRCAX-B, 'BRCA1/2-like' BRCAX-C and 'undefined' BRCAX-D subgroup. These findings introduce a new insight in the biology of hereditary breast cancer, defining specific BRCAX subgroups, which could help in the search for novel susceptibility pathways in hereditary breast cancer.
CONCLUSION: Our data demonstrate that BRCAX hereditary breast tumours can be sub-classified into four previously unknown homogenous groups characterised by specific miRNA expression signatures and histopathological features.

Related: Breast Cancer BRCA1


Antczak A, Kluźniak W, Wokołorczyk D, et al.
A common nonsense mutation of the BLM gene and prostate cancer risk and survival.
Gene. 2013; 532(2):173-6 [PubMed] Related Publications
BACKGROUND: Germline mutations of BRCA2 and NBS1 genes cause inherited recessive chromosomal instability syndromes and predispose to prostate cancer of poor prognosis. Mutations of the BLM gene cause another chromosomal instability clinical syndrome, called Bloom syndrome. Recently, a recurrent truncating mutation of BLM (Q548X) has been associated with a 6-fold increased risk of breast cancer in Russia, Belarus and Ukraine, but its role in prostate cancer etiology and survival has not been investigated yet.
METHODS: To establish whether the Q548X allele of the BLM gene is present in Poland, and whether this allele predisposes to poor prognosis prostate cancer, we genotyped 3337 men with prostate cancer and 2604 controls.
RESULTS: Q548X was detected in 13 of 3337 (0.4%) men with prostate cancer compared to 15 of 2604 (0.6%) controls (OR=0.7; 95% CI 0.3-1.4). A positive family history of any cancer in a first- or second-degree relative was seen only in 4 of the 13 (30%) mutation positive families, compared to 49% (1485/3001) of the non-carrier families (p=0.3). The mean follow-up was 49months. Survival was similar among carriers of Q548X and non-carriers (HR=1.1; p=0.9). The 5-year survival for men with a BLM mutation was 83%, compared to 72% for mutation-negative cases.
CONCLUSIONS: BLM Q548X is a common founder mutation in Poland. We found no evidence that this mutation predisposes one to prostate cancer or affect prostate cancer survival. However, based on the observed 0.6% population frequency of the Q548X allele, we estimate that one in 100,000 children should be affected by Bloom syndrome in Poland.

Related: Prostate Cancer


Rosenberg SM, Tracy MS, Meyer ME, et al.
Perceptions, knowledge, and satisfaction with contralateral prophylactic mastectomy among young women with breast cancer: a cross-sectional survey.
Ann Intern Med. 2013; 159(6):373-81 [PubMed] Related Publications
UNLABELLED: Chinese translation
BACKGROUND: Rates of contralateral prophylactic mastectomy (CPM) have increased dramatically, particularly among younger women with breast cancer, but little is known about how women approach the decision to have CPM.
OBJECTIVE: To examine preferences, knowledge, decision making, and experiences of young women with breast cancer who choose CPM.
DESIGN: Cross-sectional survey.
SETTING: 8 academic and community medical centers that enrolled 550 women diagnosed with breast cancer at age 40 years or younger between November 2006 and November 2010.
PATIENTS: 123 women without known bilateral breast cancer who reported having bilateral mastectomy.
MEASUREMENTS: A 1-time, 23-item survey that included items related to decision making, knowledge, risk perception, and breast cancer worry.
RESULTS: Most women indicated that desires to decrease their risk for contralateral breast cancer (98%) and improve survival (94%) were extremely or very important factors in their decision to have CPM. However, only 18% indicated that women with breast cancer who undergo CPM live longer than those who do not. BRCA1 or BRCA2 mutation carriers more accurately perceived their risk for contralateral breast cancer, whereas women without a known mutation substantially overestimated this risk.
LIMITATIONS: The survey, which was administered a median of 2 years after surgery, was not validated, and some questions might have been misinterpreted by respondents or subject to recall bias. Generalizability of the findings might be limited.
CONCLUSION: Despite knowing that CPM does not clearly improve survival, women who have the procedure do so, in part, to extend their lives. Many women overestimate their actual risk for cancer in the unaffected breast. Interventions aimed at improving risk communication in an effort to promote evidence-based decision making are warranted.
PRIMARY FUNDING SOURCE: Susan G. Komen for the Cure.

Related: Breast Cancer BRCA1


Lizarraga IM, Sugg SL, Weigel RJ, Scott-Conner CE
Review of risk factors for the development of contralateral breast cancer.
Am J Surg. 2013; 206(5):704-8 [PubMed] Related Publications
BACKGROUND: Women treated for breast cancer have an increased risk for developing metachronous contralateral breast cancer (CBC). Patient perception of this risk is often overestimated and has been found to contribute to the decision to undergo contralateral prophylactic mastectomy. An individual's risk is dependent on both patient and tumor characteristics. This review examines and summarizes the current literature on the factors that affect CBC risk.
DATA SOURCES: English-language publications with the keyword "contralateral breast cancer" were identified through a MEDLINE literature search.
CONCLUSIONS: The global incidence of CBC is decreasing, a trend that is attributed to more effective adjuvant therapies. Patients with BRCA germ-line mutations demonstrate the highest risk for CBC. In the absence of known genetic mutations, patients with strong family histories who are diagnosed at young ages (<35 years) with estrogen receptor-negative index tumors appear to have a higher incidence of CBC.

Related: Breast Cancer BRCA1


Keogh LA, Otlowski MF
Life insurance and genetic test results: a mutation carrier's fight to achieve full cover.
Med J Aust. 2013; 199(5):363-6 [PubMed] Related Publications
Currently, there is debate about life insurance companies' use of genetic information for assessing applicants. In his early 20s, James (pseudonym) was denied full life insurance cover because he revealed that he had discussed genetic testing with a genetic counsellor. He was later tested and found to carry a mutation in the MSH6 gene; after disclosing this, he was denied cover for cancer by two other life insurance companies. Unsatisfied with the insurance companies' risk assessments, and based on his understanding that regular colonoscopy significantly reduced his risk of cancer, James made a complaint to the Australian Human Rights Commission. After informing the third insurance company that he had done so, he was offered full coverage, which suggests that the company did not have actuarial data to justify its decision. This case provides evidence of the high level of initiative and proactivity required for a consumer to achieve a fair result. Few Australians would be in a position to pursue the level of research and advocacy undertaken by James (a professional with scientific training). We call on a collaborative approach between industry, government and researchers to address the issues that James's case raises about genetic testing and life insurance.

Related: Australia


Stan DL, Shuster LT, Wick MJ, et al.
Challenging and complex decisions in the management of the BRCA mutation carrier.
J Womens Health (Larchmt). 2013; 22(10):825-34 [PubMed] Related Publications
Women afflicted by the hereditary breast and ovarian cancer syndrome face complex decisions regarding medical interventions aimed at reducing their risk of ovarian and breast cancer, interventions which in turn may interfere with their fertility and cause early menopause. This review addresses selected topics of importance and controversy in the management of the BRCA mutation carrier, such as psychological well-being and quality of life, breast and ovarian cancer screening, risk-reducing interventions for breast cancer and ovarian cancer, the issue of hysterectomy at the time of the risk-reducing salpingo-oophorectomy, health consequences of early surgical menopause, and safety of hormonal therapy after oophorectomy. The information presented is based on an extensive review of the literature on the selected topics and on the expertise of our multidisciplinary team.

Related: BRCA1


Valentini A, Finch A, Lubinski J, et al.
Chemotherapy-induced amenorrhea in patients with breast cancer with a BRCA1 or BRCA2 mutation.
J Clin Oncol. 2013; 31(31):3914-9 [PubMed] Article available free on PMC after 01/11/2014 Related Publications
PURPOSE: To determine the likelihood of long-term amenorrhea after treatment with chemotherapy in women with breast cancer who carry a BRCA1 or BRCA2 mutation.
PATIENTS AND METHODS: We conducted a multicenter survey of 1,954 young women with a BRCA1 or BRCA2 mutation who were treated for breast cancer. We included premenopausal women who were diagnosed with invasive breast cancer between 26 and 47 years of age. We determined the age of onset of amenorrhea after breast cancer for women who were and were not treated with chemotherapy, alone or with tamoxifen. We considered chemotherapy-induced amenorrhea to have occurred when the patient experienced ≥ 2 years of amenorrhea, commencing within 2 years of initiating chemotherapy, with no resumption of menses.
RESULTS: Of the 1,426 women who received chemotherapy, 35% experienced long-term amenorrhea. Of the 528 women who did not receive chemotherapy, 5.3% developed long-term amenorrhea. The probabilities of chemotherapy-induced amenorrhea were 7.2% for women diagnosed before age 30 years, 33% for women age 31 to 44 years, and 79% for women diagnosed after age 45 years (P trend < .001). The probability of induced amenorrhea was higher for women who received tamoxifen than for those who did not (52% v 29%; P < .001).
CONCLUSION: Age at treatment and use of tamoxifen are important predictors of chemotherapy-induced amenorrhea in women who carry a BRCA1 or BRCA2 mutation. The risk of induced long-term amenorrhea does not seem to be greater among mutation carriers than among women who do not carry a mutation.

Related: Breast Cancer BRCA1


Burcoş T, Cimponeriu D, Ion DA, et al.
Analysis of several BRCA1 and BRCA2 mutations in a hospital-based series of unselected breast cancer cases.
Chirurgia (Bucur). 2013 Jul-Aug; 108(4):468-72 [PubMed] Related Publications
BACKGROUND: The distribution of BRCA mutations varies significantly between populations. The spectrum of BRCA1 and BRCA2 mutations in breast cancers in the Romanian population is incompletely known. The aim of the present study is to investigate the presence of nine BRCA mutations in patients with breast cancer identified in a surgical clinic from Bucharest.
METHODS: Unrelated women diagnosed with breast cancer from Coltea Hospital (n=114) and healthy controls (n = 150) were selected for this study. Seven mutations in BRCA1 (185delAG, 5382insC, 943ins10, E1250X, 1294del40, E1373X, R1443X) and two in BRCA2 (IVS16-2A4G and 6174delT) were tested using PCR based protocols. In addition, the presence of BRCA1 185delAG, BRCA1 5382insC, BRCA2 6174delT mutations were tested with a post amplification mutation detection system, based on the ELISA method.
RESULTS: Two patients with sporadic breast cancer (2%) and one patient with family history of the disease (7.14%) have the BRCA1 5382insC mutation. No other mutation was detected in patient and control groups. The mutations were not present in the control lot.
CONCLUSIONS: Our results indicate that BRCA1 5382insC is a common mutation in Romanian women with breast cancer (3 114).

Related: Breast Cancer BRCA1


MacInnis RJ, Bickerstaffe A, Apicella C, et al.
Prospective validation of the breast cancer risk prediction model BOADICEA and a batch-mode version BOADICEACentre.
Br J Cancer. 2013; 109(5):1296-301 [PubMed] Article available free on PMC after 03/09/2014 Related Publications
BACKGROUND: Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) is a risk prediction algorithm that can be used to compute estimates of age-specific risk of breast cancer. It is uncertain whether BOADICEA performs adequately for populations outside the United Kingdom.
METHODS: Using a batch mode version of BOADICEA that we developed (BOADICEACentre), we calculated the cumulative 10-year invasive breast cancer risk for 4176 Australian women of European ancestry unaffected at baseline from 1601 case and control families in the Australian Breast Cancer Family Registry. Based on 115 incident breast cancers, we investigated calibration, discrimination (using receiver-operating characteristic (ROC) curves) and accuracy at the individual level.
RESULTS: The ratio of expected to observed number of breast cancers was 0.92 (95% confidence interval (CI) 0.76-1.10). The E/O ratios by subgroups of the participant's relationship to the index case and by the reported number of affected relatives ranged between 0.83 and 0.98 and all 95% CIs included 1.00. The area under the ROC curve was 0.70 (95% CI 0.66-0.75) and there was no evidence of systematic under- or over-dispersion (P=0.2).
CONCLUSION: BOADICEA is well calibrated for Australian women, and had good discrimination and accuracy at the individual level.

Related: Australia Breast Cancer BRCA1


Haanpää M, Pylkäs K, Moilanen JS, Winqvist R
Evaluation of the need for routine clinical testing of PALB2 c.1592delT mutation in BRCA negative Northern Finnish breast cancer families.
BMC Med Genet. 2013; 14:82 [PubMed] Article available free on PMC after 03/09/2014 Related Publications
BACKGROUND: Testing for mutations in the BRCA1 and BRCA2 genes among high-risk breast cancer patients has become a routine practice among clinical geneticists. Unfortunately, however, the genetic background of a majority of the cases coming to the clinics remains currently unexplained, making genetic counseling rather challenging. In recent years it has become evident world-wide that also women carrying a heterozygous germline mutation in PALB2 are at significantly increased risk of getting breast cancer. We have previously studied the clinical as well as biological impact of the PALB2 c.1592delT founder mutation occurring in about 1% of Finnish breast cancer patients unselected for their family history of disease, and our results demonstrated a 40% increased breast cancer risk by age 70 for female mutation carriers. Thus, this relatively common mutation in PALB2 is associated with a high risk of developing breast cancer. The aim of the current study was to analyze whether female index individuals of breast cancer families who had tested negative for germline mutations in BRCA1/BRCA2 as part of genetic counseling services should be offered mutation testing for PALB2 c.1592delT.
METHODS: The study cohort consisted of altogether 223 individuals who had contacted the Department of Clinical Genetics at the Oulu University Hospital in Finland between the years 1997 and 2011 for counseling on hereditary breast and/or ovarian cancer risk. 101 of them met our inclusion criteria. Of these, 10 persons were now deceased, but 6 of them had participated in one of our previous studies on PALB2. Seventy (77%) of the remaining 91 persons responded positively to our study invitation. Chart review of updated pedigree data led to the exclusion of 14 further individuals not meeting the selection criteria.
RESULT: Of the 56 alive affected female individuals screened for PALB2 c.1592delT, altogether two (3.6%) tested positive for this mutation. In addition, of the previously tested but now deceased 6 persons eligible for the current study, one more mutation carrier was observed. Therefore, overall 4.8% (3/62) of the tested individuals belonging to the Northern Finnish 1997-2011 study cohort turned out to be carriers of the PALB2 c.1592delT allele.
CONCLUSIONS: Given the potential benefits versus harms of this testing, the result of our study suggest that PALB2 c.1592delT should be a routine part of the genetic counseling protocol for Finnish high-risk breast cancer cases tested negative for mutations in BRCA1/BRCA2.

Related: Breast Cancer PALB2


Saadatmand S, Tilanus-Linthorst MM, Rutgers EJ, et al.
Cost-effectiveness of screening women with familial risk for breast cancer with magnetic resonance imaging.
J Natl Cancer Inst. 2013; 105(17):1314-21 [PubMed] Related Publications
BACKGROUND: To reduce mortality, women with a family history of breast cancer are often screened with mammography before age 50 years. Additional magnetic resonance imaging (MRI) improves sensitivity and is cost-effective for BRCA1/2 mutation carriers. However, for women with a family history without a proven mutation, cost-effectiveness is unclear.
METHODS: We evaluated data of the largest prospective MRI screening study (MRISC). Between 1999 and 2007, 1597 women (8370 woman-years at risk) aged 25 to 70 years with an estimated cumulative lifetime risk of 15% to 50% for breast cancer were screened with clinical breast examination every 6 months and with annual mammography and MRI. We calculated the cost per detected and treated breast cancer. After incorporating MRISC data into a microsimulation screening analysis model (MISCAN), different schemes were evaluated, and cost per life-year gained (LYG) was estimated in comparison with the Dutch nationwide breast cancer screening program (biennial mammography from age 50 to 75 years). All statistical tests were two-sided.
RESULTS: Forty-seven breast cancers (9 ductal carcinoma in situ) were detected. Screening with additional MRI costs $123 672 (€93 639) per detected breast cancer. In increasing age-cohorts, costs per detected and treated breast cancer decreased, but, unexpectedly, the percentage of MRI-only detected cancers increased. Screening under the MRISC-scheme from age 35 to 50 years was estimated to reduce breast cancer mortality by 25% at $134 932 (€102 164) per LYG (3.5% discounting) compared with 17% mortality reduction at $54 665 (€41 390) per LYG with mammography only.
CONCLUSIONS: Screening with MRI may improve survival for women with familial risk for breast cancer but is expensive, especially in the youngest age categories.

Related: Breast Cancer Breast Cancer Screening Cancer Screening and Early Detection BRCA1


Blanco A, de la Hoya M, Osorio A, et al.
Analysis of PALB2 gene in BRCA1/BRCA2 negative Spanish hereditary breast/ovarian cancer families with pancreatic cancer cases.
PLoS One. 2013; 8(7):e67538 [PubMed] Article available free on PMC after 03/09/2014 Related Publications
BACKGROUND: The PALB2 gene, also known as FANCN, forms a bond and co-localizes with BRCA2 in DNA repair. Germline mutations in PALB2 have been identified in approximately 1% of familial breast cancer and 3-4% of familial pancreatic cancer. The goal of this study was to determine the prevalence of PALB2 mutations in a population of BRCA1/BRCA2 negative breast cancer patients selected from either a personal or family history of pancreatic cancer.
METHODS: 132 non-BRCA1/BRCA2 breast/ovarian cancer families with at least one pancreatic cancer case were included in the study. PALB2 mutational analysis was performed by direct sequencing of all coding exons and intron/exon boundaries, as well as multiplex ligation-dependent probe amplification.
RESULTS: Two PALB2 truncating mutations, the c.1653T>A (p.Tyr551Stop) previously reported, and c.3362del (p.Gly1121ValfsX3) which is a novel frameshift mutation, were identified. Moreover, several PALB2 variants were detected; some of them were predicted as pathological by bioinformatic analysis. Considering truncating mutations, the prevalence rate of our population of BRCA1/2-negative breast cancer patients with pancreatic cancer is 1.5%.
CONCLUSIONS: The prevalence rate of PALB2 mutations in non-BRCA1/BRCA2 breast/ovarian cancer families, selected from either a personal or family pancreatic cancer history, is similar to that previously described for unselected breast/ovarian cancer families. Future research directed towards identifying other gene(s) involved in the development of breast/pancreatic cancer families is required.

Related: Breast Cancer Ovarian Cancer Cancer of the Pancreas Pancreatic Cancer PALB2


Infante M, Durán M, Acedo A, et al.
The highly prevalent BRCA2 mutation c.2808_2811del (3036delACAA) is located in a mutational hotspot and has multiple origins.
Carcinogenesis. 2013; 34(11):2505-11 [PubMed] Related Publications
BRCA2-c.2808_2811del (3036delACAA) is one of the most reported germ line mutations in non-Ashkenazi breast cancer patients. We investigated its genetic origin in 51 Spanish carrier families that were genotyped with 11 13q polymorphic markers. Three independent associated haplotypes were clearly distinguished accounting for 23 [west Castilla y León (WCL)], 20 [east Castilla y León (ECL)] and 6 (South of Spain) families. Mutation age was estimated with the Disequilibrium Mapping using Likelihood Estimation software in a range of 45-68 and 45-71 generations for WCL and ECL haplotypes, respectively. The most prevalent variants, c.2808_2811del and c.2803G > A, were located in a double-hairpin loop structure (c.2794-c.2825) predicted by Quikfold that was proposed as a mutational hotspot. To check this hypothesis, random mutagenesis was performed over a 923 bp fragment of BRCA2, and 86 DNA variants were characterized. Interestingly, three mutations reported in the mutation databases (c.2680G > A, c.2944del and c.2957dup) were replicated and 20 affected the same position with different nucleotide changes. Moreover, five variants were placed in the same hairpin loop of c.2808_2811del, and one affected the same position (c.2808A > G). In conclusion, our results support that at least three different mutational events occurred to generate c.2808_2811del. Other highly prevalent DNA variants, such as BRCA1-c.68_69delAG, BRCA2-c.5946delT and c.8537delAG, are concentrated in hairpin loops, suggesting that these structures may represent mutational hotspots.

Related: Breast Cancer Polymorphisms


Phillips KA, Milne RL, Rookus MA, et al.
Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
J Clin Oncol. 2013; 31(25):3091-9 [PubMed] Article available free on PMC after 01/09/2014 Related Publications
PURPOSE: To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers.
METHODS: Analysis of pooled observational cohort data, self-reported at enrollment and at follow-up from the International BRCA1, and BRCA2 Carrier Cohort Study, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, and Breast Cancer Family Registry. Eligible women were BRCA1 and BRCA2 mutation carriers diagnosed with unilateral BC since 1970 and no other invasive cancer or tamoxifen use before first BC. Hazard ratios (HRs) for CBC associated with tamoxifen use were estimated using Cox regression, adjusting for year and age of diagnosis, country, and bilateral oophorectomy and censoring at contralateral mastectomy, death, or loss to follow-up.
RESULTS: Of 1,583 BRCA1 and 881 BRCA2 mutation carriers, 383 (24%) and 454 (52%), respectively, took tamoxifen after first BC diagnosis. There were 520 CBCs over 20,104 person-years of observation. The adjusted HR estimates were 0.38 (95% CI, 0.27 to 0.55) and 0.33 (95% CI, 0.22 to 0.50) for BRCA1 and BRCA2 mutation carriers, respectively. After left truncating at recruitment to the cohort, adjusted HR estimates were 0.58 (95% CI, 0.29 to 1.13) and 0.48 (95% CI, 0.22 to 1.05) based on 657 BRCA1 and 426 BRCA2 mutation carriers with 100 CBCs over 4,392 person-years of prospective follow-up. HRs did not differ by estrogen receptor status of the first BC (missing for 56% of cases).
CONCLUSION: This study provides evidence that tamoxifen use is associated with a reduction in CBC risk for BRCA1 and BRCA2 mutation carriers. Further follow-up of these cohorts will provide increased statistical power for future prospective analyses.

Related: Breast Cancer BRCA1


Bonache S, Gutierrez-Enriquez S, Tenés A, et al.
Mutation analysis of the BCCIP gene for breast cancer susceptibility in breast/ovarian cancer families.
Gynecol Oncol. 2013; 131(2):460-3 [PubMed] Related Publications
OBJECTIVE: About 5%-10% of breast cancer is due to inherited disease predisposition. Currently, mutations in the BRCA1 and BRCA2 genes explain less than 25% of the familial clustering of breast cancer, and additional susceptibility genes are suspected. The BCCIP gene plays an important role in the regulation of gene transcription and cell proliferation and could be involved in the maintenance of genomic integrity. The BCCIP protein binds in mammalian cells to the longest conserved region of the BRCA2 protein and is required for BRCA2 stability and function, making a critical contribution to the function of BRCA2 in mediating homologous recombination. Variants in the BCCIP gene could affect the BRCA2 functionality and be associated to the familial breast/ovarian carcinogenesis. Therefore, BCCIP gene is a potential candidate for being involved in heritable cancer susceptibility.
METHODS: We have screened the entire coding region and splice junctions of BCCIP in affected index cases from 215 Spanish breast/ovarian cancer families for germ line defects, using direct sequencing.
RESULTS: Mutation analysis revealed 3 different intronic sequence changes.
CONCLUSIONS: Based on the in silico and in vitro RNA analyses of these sequence alterations, none of them were predicted to be pathogenic or associated with cancer susceptibility. Our results indicate that BCCIP germ line mutations are unlikely to be a major contributor to familial breast/ovarian cancer risk in our population.

Related: Breast Cancer Male Breast Cancer Ovarian Cancer


Yi EJ, Park JH, Lee HW, et al.
BRCA1 gene mutation in thymic malignant melanoma.
Ann Thorac Surg. 2013; 96(2):677-80 [PubMed] Related Publications
We present a patient with triple primary malignancies: thyroid cancer, ovarian cancer, and thymic malignant melanoma. We suspected that gene mutations were involved in the occurrence of these multiple primary cancers, and blood analysis revealed the presence of BRCA1 gene mutations.

Related: Melanoma


Mahdi KM, Nassiri MR, Nasiri K
Hereditary genes and SNPs associated with breast cancer.
Asian Pac J Cancer Prev. 2013; 14(6):3403-9 [PubMed] Related Publications
Breast cancer is the most common cancer among women affecting up to one third of tehm during their lifespans. Increased expression of some genes due to polymorphisms increases the risk of breast cancer incidence. Since mutations that are recognized to increase breast cancer risk within families are quite rare, identification of these SNPs is very important. The most important loci which include mutations are; BRCA1, BRCA2, PTEN, ATM, TP53, CHEK2, PPM1D, CDH1, MLH1, MRE11, MSH2, MSH6, MUTYH, NBN, PMS1, PMS2, BRIP1, RAD50, RAD51C, STK11 and BARD1. Presence of SNPs in these genes increases the risk of breast cancer and associated diagnostic markers are among the most reliable for assessing prognosis of breast cancer. In this article we reviewed the hereditary genes of breast cancer and SNPs associated with increasing the risk of breast cancer that were recently were reported from candidate gene, meta-analysis and GWAS studies. SNPs of genes associated with breast cancer can be used as a potential tool for improving cancer diagnosis and treatment planning.

Related: Breast Cancer


Schoeman M, Apffelstaedt JP, Baatjes K, Urban M
Implementation of a breast cancer genetic service in South Africa - lessons learned.
S Afr Med J. 2013; 103(8):529-33 [PubMed] Related Publications
BACKGROUND: Genetic testing for BRCA mutations has been available in the Western Cape of South Africa since 2005, but practical implementation of genetic counselling and testing has been challenging.
OBJECTIVE: To describe an approach to breast cancer genetic counselling and testing developed in a resource-constrained environment at Tygerberg Hospital in Cape Town, Western Cape.
METHODS: Genetic counselling is offered in a stepwise manner to our diverse patient population, with a focus on affected probands, and subsequent cascade testing. A record review of BRCA testing between 2005 and 2011 was performed. RESULTS; During this period 302 probands received genetic testing, with increasing numbers tested over time. Of 1 520 women treated for breast cancer since 2008, 226 (14.9%) accepted BRCA testing, and 39 tested positive (17.3% of those tested, and 2.6% of all women). Common founder mutations were detected in 11.9% of women (36/302), and comprised 73% (36/49) of mutations detected. Cascade testing increased after 2010: 16 female and 4 male family members of 19 probands accepted testing, with 6 positives being detected.
CONCLUSION: A protocol-driven approach focusing on probands, with initial pre-test counselling by primary care staff has proven effective in establishing the service. Involvement of a clinical geneticist/genetic counsellor has permitted more detailed post-test counselling and increased use of cascade testing.

Related: Breast Cancer BRCA1


Moon DH, Lee JM, Noonan AM, et al.
Deleterious BRCA1/2 mutation is an independent risk factor for carboplatin hypersensitivity reactions.
Br J Cancer. 2013; 109(4):1072-8 [PubMed] Article available free on PMC after 20/08/2014 Related Publications
BACKGROUND: We tested the hypothesis that BRCA1/2 mutation carriers with ovarian cancer are at higher risk of carboplatin hypersensitivity reactions (HSRs).
METHODS: Medical records of women enrolled in two carboplatin+olaparib clinical trials (NCT01237067/NCT01445418) were reviewed. A maximum of eight cycles containing carboplatin were administered.
RESULTS: All women (N=87) had good performance status and end-organ function. Incidences of carboplatin HSR before enrolment and on study were 17% and 21%, respectively. Most patients who developed carboplatin HSR had a deleterious BRCA1/2 mutation (93%) vs 50% in patients without HSR (P<0.0001). Multivariable analysis accounting for potential confounding variables including age, history of allergies, and cumulative prior carboplatin cycles confirmed deleterious BRCA1/2 mutation as an independent risk factor for carboplatin HSR (odds ratio 13.1 (95% confidence interval 2.6-65.4), P=0.0017). Mutation carriers had onset of carboplatin HSR at lower cumulative exposure (P=0.003). No significant difference in outcome was observed on our study between patients with and without a history of HSR.
CONCLUSION: Deleterious BRCA1/2 mutation increased susceptibility and shortened time to carboplatin HSR, independently of other reported factors. These data suggest that at-risk women should be counselled regarding likelihood, symptoms, and potential earlier onset of carboplatin HSRs.

Related: Carboplatin BRCA1 Ovarian Cancer


Brennan GT, Relias V, Saif MW
BRCA and pancreatic cancer.
JOP. 2013; 14(4):325-8 [PubMed] Related Publications
Germline mutations in BRCA genes have been associated with pancreatic cancer. Laboratory and clinical data suggest that patients with BRCA mutations may be more responsive to therapy consisting of conventional chemotherapy with a poly(ADP-ribose) polymerase inhibitor (PARPi). The most recent data from the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting will be reviewed (Abstracts #11024 and #TPS4144).

Related: Cancer of the Pancreas Pancreatic Cancer PALB2


Pataky R, Armstrong L, Chia S, et al.
Cost-effectiveness of MRI for breast cancer screening in BRCA1/2 mutation carriers.
BMC Cancer. 2013; 13:339 [PubMed] Article available free on PMC after 20/08/2014 Related Publications
BACKGROUND: Women with mutations in BRCA1 or BRCA2 are at high risk of developing breast cancer and, in British Columbia, Canada, are offered screening with both magnetic resonance imaging (MRI) and mammography to facilitate early detection. MRI is more sensitive than mammography but is more costly and produces more false positive results. The purpose of this study was to calculate the cost-effectiveness of MRI screening for breast cancer in BRCA1/2 mutation carriers in a Canadian setting.
METHODS: We constructed a Markov model of annual MRI and mammography screening for BRCA1/2 carriers, using local data and published values. We calculated cost-effectiveness as cost per quality-adjusted life-year gained (QALY), and conducted one-way and probabilistic sensitivity analysis.
RESULTS: The incremental cost-effectiveness ratio (ICER) of annual mammography plus MRI screening, compared to annual mammography alone, was $50,900/QALY. After incorporating parameter uncertainty, MRI screening is expected to be a cost-effective option 86% of the time at a willingness-to-pay of $100,000/QALY, and 53% of the time at a willingness-to-pay of $50,000/QALY. The model is highly sensitive to the cost of MRI; as the cost is increased from $200 to $700 per scan, the ICER ranges from $37,100/QALY to $133,000/QALY.
CONCLUSIONS: The cost-effectiveness of using MRI and mammography in combination to screen for breast cancer in BRCA1/2 mutation carriers is finely balanced. The sensitivity of the results to the cost of the MRI screen itself warrants consideration: in jurisdictions with higher MRI costs, screening may not be a cost-effective use of resources, but improving the efficiency of MRI screening will also improve cost-effectiveness.

Related: Breast Cancer Canada Cancer Screening and Early Detection BRCA1


Cramer-Morales K, Nieborowska-Skorska M, Scheibner K, et al.
Personalized synthetic lethality induced by targeting RAD52 in leukemias identified by gene mutation and expression profile.
Blood. 2013; 122(7):1293-304 [PubMed] Article available free on PMC after 15/08/2014 Related Publications
Homologous recombination repair (HRR) protects cells from the lethal effect of spontaneous and therapy-induced DNA double-stand breaks. HRR usually depends on BRCA1/2-RAD51, and RAD52-RAD51 serves as back-up. To target HRR in tumor cells, a phenomenon called "synthetic lethality" was applied, which relies on the addiction of cancer cells to a single DNA repair pathway, whereas normal cells operate 2 or more mechanisms. Using mutagenesis and a peptide aptamer approach, we pinpointed phenylalanine 79 in RAD52 DNA binding domain I (RAD52-phenylalanine 79 [F79]) as a valid target to induce synthetic lethality in BRCA1- and/or BRCA2-deficient leukemias and carcinomas without affecting normal cells and tissues. Targeting RAD52-F79 disrupts the RAD52-DNA interaction, resulting in the accumulation of toxic DNA double-stand breaks in malignant cells, but not in normal counterparts. In addition, abrogation of RAD52-DNA interaction enhanced the antileukemia effect of already-approved drugs. BRCA-deficient status predisposing to RAD52-dependent synthetic lethality could be predicted by genetic abnormalities such as oncogenes BCR-ABL1 and PML-RAR, mutations in BRCA1 and/or BRCA2 genes, and gene expression profiles identifying leukemias displaying low levels of BRCA1 and/or BRCA2. We believe this work may initiate a personalized therapeutic approach in numerous patients with tumors displaying encoded and functional BRCA deficiency.

Related: Apoptosis Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology



A victory for genes.
Nat Med. 2013; 19(7):792 [PubMed] Related Publications
The ability to patent human genes has been costly to researchers and patients, and has restricted competition in the biotech marketplace. The recent US Supreme Court decision making isolated human genes unpatentable will bring freedom of choice to the patient, and level the playing field for research and development.

Related: Breast Cancer Cancer Screening and Early Detection BRCA1 Ovarian Cancer USA


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