Gene Summary

Gene:BLID; BH3-like motif containing, cell death inducer
Aliases: BRCC2
Summary:This gene encodes a BH3-like motif containing protein involved in cell death. The encoded protein may induce apoptosis in a caspase-dependent manner. The protein is localized in both the cytoplasm and the mitochondrion. [provided by RefSeq, Aug 2011]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:BH3-like motif-containing cell death inducer
Source:NCBIAccessed: 09 March, 2017


What does this gene/protein do?
BLID is implicated in:
- apoptotic process
- mitochondrion
Data from Gene Ontology via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 10 March 2017 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.

  • Risk Reduction Behavior
  • Staging
  • Exons
  • Young Adult
  • Genetic Predisposition
  • Apoptosis Regulatory Proteins
  • Age Factors
  • DNA Repair
  • BRCA1 Protein
  • Biomarkers, Tumor
  • Cancer DNA
  • DNA Damage
  • Pedigree
  • Protein-Serine-Threonine Kinases
  • RB1
  • Missense Mutation
  • Ovariectomy
  • Chromosome 11
  • Cancer Gene Expression Regulation
  • Germ-Line Mutation
  • Genetic Counseling
  • Mastectomy
  • Ovarian Cancer
  • Mutation
  • Heterozygote Detection
  • Survival Rate
  • p53 Protein
  • Polymerase Chain Reaction
  • Nuclear Proteins
  • BRCA2
  • Heterozygote
  • DNA Mutational Analysis
  • Breast Cancer
  • Single Nucleotide Polymorphism
  • Case-Control Studies
  • BRCA2 Protein
  • BRCA1
  • Genotype
  • Genetic Testing
  • Age of Onset
Tag cloud generated 09 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: BLID (cancer-related)

van Marcke C, De Leener A, Berlière M, et al.
Routine use of gene panel testing in hereditary breast cancer should be performed with caution.
Crit Rev Oncol Hematol. 2016; 108:33-39 [PubMed] Related Publications
Breast cancer is the most frequent cancer occurring in women. Ten percent of these cancers are considered hereditary. Among them, 30% are attributed to germline mutations in the tumor suppressor genes BRCA1 and BRCA2. Other genes of lower penetrance are also known, explaining together up to 40% of the hereditary risk of breast cancer. New techniques, such as next-generation sequencing, allow the simultaneous analysis of multiple genes in a cost-effective way. As a logical consequence, gene panel testing is entering clinical practice with the promise of personalized care. We however advocate that gene panel testing is not ready for non-specialist clinical use, as it generates many variants of unknown significance and includes more genes than are presently considered clinically useful. We hereby review the data for each gene that can change the risk management of patients carrying a pathogenic variant.

Márquez-Rodas I, Lobo M, Flores-Sanchez C, et al.
Five Years of Multidisciplinary Care in Hereditary Cancer: Our Experience in a Spanish University Hospital.
Oncology. 2017; 92(2):68-74 [PubMed] Related Publications
OBJECTIVE: To analyse the evolution of a multidisciplinary heredofamilial cancer unit (HFCU) in a university hospital.
METHODS: This was a retrospective analysis of the activity of our HFCU in its first 5 years of existence.
RESULTS: Between July 2010 and July 2015, 1,518 patients from 1,318 families attended our HFCU. Genetic testing was offered to 862 patients. Of those, 833 (96.6%) accepted testing, with available results for 636 (76.4%). Pathogenic mutations in BRCA1 and BRCA2 were found in 175 patients. Lynch syndrome and adenomatous polyposis were the most frequent syndromes diagnosed (151/175, 86.3%) among 17 different syndromes studied. Of the 404 patients without a previous genetic diagnosis in the family, 62 (15.3%) were found to have mutations in disease-causing genes. Prophylactic surgery and follow-up (33.7%) or follow-up only (66.3%) was proposed for mutation carriers according to international guidelines and patients' preferences.
CONCLUSION: We have a high mutation detection rate, genetic test acceptance, and compliance with risk reduction strategies. However, there is room for improvement, especially in genetic testing timing, considering that an increase in the indications for genetic testing is expected.

Brédart A, Kop JL, De Pauw A, et al.
Effect on perceived control and psychological distress of genetic knowledge in women with breast cancer receiving a BRCA1/2 test result.
Breast. 2017; 31:121-127 [PubMed] Related Publications
Information provision during BRCA1/2 genetic counseling is complex and expected to be increasingly so with gene panel testing. This prospective study evaluated whether genetic knowledge in counselees with breast cancer (BC) after a pre-test genetic counseling visit (T1) enhance their feeling of personal control while minimizing distress after the notification of BRCA1/2 result (T2). At T1, 243 (89% response rate) counselees completed questionnaires on genetic knowledge (BGKQ), perceived cancer genetic risk; of which, at T2, 180 (66%) completed the BGKQ again, scales of anxiety/depression, distress specific to genetic risk, and perceived control. Multilevel models were performed accounting for clinician, and testing an effect of knowledge on psychological outcomes according to the adequacy of counselees' perceived genetic predisposition to cancer. The mean knowledge score was moderate at T1, decreased while not significantly differing by BRCA1/2 test result at T2. Knowledge at T1 had no direct effect on psychological outcomes, but in counselees who over-estimated their cancer genetic risk, higher knowledge at T1 predicted higher specific distress at T2. In BC affected counselees who over-estimate their cancer genetic risk, higher BRCA1/2 pre-test genetic knowledge seem to lead to increased specific distress. Identifying these BC affected counselees who over-estimate their genetic cancer risk and helping them to interpret their genetic knowledge instead of providing them with exhaustive genetic information could minimize their distress after test result receipt.

Egloff H, Jatoi A
Do Ovarian Cancer Patients with a Family History of Cancer (Suspected BRCA1 or BRCA2 Mutation) Suffer Greater Chemotherapy Toxicity?
Cancer Invest. 2016; 34(10):531-535 [PubMed] Related Publications
OBJECTIVE: Few studies have examined toxicity from potentially curative chemotherapy in ovarian cancer patients at risk for breast cancer susceptibility (BRCA) mutation.
METHODS/RESULTS: Ninety-four of the 482 patients appeared at risk for a mutation based on family history and 23 had a confirmed mutation. Hospitalization or emergency department visits were not increased based on family history with odds ratios (95% confidence intervals) of 0.88 (0.52, 1.45) (p =.62) and 0.90 (0.49, 1.58) (p =.71), respectively; similar findings were observed with confirmed mutations. Trends favored improved survival.
CONCLUSIONS: Concern for a BRCA mutation should not preclude full dose chemotherapy in ovarian cancer patients treated with curative intent.

Zolot J
New Advisory on Contralateral Prophylactic Mastectomy.
Am J Nurs. 2016; 116(11):17 [PubMed] Related Publications
Breast surgeons recommend against the procedure unless cancer risk is increased.

Monk BJ, Lorusso D, Italiano A, et al.
Trabectedin as a chemotherapy option for patients with BRCA deficiency.
Cancer Treat Rev. 2016; 50:175-182 [PubMed] Related Publications
Trabectedin is a marine-derived product that was originally isolated from the Caribbean sea squirt Ecteinascidia turbinata and the first anticancer marine drug to be approved by the European Union. It is currently used as a single agent for the treatment of patients with soft tissue sarcoma after failure of anthracyclines and ifosfamide, or for those patients who are unsuited to receive these agents, and in patients with relapsed, platinum-sensitive ovarian cancer in combination with pegylated liposomal doxorubicin. Trabectedin has a unique multi-faceted mechanism of action that involves transcription regulation and DNA repair systems, including transcription-coupled nucleotide excision repair and homologous recombination repair (HRR) as the main hallmarks of its antiproliferative activity. In addition, trabectedin has shown the ability to modulate the tumor microenvironment. Indeed, the activity of trabectedin is related to altered function and expression of DNA repair genes, such as BRCA1 (BReast-CAncer susceptibility gene 1) and BRCA2. The particular sensitivity of sarcoma, ovarian and breast cancer cells deficient in HRR, previously observed in preclinical models, now has been confirmed in the clinical setting as well, suggesting that BRCA mutations are associated with improved clinical responses to trabectedin. Current efforts are focused on the evaluation of these unique features of trabectedin and on the identification of predictive factors for patients with an objective to determine whether a deficiency of HRR DNA repair pathway could impact the clinical benefit achieved from trabectedin.

Larouche G, Chiquette J, Plante M, et al.
Usefulness of Canadian Public Health Insurance Administrative Databases to Assess Breast and Ovarian Cancer Screening Imaging Technologies for BRCA1/2 Mutation Carriers.
Can Assoc Radiol J. 2016; 67(4):308-312 [PubMed] Related Publications
PURPOSE: In Canada, recommendations for clinical management of hereditary breast and ovarian cancer among individuals carrying a deleterious BRCA1 or BRCA2 mutation have been available since 2007. Eight years later, very little is known about the uptake of screening and risk-reduction measures in this population. Because Canada's public health care system falls under provincial jurisdictions, using provincial health care administrative databases appears a valuable option to assess management of BRCA1/2 mutation carriers. The objective was to explore the usefulness of public health insurance administrative databases in British Columbia, Ontario, and Quebec to assess management after BRCA1/2 genetic testing.
METHODS: Official public health insurance documents were considered potentially useful if they had specific procedure codes, and pertained to procedures performed in the public and private health care systems.
RESULTS: All 3 administrative databases have specific procedures codes for mammography and breast ultrasounds. Only Quebec and Ontario have a specific procedure code for breast magnetic resonance imaging. It is impossible to assess, on an individual basis, the frequency of others screening exams, with the exception of CA-125 testing in British Columbia. Screenings done in private practice are excluded from the administrative databases unless covered by special agreements for reimbursement, such as all breast imaging exams in Ontario and mammograms in British Columbia and Quebec. There are no specific procedure codes for risk-reduction surgeries for breast and ovarian cancer.
CONCLUSION: Population-based assessment of breast and ovarian cancer risk management strategies other than mammographic screening, using only administrative data, is currently challenging in the 3 Canadian provinces studied.

Cecener G, Guney Eskiler G, Egeli U, et al.
Association of PALB2 sequence variants with the risk of early-onset breast cancer in patients from Turkey.
Mol Biol Rep. 2016; 43(11):1273-1284 [PubMed] Related Publications
The PALB2 gene, has been accepted as a moderate-penetrance gene associated with breast cancer susceptibility and this gene product is involved in the DNA damage repair pathway via co-localization with BRCA2. Germline PALB2 mutations are associated with an increased breast cancer risk. However, the prevalence of the diverse types of PALB2 variants depend on the population. Thus, the aim of the present study was to determine, for the first time, the prevalence of PALB2 variants in a Turkish population of BRCA1/BRCA2-negative early-onset patients with breast cancer. In total, 223 Turkish patients with BRCA1/BRCA2 negative early-onset breast cancer and 60 unaffected women were included in the study. All the coding exons and intron/exon boundaries of PALB2 were subjected to mutational analysis by heteroduplex analysis (HDA)and DNA sequencing. Eighteen PALB2 variants were found in breast cancer patients within the Turkish population. Three variants (c.271G>A, c.404C>A and c.2981T>A) have not been previously reported. In addition, nine intronic variants were described, and this study is the first to describe the c.1685-44T>A intronic variant. The prevalence of possible pathogenic PALB2 variants was found to be 4.03 % in BRCA1/2-negative Turkish patients with early-onset breast cancer. Different variants of PALB2 have been reported in the literature, and the prevalence of these variants could different for each population. This is the first study to investigate the prevalence of PALB2 variants in Turkish patients with early-onset breast cancer.

Baretta Z, Mocellin S, Goldin E, et al.
Effect of BRCA germline mutations on breast cancer prognosis: A systematic review and meta-analysis.
Medicine (Baltimore). 2016; 95(40):e4975 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The contribution of BRCA germline mutational status to breast cancer patients' prognosis is unclear. We aimed to systematically review and perform meta-analysis of the available evidence of effects of BRCA germline mutations on multiple survival outcomes of breast cancer patients as a whole and in specific subgroups of interest, including those with triple negative breast cancer, those with Ashkenazi Jewish ancestry, and patients with stage I-III disease.
METHODS: Sixty studies met all inclusion criteria and were considered for this meta-analysis. These studies involved 105,220 breast cancer patients, whose 3588 (3.4%) were BRCA mutations carriers. The associations between BRCA genes mutational status and overall survival (OS), breast cancer-specific survival (BCSS), recurrence-free survival (RFS), and distant metastasis-free survival (DMFS) were evaluated using random-effect models.
RESULTS: BRCA1 mutation carriers have worse OS than BRCA-negative/sporadic cases (hazard ratio, HR 1.30, 95% CI: 1.11-1.52) and worse BCSS than sporadic/BRCA-negative cases among patients with stage I-III breast cancer (HR 1.45, 95% CI: 1.01-2.07). BRCA2 mutation carriers have worse BCSS than sporadic/BRCA-negative cases (HR 1.29, 95% CI: 1.03-1.62), although they have similar OS. Among triple negative breast cancer, BRCA1/2 mutations carriers had better OS than BRCA-negative counterpart (HR 0.49, 95% CI: 0.26-0.92). Among Ashkenazi Jewish women, BRCA1/2 mutations carriers presented higher risk of death from breast cancer (HR 1.44, 95% CI: 1.05-1.97) and of distant metastases (HR 1.82, 95% CI: 1.05-3.16) than sporadic/BRCA-negative patients.
CONCLUSION: Our results support the evaluation of BRCA mutational status in patients with high risk of harboring BRCA germline mutations to better define the prognosis of breast cancer in these patients.

Manfredini M, Pellacani G, Losi L, et al.
Desmoplastic melanoma: a challenge for the oncologist.
Future Oncol. 2017; 13(4):337-345 [PubMed] Related Publications
AIM: To evaluate clinical, pathologic and genetic features of desmoplastic melanoma (DM).
MATERIALS & METHODS: Analysis of all DM records from 1991 to 2015.
RESULTS: The most common location of DMs was the head and neck (69%); median age and follow-up were 60.5 and 7.3 years, respectively. A familial predisposition for DMs and others malignancies was analyzed. Thin Breslow thickness (<4.5 mm) was associated with an intraepidermal component or a previous lentigo maligna, whereas high Breslow thickness (>4.5 mm) was observed in 'pure' DM.
CONCLUSION: DM could progress from an early phase, characterized by an intraepidermal component, to late phase, characterized by a dermal nodule. This hypothesis correlates with melanoma genetic and NF1 mutation, which could be an early event in the progression of DM.

Miller RE, Ledermann JA
The status of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors in ovarian cancer, part 2: extending the scope beyond olaparib and BRCA1/2 mutations.
Clin Adv Hematol Oncol. 2016; 14(9):704-11 [PubMed] Related Publications
Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have shown clinical activity in epithelial ovarian cancer, leading both the US Food and Drug Administration (FDA) and the European Medicines Agency to approve olaparib for tumors characterized by BRCA1 and BRCA2 mutations. However, it is becoming increasingly evident that tumors that share molecular features with BRCA-mutant tumors-a concept known as BRCAness-also may exhibit defective homologous recombination DNA repair, and therefore will respond to PARP inhibition. A number of strategies have been proposed to identify BRCAness, including identifying defects in other genes that modulate homologous recombination and characterizing the mutational and transcriptional signatures of BRCAness. In addition to olaparib, a number of other PARP inhibitors are in clinical development. This article reviews the development of PARP inhibitors other than olaparib, and discusses the evidence for PARP inhibitors beyond BRCA1/2-mutant ovarian cancer.

Dasgupta H, Mukherjee N, Islam S, et al.
Frequent alterations of homologous recombination repair pathway in primary and chemotolerant breast carcinomas: clinical importance.
Future Oncol. 2017; 13(2):159-174 [PubMed] Related Publications
AIM: To understand the importance of homologous recombination repair pathway in development of breast carcinoma (BC), alterations of some key regulatory genes like BRCA1, BRCA2, FANCC and FANCD2 were analyzed in pretherapeutic/neoadjuvant chemotherapy (NACT)-treated BC samples.
MATERIALS & METHODS: Alterations (deletion/methylation/expression) of the genes were analyzed in 118 pretherapeutic and 41 NACT-treated BC samples.
RESULTS: High deletion/methylation (29-68%) and 64-78% overall alterations of the genes were found in the samples. Concordance was evident between alteration and protein expression of the genes. Estrogen/progesterone receptor-negative tumors showed significantly high alterations even in NACT-treated samples having low CD44 and proliferating cell nuclear antigen expression. Pretherapeutic patients with alterations showed poor prognosis.
CONCLUSION: Alterations of homologous recombination repair pathway genes are needed for the development of BC.

Kappil M, Terry MB, Delgado-Cruzata L, et al.
Mismatch Repair Polymorphisms as Markers of Breast Cancer Prevalence in the Breast Cancer Family Registry.
Anticancer Res. 2016; 36(9):4437-41 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Major breast cancer susceptibility genes involved in DNA repair, including BRCA1 and BRCA2, have been identified. However, mutations in these genes account for only 5-10% of identified breast cancer cases. Additional DNA repair pathway genes may also contribute to susceptibility.
MATERIALS AND METHODS: We investigated the association between 12 single nucleotide polymorphisms (SNPs) in mismatch repair (MMR) genes and breast cancer risk among 313 sister-sets enrolled in the New York site of the Breast Cancer Family Registry (BCFR) (n=744) using conditional logistic regression analysis.
RESULTS: An increase in breast cancer risk was observed for women with the MUTYH_rs3219489 variant allele (odds ratio (OR)=2.23, 95% confidence interval (CI)=1.10-4.52) and for women with the MSH2_rs2303428 variant allele (OR=1.73, 95% CI=1.00-2.99).
CONCLUSION: Deficiencies in DNA repair pathways, such as MMR, have implications for the onset of familial breast cancer.

El Ghorayeb N, Grunenwald S, Nolet S, et al.
First case report of an adrenocortical carcinoma caused by a BRCA2 mutation.
Medicine (Baltimore). 2016; 95(36):e4756 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Adrenocortical carcinoma (ACC) may rarely be a component of inherited cancer syndromes such as Li-Fraumeni syndrome and Beckwith-Wiedemann syndrome. ACC caused by a BRCA2 mutation has never been reported.
METHODS: Nucleotide sequencing of BRCA2 in lymphocyte and tumoral DNA of a 50-year-old male who presented with an androgen-secreting ACC and a strong family history of breast, ovarian, and pancreatic cancers.
RESULTS: A germline BRCA2 2 bp heterozygous deletion at nucleotide 8765 (8765delAG) leading to a frameshift mutation (p.Glu2846GlyfsX23) was detected. Only the BRCA2 deleted allele was retained in the ACC tumoral DNA compared with the control DNA supporting a loss of heterozygosity in the tumor.
CONCLUSION: This is the first reported case of a patient with ACC associated with a BRCA2 germline mutation. Loss of heterozygosity in ACC DNA suggests a causal link with the BRCA2 8765delAG mutation.

Pokharel HP, Hacker NF, Andrews L
Changing patterns of referrals and outcomes of genetic participation in gynaecological-oncology multidisciplinary care.
Aust N Z J Obstet Gynaecol. 2016; 56(6):633-638 [PubMed] Related Publications
BACKGROUND: Genetic participation in gynaecological oncology multidisciplinary team meetings (MDT) may identify the sentinel cancer in women with hereditary breast-ovarian cancer syndrome or Lynch syndrome.
AIMS: To identify the changing patterns of genetic referral from 2010 to 2014 and the outcomes of referrals through clinical MDT case review.
MATERIALS AND METHODS: Medical records of cases of gynaecological cancer presented at the MDT meetings and genetics databases were reviewed to determine the frequency and outcomes of recommendations for genetic referral between 2010 and 2014.
RESULTS: Four hundred and sixty-two women of 2523 cases reviewed were recommended for referral, increasing from 8% in 2010 to 25% in 2014. However, 167 of 462 patients (36%) had not registered with a Hereditary Cancer Clinic in NSW/ACT, including 11 women with high-grade serous ovarian cancer and seven women with abnormal MMR immunohistochemistry. Mutations were identified in 40 of 165 women (24%) undergoing breast cancer BRCA1/2 testing and in ten of 25 women (40%) who underwent MMR genetic testing. Eighty-one first- or second-degree relatives of these women have undergone predictive testing, identifying 48 mutation carriers and 33 non-carriers.
CONCLUSION: Changing indications and increased participation by a genetic consultant in the weekly MDT meeting has led to increasing genetic referrals over the last five years. Follow up of referrals needs to be addressed. With decreasing costs of genetic testing and use of readily transportable DNA collected through saliva or mouth swabs, we propose that distance should not be a barrier to this model being extended to all centres providing care to gynaecological cancer patients.

Basra MA, Saher M, Athar MM, Raza MH
Breast Cancer in Pakistan a Critical Appraisal of the Situation Regarding Female Health and Where the Nation Stands?
Asian Pac J Cancer Prev. 2016; 17(7):3035-41 [PubMed] Related Publications
Breast cancer (BC) is the most common malignancy of women worldwide. In the past it was considered as disease of older middle aged women, but the incidence of BC in young females is growing in recent years concordant with studies in Pakistan. In this paper, we reviewed the mutant functions of tumor suppressor genes (BRCA1, BRCA2, p53, ATM and PTEN), epigenetic transformation and involvement of estrogen receptors in development of breast cancer. We further reviewed the current situation of BC in Pakistan that depicts a higher incidence in young females. According to SKMCH and RC data, age group 4549 years is more prone to BC with high rate of incidence 45.42%. A few studies explored the high expression of ER, PR and HER2/neu in Pakistani females. Moreover, presence of BRCA1 (c.1961dupA) mutation in Pakistani shows concordance with data in different areas of world. But we are unable to find an authentic study that can explore epigenetic based transformation of breast tumors in Pakistan. This area of research needs more attention to explore the complete picture of BC in Pakistan.

Hellner K, Miranda F, Fotso Chedom D, et al.
Premalignant SOX2 overexpression in the fallopian tubes of ovarian cancer patients: Discovery and validation studies.
EBioMedicine. 2016; 10:137-49 [PubMed] Free Access to Full Article Related Publications
Current screening methods for ovarian cancer can only detect advanced disease. Earlier detection has proved difficult because the molecular precursors involved in the natural history of the disease are unknown. To identify early driver mutations in ovarian cancer cells, we used dense whole genome sequencing of micrometastases and microscopic residual disease collected at three time points over three years from a single patient during treatment for high-grade serous ovarian cancer (HGSOC). The functional and clinical significance of the identified mutations was examined using a combination of population-based whole genome sequencing, targeted deep sequencing, multi-center analysis of protein expression, loss of function experiments in an in-vivo reporter assay and mammalian models, and gain of function experiments in primary cultured fallopian tube epithelial (FTE) cells. We identified frequent mutations involving a 40kb distal repressor region for the key stem cell differentiation gene SOX2. In the apparently normal FTE, the region was also mutated. This was associated with a profound increase in SOX2 expression (p<2(-16)), which was not found in patients without cancer (n=108). Importantly, we show that SOX2 overexpression in FTE is nearly ubiquitous in patients with HGSOCs (n=100), and common in BRCA1-BRCA2 mutation carriers (n=71) who underwent prophylactic salpingo-oophorectomy. We propose that the finding of SOX2 overexpression in FTE could be exploited to develop biomarkers for detecting disease at a premalignant stage, which would reduce mortality from this devastating disease.

Chen P, Li J, Chen YC, et al.
The functional status of DNA repair pathways determines the sensitization effect to cisplatin in non-small cell lung cancer cells.
Cell Oncol (Dordr). 2016; 39(6):511-522 [PubMed] Related Publications
PURPOSE: Cisplatin can cause a variety of DNA crosslink lesions including intra-strand and inter-strand crosslinks (ICLs), which are associated with the sensitivity of cancer cells to cisplatin. Here, we aimed to assess the contribution of the Fanconi anemia (FA), homologous recombination (HR) and nucleotide excision repair (NER) pathways to cisplatin resistance in non-small cell lung cancer (NSCLC)-derived cells.
METHODS: The expression of FA, HR and NER pathway-associated genes was assessed by RT-qPCR and Western blotting. siRNAs were used to knock down the expression of these genes. CCK-8 and flow cytometry assays were used to assess the viability and apoptotic rate of NSCLC-derived cells, respectively. Immunofluorescence and alkaline comet assays were used to assess the repair of ICLs.
RESULTS: We found that acquired cisplatin-resistant NSCLC-derived A549/DR cells exhibited markedly enhanced FA and HR repair pathway capacities compared to its parental A549 cells and another independent NSCLC-derived cell line, Calu-1, which possesses a moderate innate resistance to cisplatin. siRNA-mediated silencing of the FA-associated genes FANCL and RAD18 and the HR-associated genes BRCA1 and BRCA2 significantly potentiated the sensitivity of A549/DR cells to cisplatin compared to A549 and Calu-1 cells, suggesting that the acquired cisplatin resistance in A549/DR cells may be attributed to enhanced FA and HR pathway capacities responsible for ICL repair. Although we found that expression knockdown of the NER-associated genes XPA and ERCC1 sensitized the three NSCLC-derived cell lines to cisplatin, the sensitization effect was more significant in Calu-1 cells than in A549 and A549/DR cells, implying that the innate cisplatin resistance in Calu-1 cells may result from an increased NER activity.
CONCLUSIONS: Our results indicate that the functional status of DNA repair pathways determine the sensitivity of NSCLC cells to cisplatin. Direct targeting of the pathway that is involved in cisplatin resistance may be an effective strategy to surmount cisplatin resistance in NSCLC.

Pritchard CC, Mateo J, Walsh MF, et al.
Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer.
N Engl J Med. 2016; 375(5):443-53 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Inherited mutations in DNA-repair genes such as BRCA2 are associated with increased risks of lethal prostate cancer. Although the prevalence of germline mutations in DNA-repair genes among men with localized prostate cancer who are unselected for family predisposition is insufficient to warrant routine testing, the frequency of such mutations in patients with metastatic prostate cancer has not been established.
METHODS: We recruited 692 men with documented metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis. We isolated germline DNA and used multiplex sequencing assays to assess mutations in 20 DNA-repair genes associated with autosomal dominant cancer-predisposition syndromes.
RESULTS: A total of 84 germline DNA-repair gene mutations that were presumed to be deleterious were identified in 82 men (11.8%); mutations were found in 16 genes, including BRCA2 (37 men [5.3%]), ATM (11 [1.6%]), CHEK2 (10 [1.9% of 534 men with data]), BRCA1 (6 [0.9%]), RAD51D (3 [0.4%]), and PALB2 (3 [0.4%]). Mutation frequencies did not differ according to whether a family history of prostate cancer was present or according to age at diagnosis. Overall, the frequency of germline mutations in DNA-repair genes among men with metastatic prostate cancer significantly exceeded the prevalence of 4.6% among 499 men with localized prostate cancer (P<0.001), including men with high-risk disease, and the prevalence of 2.7% in the Exome Aggregation Consortium, which includes 53,105 persons without a known cancer diagnosis (P<0.001).
CONCLUSIONS: In our multicenter study, the incidence of germline mutations in genes mediating DNA-repair processes among men with metastatic prostate cancer was 11.8%, which was significantly higher than the incidence among men with localized prostate cancer. The frequencies of germline mutations in DNA-repair genes among men with metastatic disease did not differ significantly according to age at diagnosis or family history of prostate cancer. (Funded by Stand Up To Cancer and others.).

Shu CA, Pike MC, Jotwani AR, et al.
Uterine Cancer After Risk-Reducing Salpingo-oophorectomy Without Hysterectomy in Women With BRCA Mutations.
JAMA Oncol. 2016; 2(11):1434-1440 [PubMed] Related Publications
Importance: The link between BRCA mutations and uterine cancer is unclear. Therefore, although risk-reducing salpingo-oophorectomy (RRSO) is standard treatment among women with BRCA mutations (BRCA+ women), the role of concomitant hysterectomy is controversial.
Objective: To determine the risk for uterine cancer and distribution of specific histologic subtypes in BRCA+ women after RRSO without hysterectomy.
Design, Setting, and Participants: This multicenter prospective cohort study included 1083 women with a deleterious BRCA1 or BRCA2 mutation identified from January 1, 1995, to December 31, 2011, at 9 academic medical centers in the United States and the United Kingdom who underwent RRSO without a prior or concomitant hysterectomy. Of these, 627 participants were BRCA1+; 453, BRCA2+; and 3, both. Participants were prospectively followed up for a median 5.1 (interquartile range [IQR], 3.0-8.4) years after ascertainment, BRCA testing, or RRSO (whichever occurred last). Follow up data available through October 14, 2014, were included in the analyses. Censoring occurred at uterine cancer diagnosis, hysterectomy, last follow-up, or death. New cancers were categorized by histologic subtype, and available tumors were analyzed for loss of the wild-type BRCA gene and/or protein expression.
Main Outcomes and Measures: Incidence of uterine corpus cancer in BRCA+ women who underwent RRSO without hysterectomy compared with rates expected from the Surveillance, Epidemiology, and End Results database.
Results: Among the 1083 women women who underwent RRSO without hysterectomy at a median age 45.6 (IQR: 40.9 - 52.5), 8 incident uterine cancers were observed (4.3 expected; observed to expected [O:E] ratio, 1.9; 95% CI, 0.8-3.7; P = .09). No increased risk for endometrioid endometrial carcinoma or sarcoma was found after stratifying by subtype. Five serous and/or serous-like (serous/serous-like) endometrial carcinomas were observed (4 BRCA1+ and 1 BRCA2+) 7.2 to 12.9 years after RRSO (BRCA1: 0.18 expected [O:E ratio, 22.2; 95% CI, 6.1-56.9; P < .001]; BRCA2: 0.16 expected [O:E ratio, 6.4; 95% CI, 0.2-35.5; P = .15]). Tumor analyses confirmed loss of the wild-type BRCA1 gene and/or protein expression in all 3 available serous/serous-like BRCA1+ tumors.
Conclusions and Relevance: Although the overall risk for uterine cancer after RRSO was not increased, the risk for serous/serous-like endometrial carcinoma was increased in BRCA1+ women. This risk should be considered when discussing the advantages and risks of hysterectomy at the time of RRSO in BRCA1+ women.

Percival N, George A, Gyertson J, et al.
The integration of BRCA testing into oncology clinics.
Br J Nurs. 2016; 25(12):690-4 [PubMed] Related Publications
PURPOSE: The PARP inhibitor, Olaparib, is approved for women with BRCA-mutated ovarian cancer. Therefore there is an urgent need to test patients and obtain results in time to influence treatment. Models of BRCA testing, such as the mainstreaming oncogenetic pathway, involving oncology health professionals are being used. The authors report on the establishment of the extended role of the clinical nurse specialist in consenting women for BRCA testing in routine gynaecology-oncology clinics using the mainstreaming model.
METHODS: Nurses undertook generic consent training and specific counselling training for BRCA testing in the form of a series of online videos, written materials and checklists before obtaining approval to consent patients for germline BRCA1 and BRCA2 mutations.
RESULTS: Between July 2013 and December 2015, 108 women with ovarian cancer were counselled and consented by nurses in the medical oncology clinics at a single centre (The Royal Marsden, UK). This represented 36% of all ovarian cancer patients offered BRCA testing in the oncology clinics at the centre. Feedback from patients and nurses was encouraging with no significant issues raised in the counselling and consenting process.
CONCLUSION: The mainstreaming model allows for greater access to BRCA testing for ovarian cancer patients, many of whom may benefit from personalised therapy (PARP inhibitors). This is the first report of oncology nurses in the BRCA testing pathway. Specialist oncology nurses trained in BRCA testing have an important role within a multidisciplinary team counselling and consenting patients to undergo BRCA testing.

Gerratana L, Fanotto V, Pelizzari G, et al.
Do platinum salts fit all triple negative breast cancers?
Cancer Treat Rev. 2016; 48:34-41 [PubMed] Related Publications
Triple-negative breast cancer (TNBC) is an aggressive disease with limited treatment options and poor prognosis once metastatic. Pre-clinical and clinical data suggest that TNBC could be more sensitive to platinum-based chemotherapy, especially among BRCA1/2-mutated patients. In recent years, several randomised trials have been conducted to evaluate platinum efficacy in both early-stage and advanced TNBC, with conflicting results especially for long-term outcomes. Experimental studies are now focusing on identifying biomarkers of response to help selecting patients who may benefit most from platinum-based therapies, including BRCA1/2 mutational status and genomic instability signatures (such as HRD-LOH or HRD-LST scores). A standard therapy for TNBC is still missing and platinum-based regimens represent an emerging therapeutic option for selected patients with a defect in the homologous recombination repair system. The identification of these patients through validated biomarker assays will be crucial to optimize the use of currently approved agents in TNBC.

Redzović A, Dintinjana RD, Nacinović AD
Indicators of Cellular and Developmental Disorders in Multiple Primary Cancers.
Coll Antropol. 2016; 40(1):59-62 [PubMed] Related Publications
In human organism development is a very complex and highly regulated system that enables the functional balance of each organ in a whole body. Disorders and tumor micro-environment weaken host immune system that is not able to recognize the tumor as a unknown body and fight against its uncontrollable forces. Tumor avoids the immune system in a way that promotes immunosuppression and orientation cytokine production towards Th2 immune responses which are responsible for infection appearances. Some of infectious agents (viruses) can cause oncogene activation and inhibition of tumor suppressor genes. It is also known that oncology treatment can be detrimental to the host immune system. The drugs or radiation can activate different signaling pathways which lead to a vicious circle from which there is no return. Experimental models of tumor biology and molecular events in vivo are patients who have multiple primary cancers (MPC) diagnosed during life. Such patients confirm the complexity of disorders that occur in the cell and explain all the influences and contributions to developmental tumor cascade.

Kolben T, Hary T, Holdt LM, et al.
Thyroid Hormones and Vitamin D in Patients with Breast Cancer with Mutations in BRCA1 or BRCA2 Genes.
Anticancer Res. 2016; 36(6):3185-90 [PubMed] Related Publications
AIM: The thyroid hormones free triiodothyronine (fT3), free thyroxine (fT4), thyroid-stimulating hormone (TSH) and vitamin D seem to be involved in the process of differentiation and proliferation of breast tissue. Little is known about these factors in breast cancer 1 and 2 (BRCA1/BRCA2)-mutation carriers with breast cancer (BC). The purpose of this investigation was to evaluate the association of thyroid gland function and vitamin D with BC in patients with BRCA mutations.
PATIENTS AND METHODS: At the Department of Hereditary Breast and Ovarian Cancer of the Ludwig Maximilian University Hospital of Munich, 40 patients with BC (10 patients with mutations in the BRCA1 gene, 10 with mutations in the BRCA2 gene, and 20 without mutations, as control group) were selected for analysis of the following parameters: fT3, fT4, TSH and vitamin D. The primary diagnosis was made between 21 and 62 years of age. The patients were matched by age. Anamnestic data were evaluated concerning disorders of the thyroid gland and primary BC diagnosis.
RESULTS: In patients with BC, BRCA mutations are not associated with thyroidal dysfunctions. A significantly increased level of vitamin D in BRCA2-mutation carriers compared to those without mutation (p=0.02) was detected. The grade of the tumors in the BRCA2 group was better than in those with mutation. BRCA1-mutation carriers had an increased incidence of primary BC diagnosis during pregnancy (30% vs. 0%) in comparison to those without mutation.
CONCLUSION: No association between the thyroid hormones and BC in BRCA1/2-mutation carriers was found. Vitamin D was significantly elevated in BRCA2-mutation carriers and the observation of a better tumor grade in this group could be consistent with the ability of vitamin D to inhibit growth and induce differentiation.

Lynce F, Isaacs C
How Far Do We Go With Genetic Evaluation? Gene, Panel, and Tumor Testing.
Am Soc Clin Oncol Educ Book. 2016; 35:e72-8 [PubMed] Related Publications
The traditional model by which an individual was identified as harboring a hereditary susceptibility to cancer was to test for a mutation in a single gene or a finite number of genes associated with a particular syndrome (e.g., BRCA1 and BRCA2 for hereditary breast and ovarian cancer or mismatch repair genes for Lynch syndrome). The decision regarding which gene or genes to test for was based on a review of the patient's personal medical history and their family history. With advances in next-generation DNA sequencing technology, offering simultaneous testing for multiple genes associated with a hereditary susceptibility to cancer is now possible. These panels typically include high-penetrance genes, but they also often include moderate- and low-penetrance genes. A number of the genes included in these panels have not been fully characterized either in terms of their cancer risks or their management options. Another way some patients are unexpectedly identified as carrying a germline mutation in a cancer susceptibility gene is at the time they undergo molecular profiling of their tumor, which typically has been carried out to guide treatment choices for their cancer. This article first focuses on the issues that need to be considered when deciding between recommending more targeted testing of a single or a small number of genes associated with a particular syndrome (single/limited gene testing) versus performing a multigene panel. This article also reviews the issues regarding germline risk that occur within the setting of ordering molecular profiling of tumors.

Anwar SL, Haryono SJ, Aryandono T, Datasena IG
Screening of BRCA1/2 Mutations Using Direct Sequencing in Indonesian Familial Breast Cancer Cases.
Asian Pac J Cancer Prev. 2016; 17(4):1987-91 [PubMed] Related Publications
Breast cancer has emerged as the most prevalent cancer among women worldwide, including in Indonesia. The contribution of genes associated with high-risk breast-ovarian cancers, BRCA1 and BRCA2, in the Indonesian population is relatively unknown. We have characterized family history of patients with moderate- to high-risk of breast cancer predisposition in 26 unrelated cases from Indonesia for BRCA1/2 mutation analyses using direct sequencing. Known deleterious mutations were not found in either BRCA1 or BRCA2 genes. Seven variants in BRCA2 were documented in 10 of 26 patients (38%). All variants were categorized as unclassified (VUSs). Two synonymous variants, c.3623A>G and c.4035T>C, were found in 5 patients. One variant, c4600T>C, was found in a 38 year old woman with a family history of breast cancer. We have found 4 novel variants in BRCA2 gene including c.6718C>G, c.3281A>G, c.10176C>G, and c4490T>C in 4 unrelated patients, all of them having a positive family history of breast cancer. In accordance to other studies in Asian population, our study showed more frequent variants in BRCA2 compared to BRCA1. Further studies involving larger numbers of hereditary breast cancer patients are required to reveal contribution of BRCA1/2 mutations and/or other predisposing genes among familial breast cancer patients in Indonesia.

Bhatta B, Thapa R, Shahi S, et al.
A Pilot Study on Screening of BRCA1 Mutations (185delAG, 1294del40) in Nepalese Breast Cancer Patients.
Asian Pac J Cancer Prev. 2016; 17(4):1829-32 [PubMed] Related Publications
BACKGROUND: Breast cancer is the second most common malignancy among Nepalese women, accounting for 60% of the total cancer cases in females. Women diagnosed with germline mutations in BRCA1 like 185delAG, 1294del40 develop breast and/or ovarian cancer with a lifelong likelihood of up to 85% whereas presence of a mutation increases the risk for mutations to occur in other genes. The major objective of this study was to find the prevalence of these mutations in Nepalese cancer patients.
MATERIALS AND METHODS: This prospective study was carried out at two cancer hospitals in the Kathmandu valley over a period of 11 months. Irrespective of age group and stage of canceran appropriate amount of blood was withdrawn from 50 breast cancer patients and 20 controls. DNA was extracted manually and subjected to PCR using primers for 185delAG and 1294del40 mutations. PCR products were then digested with restriction enzyme (DdeII) followed by electrophoresis.
RESULTS: Prevalence of 185delAG in reference breast cancer patients was found to be 4/50 (8%) but no 1294del40 was apparent.
CONCLUSIONS: Several mutations occurring in different exons of BRCA1 as well as mutations in other genes like BRCA2, for example, should also be taken in account.

Aziz F, Fatima W, Mahmood S, Khokher S
Screening for Del 185 AG and 4627C>A BRCA1 Mutations in Breast Cancer Patients from Lahore, Pakistan.
Asian Pac J Cancer Prev. 2016; 17(4):1725-7 [PubMed] Related Publications
Breast cancer contributes to approximately 23% of the cancer cases identified and 14% of cancer related deaths worldwide. Including a strong association between genetic and environmental factors, breast cancer is a complex and multi factorial disorder. Two high penetration breast cancer susceptibility genes (BRCA1 and BRCA2) have been identified, and germ line mutations in these are thought to account for between 5% and 10% of all breast cancer cases. The human BRCA1 gene, located on 17q, is involved in the regulation of cell proliferation by aiding in DNA repair, transcriptional responses to DNA damage and cell cycle check points. Mutations in this gene enhance cell proliferation and facilitate formation of tumors. Two mutations, the 185 deletion of AG and the 4627 substitution from C to A, are founder mutations in the BRCA1 gene for breast cancer in Asian populations. Allele specific PCR was performed to detect these selected mutations in 120 samples. No mutation of 4627 C to A was detected in the samples and only one of the patients had the 185 del AG mutation in the heterozygous condition. Our collected samples had lower consanguinity and family history indicating the greater involvement of environmental as compared to genetic factors.

Palmbos PL, Hussain MH
Targeting PARP in Prostate Cancer: Novelty, Pitfalls, and Promise.
Oncology (Williston Park). 2016; 30(5):377-85 [PubMed] Related Publications
Metastatic prostate cancer remains a highly lethal disease with no curative therapeutic options. A significant subset of patients with prostate cancer harbor either germline or somatic mutations in DNA repair enzyme genes such as BRCA1, BRCA2, or ATM. Emerging data suggest that drugs that target poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) enzymes may represent a novel and effective means of treating tumors with these DNA repair defects, including prostate cancers. Here we will review the molecular mechanism of action of PARP inhibitors and discuss how they target tumor cells with faulty DNA repair functions and transcriptional controls. We will review emerging data for the utility of PARP inhibition in the management of metastatic prostate cancer. Finally, we will place PARP inhibitors within the framework of precision medicine-based care of patients with prostate cancer.

Yassaee VR, Ravesh Z, Soltani Z, et al.
Mutation Spectra of BRCA Genes in Iranian Women with Early Onset Breast Cancer - 15 Years Experience.
Asian Pac J Cancer Prev. 2016; 17 Spec No.:149-53 [PubMed] Related Publications
Breast cancer is the most common cancer in Iran. In the recent years an upward trend has been observed in the Iranian population. Early detection by molecular approaches may reduce breast cancer morbidity and mortality. We provided consultation to 3,782 women diagnosed with early onset breast cancer during the past 15 years (1999-2014). To establish a data set for BRCA gene alterations of the Iranian families at risk, two hundred and fifty four women who met our criteria were analyzed. A total number of 46 alterations including 18 variants with unknown clinical significance (39.1%), 18 missense mutations (39.1%), 7 Indels (15.2%) and 3 large rearrangement sequences (6%) were identified. Further scanning of affected families revealed that 49% of healthy relatives harbor identical causative mutations. This is the first report of comprehensive BRCA analysis in Iranian women with early onset breast cancer. Our findings provide valuable molecular data to support physicians as well as patients for the best decision making on disease management.

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