scholarly journals Literature Review of BARD1 as a Cancer Predisposing Gene with a Focus on Breast and Ovarian Cancers

Genes ◽  
2020 ◽  
Vol 11 (8) ◽  
pp. 856 ◽  
Author(s):  
Wejdan M. Alenezi ◽  
Caitlin T. Fierheller ◽  
Neil Recio ◽  
Patricia N. Tonin
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Cancer Risk ◽  
Protein Function ◽  
Association Studies ◽  
Study Groups ◽  
Cancer Syndrome ◽  
Brca1 And Brca2 ◽  
Germline Variants ◽  
Family Based

Soon after the discovery of BRCA1 and BRCA2 over 20 years ago, it became apparent that not all hereditary breast and/or ovarian cancer syndrome families were explained by germline variants in these cancer predisposing genes, suggesting that other such genes have yet to be discovered. BRCA1-associated ring domain (BARD1), a direct interacting partner of BRCA1, was one of the earliest candidates investigated. Sequencing analyses revealed that potentially pathogenic BARD1 variants likely conferred a low–moderate risk to hereditary breast cancer, but this association is inconsistent. Here, we review studies of BARD1 as a cancer predisposing gene and illustrate the challenge of discovering additional cancer risk genes for hereditary breast and/or ovarian cancer. We selected peer reviewed research articles that focused on three themes: (i) sequence analyses of BARD1 to identify potentially pathogenic germline variants in adult hereditary cancer syndromes; (ii) biological assays of BARD1 variants to assess their effect on protein function; and (iii) association studies of BARD1 variants in family-based and case-control study groups to assess cancer risk. In conclusion, BARD1 is likely to be a low–moderate penetrance breast cancer risk gene.

BRCA1 and BRCA2 Mutation Frequency in Women Evaluated in a Breast Cancer Risk Evaluation Clinic

2002 ◽  
Vol 20 (4) ◽  
pp. 994-999 ◽  
Author(s):  
Helen A. Shih ◽  
Fergus J. Couch ◽  
Katherine L. Nathanson ◽  
M. Anne Blackwood ◽  
Timothy R. Rebbeck ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Risk Evaluation ◽  
Brca2 Mutation ◽  
Brca1 And Brca2 ◽  
Brca1 Mutations ◽  
Brca2 Mutations ◽  
Brca1 And Brca2 Mutations

PURPOSE: To determine the prevalence of BRCA1 and BRCA2 mutations in families identified in a breast cancer risk evaluation clinic. PATIENTS AND METHODS: One hundred sixty-four families seeking breast cancer risk evaluation were screened for coding region mutations in BRCA1 and BRCA2 by conformation-sensitive gel electrophoresis and DNA sequencing. RESULTS: Mutations were identified in 37 families (22.6%); 28 (17.1%) had BRCA1 mutations and nine (5.5%) had BRCA2 mutations. The Ashkenazi Jewish founder mutations 185delAG and 5382insC (BRCA1) were found in 10 families (6.1%). However, 6174delT (BRCA2) was found in only one family (0.6%) despite estimates of equal frequency in the Ashkenazi population. In contrast to other series, the average age of breast cancer diagnosis was earlier in BRCA2 mutation carriers (32.1 years) than in women with BRCA1 mutations (37.6 years, P = .028). BRCA1 mutations were detected in 20 (45.5%) of 44 families with ovarian cancer and 12 (75%) of 16 families with both breast and ovarian cancer in a single individual. Significantly fewer BRCA2 mutations (two [4.5%] of 44) were detected in families with ovarian cancer (P = .01). Eight families had male breast cancer; one had a BRCA1 mutation and three had BRCA2 mutations. CONCLUSION: BRCA1 mutations were three times more prevalent than BRCA2 mutations. Breast cancer diagnosis before 50 years of age, ovarian cancer, breast and ovarian cancer in a single individual, and male breast cancer were all significantly more common in families with BRCA1 and BRCA2 mutations, but none of these factors distinguished between BRCA1 and BRCA2 mutations. Evidence for reduced breast cancer penetrance associated with the BRCA2 mutation 6174delT was noted.

scholarly journals Common Variants at the 19p13.1 and ZNF365 Loci Are Associated with ER Subtypes of Breast Cancer and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

2012 ◽  
Vol 21 (4) ◽  
pp. 645-657 ◽  
Author(s):  
Fergus J. Couch ◽  
Mia M. Gaudet ◽  
Antonis C. Antoniou ◽  
Susan J. Ramus ◽  
Karoline B. Kuchenbaecker ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Cancer Risk ◽  
Brca2 Mutation ◽  
Ovarian Cancer Risk ◽  
Common Variants ◽  
Brca1 And Brca2 ◽  
Mutation Carriers

A family-based approach to primary prevention of breast cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. s2-s2
Author(s):  
Olufunmilayo Olopade
Keyword(s):  
Breast Cancer ◽  
Risk Assessment ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Minimal Risk ◽  
Brca1 And Brca2 ◽  
Cancer Susceptibility Genes ◽  
Genes And Environment ◽  
Breast Cancer Risk Assessment ◽  
Family Based

s2 We are currently focusing on the interplay of genes and environment in the development of estrogen receptor (ER)-negative breast cancer, which is aggressive, less responsive to treatment, and more likely to strike young women and those of African ancestry. Unfortunately, there are no strategies to prevent ER-negative breast cancer and research is urgently needed. Nevertheless, we have made progress in understanding genetic risk factors for some familial forms of breast cancer, which is reason enough to adopt family-based interventions for breast cancer prevention, especially among families with identifiable highly penetrant mutations in breast cancer susceptibility genes. In 1997, I chaired the ASCO Task Force on Cancer Genetics Education, charged to educate oncologists about the importance of genetics in clinical oncology practice. Since then, a growing body of evidence documents the benefits of preventive measures with minimal risk to women with identifiable highly penetrant mutations in BRCA1 and BRCA2 genes. Whereas other genes, such as TP53 in Li-Fraumeni Syndrome and PTEN in Cowden syndrome, contribute to a small fraction of hereditary breast cancer, mutations in these genes are rare. Germ-line mutations in BRCA1 or BRCA2 are strong predictors of breast and/or ovarian cancer development, and the contribution of these mutations to breast cancer risk within any specific population is a function of both their prevalence and penetrance. Mutation prevalence varies among ethnic groups and may be influenced by founder mutations as observed in Ashkenazi Jews and Icelanders. Although estimates of mutation prevalence and penetrance rates are inconsistent and occasionally controversial, understanding them is critical for providing individualized risk assessment. Although the contribution of other genes to early onset and familial breast cancer needs clarification, genetic testing for BRCA1 and BRCA2 has become standard of care and an important component of personalized breast cancer risk assessment and prevention.

Genetic risk factors for familial ovarian cancer

2002 ◽  
Vol 8 (3) ◽  
pp. 92-97
Author(s):  
Elmar Stickeler ◽  
Ingo B Runnebaum
Keyword(s):  
Ovarian Cancer ◽  
Family History ◽  
Cancer Risk ◽  
Brca2 Mutation ◽  
Individual Risk ◽  
Ovarian Cancer Risk ◽  
Cancer Syndrome ◽  
Brca1 And Brca2 ◽  
Ovarian Cancers ◽  
Mutation Carriers

In Europe ovarian cancer represents the third most common cancer of the female genital tract, with 30,000 newly diagnosed patients per year. Family history is the most significant risk factor. Lifetime risk for ovarian cancer increases from 1.4% for women with a negative family history to 14.6-32.2% in women from affected families. About 5-10% of ovarian cancers are hereditary and supposed to occur in three different forms: hereditary breast and ovarian cancer syndrome (HBOC), site-specific hereditary ovarian cancer (HOC) and hereditary nonpolyposis colorectal cancer syndrome (HNPCC). HBOC and HOC account for 80-90% of the cases and are associated with inactivating germline mutations of the BRCA1 and BRCA2 genes. For BRCA1 and BRCA2 mutation carriers the cumulative risk by age 70 of developing ovarian cancer is 45-60% and 25-30%, respectively. Approximately 10-15% of familial ovarian cancers are related to the HNPCC syndrome with a cumulative ovarian cancer risk of 9% by age 70. Germline polymorphisms may further modify ovarian cancer risk. Bilateral prophylactic oophorectomy reduces the risk of developing ovarian cancer in HBOC and HOC families by 50%. Tubal ligation also significantly reduces the risk in BRCA1 mutation carriers (odds ratio 0.39). Knowledge of the genetic background provides an objective basis for individual risk assessment and prevention.

Retrospective evaluation of risk-reducing salpingo-oophorectomy for BRCA1/2 pathogenic variant carriers among a cohort study in a single institution

2020 ◽  
Author(s):  
Yusuke Kobayashi ◽  
Akira Hirasawa ◽  
Tatsuyuki Chiyoda ◽  
Arisa Ueki ◽  
Kenta Masuda ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Cohort Study ◽  
Primary Prevention ◽  
Hormone Replacement ◽  
Cancer Syndrome ◽  
Brca1 And Brca2 ◽  
History Of ◽  
First Time ◽  
Risk Reducing

Abstract Background Risk-reducing salpingo-oophorectomy is performed for the primary prevention of ovarian cancer in patients with hereditary breast–ovarian cancer syndrome. We performed risk-reducing salpingo-oophorectomy for the first time in Japan in 2008, and we experienced 20 cases of risk-reducing salpingo-oophorectomy through 2019. In the past, the use of risk-reducing salpingo-oophorectomy in Japan was restricted because it was not covered by a Japanese National Health Insurance. Since April 2020, risk-reducing salpingo-oophorectomy has been covered by insurance for patients with breast–ovarian cancer syndrome and pre-existing breast cancer, and this surgery is expected to become more widely implemented in Japan. Methods To contribute to the widespread use of risk-reducing salpingo-oophorectomy in the future, we retrospectively reviewed 20 cases of risk-reducing salpingo-oophorectomy at our hospital cohort study to clarify the issues in its implementation. Results The variant genes for which risk-reducing salpingo-oophorectomy was indicated were BRCA1 and BRCA2 in 13 (65%) and 7 patients (35%), respectively. The median age at which risk-reducing salpingo-oophorectomy was performed was 49 years (range, 38–58), 13 patients (65%) had gone through menopause, and 16 patients (80%) had a history of breast cancer. Of the five patients (25%) with vasomotor symptoms, four received Chinese medicine, and only one received hormone replacement therapy. Occult cancer was detected in the removed ovaries in two patients (10%), although no postoperative peritoneal carcinogenesis has been observed to date. Conclusions Women who paid for risk-reducing salpingo-oophorectomy out of pocket were older than the recommended age at which the procedure should be performed, and this may explain the higher rate of occult cancers than previously reported. We need to perform risk-reducing salpingo-oophorectomy at the recommended age to ensure that the procedure is effective for primary prevention.

Germline Mutations in BRCA1 and BRCA2 in Breast-Ovarian Families From a Breast Cancer Risk Evaluation Clinic

2001 ◽  
Vol 19 (8) ◽  
pp. 2247-2253 ◽  
Author(s):  
A.-M. Martin ◽  
M.A. Blackwood ◽  
D. Antin-Ozerkis ◽  
H.A. Shih ◽  
K. Calzone ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Risk Evaluation ◽  
Germline Mutations ◽  
Study Group ◽  
Breast And Ovarian Cancer ◽  
Brca1 And Brca2 ◽  
Ovarian Cancers

PURPOSE: Data from the Breast Cancer Linkage Consortium suggest that the proportion of familial breast and ovarian cancers linked to BRCA1 or BRCA2 may be as high as 98% depending on the characteristics of the families, suggesting that mutations in BRCA1 or BRCA2 may entirely account for hereditary breast and ovarian cancer families. We sought to determine what proportion of families with both breast and ovarian cancers seen in a breast cancer risk evaluation clinic are accounted for by coding region germline mutations in BRCA1 and BRCA2 as compared to a linkage study group. We also evaluated what clinical parameters were predictive of mutation status. PATIENTS AND METHODS: Affected women from 100 families with at least one case of breast cancer and at least one case of ovarian cancer in the same lineage were screened for germline mutations in the entire coding regions of BRCA1 and BRCA2 by conformation-sensitive gel electrophoresis, apolymerase chain reaction–based heteroduplex analysis, or direct sequencing. RESULTS: Unequivocal deleterious mutations were found in 55% (55 of 100) of the families studied. Mutations in BRCA1 and BRCA2 accounted for 80% and 20% of the mutations overall, respectively. Using multivariate analysis, the strongest predictors of detecting a mutation in BRCA1 or BRCA2 in this study group were the presence of a single family member with both breast and ovarian cancer (P < .0009; odds ratio [OR], 5.68; 95% confidence interval [CI], 2.04 to 15.76) and a young average age at breast cancer diagnosis in the family (P < .0016; OR, 1.69; 95% CI, 1.23 to 2.38). CONCLUSION: These results suggest that at least half of breast/ovarian families evaluated in a high-risk cancer evaluation clinic may have germline mutations in BRCA1 or BRCA2. Whether the remaining families have mutations in noncoding regions in BRCA1, mutations in other, as-yet-unidentified, low-penetrance susceptibility genes, or represent chance clustering remains to be determined.

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