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BRCA Mutation and PARP Inhibitors
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Arjun Mittra, James H. Doroshow, Alice P. Chen
Genetic mutations in BRCA1 or 2 genes predispose to an increased risk of developing cancer, mainly breast, ovarian, prostate, and pancreatic cancers, at a relatively young age. Having a BRCA mutation increases the risk of developing ovarian cancer by up to 63% and breast cancer by up to 87% during a patient’s lifetime. BRCA1 is associated more with ovarian, cervical, uterine, pancreatic, and colon cancer in women, and possibly testicular cancer in men. BRCA2 has a higher association with male breast cancer, prostate cancer, pancreatic, stomach, bile duct cancers, and melanoma. BRCA mutations are most prevalent in Ashkenazi Jews (Jews of Eastern European descent). In this population, the predominant mutations are 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2. Although these mutations occur in only 2.5% of the Ashkenazi population, they account for 70–85% of germline mutations in patients with hereditary breast and ovarian cancer. Although the incidence appears high, when the general population is considered, only 5–10% of breast cancers and 13% of high-grade serous ovarian cancers are associated with germline mutations in the BRCA gene [16, 31, 90, 91]. Interestingly, 50% of high-grade serous ovarian carcinomas are associated with HR mutations including BRCA and others. In addition, high-grade serous ovarian carcinoma was found to have a 22% prevalence of BRCA mutations, when sporadic mutations were also included. It has also been reported that twenty percent of triple-negative breast cancers (TNBC) have BRCA mutations [41].
Ethical consideration about health risk communication and professional responsibility
Published in Ulrik Kihlbom, Mats G. Hansson, Silke Schicktanz, Ethical, Social and Psychological Impacts of Genomic Risk Communication, 2020
Our current knowledge about rare genetic variants that increase the risk for breast cancer such as BRCA 1 and 2 (two tumour suppressor genes) has added to the ethical challenges of adequate risk communication. According to the lay-relevant website of the US NIH, ‘12% of women in the general population will develop breast cancer sometime during their lives… By contrast, a recent large study estimated that about 72% of women who inherit a harmful BRCA1 mutation and about 69% of women who inherit a harmful BRCA2 mutation will develop breast cancer by the age of 80’.1 Risk-reduction for those who have inherited the respective BRCA 1 or 2 mutations, includes several options, such as regular screening, chemotherapy and ‘preventive’ mastectomy. NIH recommends that counselling and genetic testing should only be done in particular cases with family history because both mutations are rare (2–3 in 1000 women of the general population, and only 10–15 per cent of breast cancer are related to these BRCA mutations), and genetic testing should only be done after proper counselling and in case of particular family history (Nelson et al. 2013).
Radiation-Induced Cancer
Published in K. H. Chadwick, Understanding Radiation Biology, 2019
The occurrence of breast and ovarian cancers in women carrying a BRCA mutation some 10 to 30 years before the occurrence of sporadic cancers of the breast and ovary in non-carriers has been well documented and is almost certainly a consequence of an inherited DNA repair deficiency in BRCA carriers. Cancer therapy, with radiation or chemicals causing DNA double strand breaks following a standard therapy regime, will have a more aggressive effect in any patient with a DNA repair defect, including BRCA carriers. More cell killing and more chromosomal damage will occur in DNA repair deficient patients than in patients with a normal DNA repair efficiency, not only in the malignant cells but also in any healthy tissue cells affected by the treatment. Consequently, a first check on any young adult presenting with any cancer should be a test for a DNA repair deficiency or radiation and chemical mutagen sensitivity. An appropriately modified therapy treatment regime should then be selected.
Changing patterns of referral into a family history clinic and detection of ovarian cancer: a retrospective 10-year review
Published in Journal of Obstetrics and Gynaecology, 2022
K. G. Smallwood, S. Crockett, V. Huang, V. Cullimore, J. Davies, G. Satti, A Phillips
The overall median age at RRS was 47, ranging from 29 to 78. The median age has gradually reduced since 2009 and will most likely continue to do so with more women being offered genetic testing. The recommendation is that surgery is performed at or before the ovarian cancer risk period, which is 35–40 years in BRCA1 patients and 40−45 years in BRCA2 patients (Evans et al. 2008). All of the BRCA mutation carriers diagnosed with cancer in our cohort were over the age of 45 at RRS and therefore outside of the risk reduction window. Targeting women at the appropriate age may improve outcomes however this raises its own challenges. In addition to this, with an increase in germline testing of seemingly sporadic tumours (often in older women) there will be an increase in diagnosis of BRCA mutations and therefore potential to increase referrals at a younger age for the descendants of these patients.
PARP inhibitors as single agents and in combination therapy: the most promising treatment strategies in clinical trials for BRCA-mutant ovarian and triple-negative breast cancers
Published in Expert Opinion on Investigational Drugs, 2022
The prevalence of BRCA mutations varies by ethnic and racial background. In the general population, the presence of these germline mutations is rare, while the highest rate occurs among Ashkenazi Jewish women (8.3%), followed by Hispanic women (3.5%) [11]. Founder mutations of BRCA genes (185delAG, 538insC in BRCA1; 6174delT in BRCA2) are identified among Ashkenazi Jewish women [12]. Interestingly, some sporadic breast cancers without germline mutations in BRCA display similar alterations as those tumors harboring germline BRCA mutations with consequent defective HR. Breast cancer cases where sporadic BRCA mutations occur in the absence of germline mutations are referred to as cases with BRCA like properties or ‘BRCAness’. The overall frequency of BRCAness phenotypes in sporadic breast cancer is unknown. However, data on BRCA1 methylation, FANCF methylation, and EMSY amplification indicate that approximately up to 25% of sporadic breast cancer could show BRCAness phenotypes [13]. Other biomarkers for assessing BRCAness include mutational genes associated with HR repair, mutational or transcriptomic signatures related to HRD, and functional biomarkers of HRD [7].
Fallopian tube cancer– challenging to diagnose but not as infrequent as originally thought
Published in Journal of Community Hospital Internal Medicine Perspectives, 2021
Jasmin Hundal, Nerea Lopetegui-Lia, William Rabitaille
Genetic testing can also be undertaken to identify any familial genetic mutation or the onset of sporadic mutations. Primary care physicians are recommended to utilize familial risk assessments, such as Ontario Family History Assessment Tool, Manchester Scoring System, Pedigree Assessment Tool, International Breast Cancer Intervention Study Instrument, 7-Question Family History Screening Tool, as screening tools to assess the risk of a BRCA1 and BRCA 2 mutation [11]. However, trained health professionals should perform genetic counseling about mutation testing. According to the American Cancer Society, genetic testing is recommended for women who have a known family history of BRCA mutation, women diagnosed with ovarian cancer, pancreatic cancer, family history of breast cancer at a younger age, more than one family member with breast cancer and breast cancer in a male family member [12].