Clinical Characteristics of Individuals With Germline Mutations in <i>BRCA1</i> and <i>BRCA2</i>: Analysis of 10,000 Individuals

Frank, Thomas; Deffenbaugh, Amie M.; Reid, Julia; Hulick, Mark; Ward, Benjamin D.; Lingenfelter, Beth; Gumpper, Kathi L.; Scholl, Thomas; Tavtigian, Sean V.; Pruss, Dmitry; Critchfield, Gregory C.

doi:10.1200/jco.2002.20.6.1480

Cited by 566 publications

(247 citation statements)

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“…Our numbers are comparable to what others have revealed [43]. Studies have reported that physicians, with limited formal training in genetics, may misinterpret VUS results [44–46].…”

Section: Discussionsupporting

confidence: 88%

Current guidelines for BRCA testing of breast cancer patients are insufficient to detect all mutation carriers

et al. 2017

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BackgroundIdentification of BRCA mutations in breast cancer (BC) patients influences treatment and survival and may be of importance for their relatives. Testing is often restricted to women fulfilling high-risk criteria. However, there is limited knowledge of the sensitivity of such a strategy, and of the clinical aspects of BC caused by BRCA mutations in less selected BC cohorts. The aim of this report was to address these issues by evaluating the results of BRCA testing of BC patients in South-Eastern Norway.Methods1371 newly diagnosed BC patients were tested with sequencing and Multi Ligation Probe Amplification (MLPA). Prevalence of mutations was calculated, and BC characteristics among carriers and non-carriers compared. Sensitivity and specificity of common guidelines for BRCA testing to identify carriers was analyzed. Number of identified female mutation positive relatives was evaluated.ResultsA pathogenic BRCA mutation was identified in 3.1%. Carriers differed from non-carriers in terms of age at diagnosis, family history, grade, ER/PR-status, triple negativity (TNBC) and Ki67, but not in HER2 and TNM status. One mutation positive female relative was identified per mutation positive BC patient. Using age of onset below 40 or TNBC as criteria for testing identified 32-34% of carriers. Common guidelines for testing identified 45-90%, and testing all below 60 years identified 90%. Thirty-seven percent of carriers had a family history of cancer that would have qualified for predictive BRCA testing. A Variant of Uncertain Significance (VUS) was identified in 4.9%.ConclusionsMutation positive BC patients differed as a group from mutation negative. However, the commonly used guidelines for testing were insufficient to detect all mutation carriers in the BC cohort. Thirty-seven percent had a family history of cancer that would have qualified for predictive testing before they were diagnosed with BC. Based on our combined observations, we suggest it is time to discuss whether all BC patients should be offered BRCA testing, both to optimize treatment and improve survival for these women, but also to enable identification of healthy mutation carriers within their families. Health services need to be aware of referral possibility for healthy women with cancer in their family.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3422-2) contains supplementary material, which is available to authorized users.

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“…Our numbers are comparable to what others have revealed [43]. Studies have reported that physicians, with limited formal training in genetics, may misinterpret VUS results [44–46].…”

Section: Discussionsupporting

confidence: 88%

Current guidelines for BRCA testing of breast cancer patients are insufficient to detect all mutation carriers

et al. 2017

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“…The referred criteria for breast cancer were: (1) breast cancer patients with a family history of breast or ovarian cancer; (2) breast cancer patients who were 40 years or younger during diagnosis, who had bilateral breast cancer or breast cancer with other primary malignancy, or male breast cancer patients, in accordance with the standard of National Medical Insurance Reimbursement in Korea. In the genetic counseling process, all patients’ mutation probabilities were estimated by CaGene5.0 software [15] using pedigree information up to second-degree relatives and considering estimates by BRCAPRO [16] and Myriad [17]. Clinicopathological characteristics of cancer, such as the stage and the hormone receptor and human epidermal growth factor receptor 2 (HER2) status, were evaluated by reviewing medical records.…”

Section: Methodsmentioning

confidence: 99%

Characteristics of BRCA1/2 mutations carriers including large genomic rearrangements in high risk breast cancer patients

Park

Sohn

Yoon

et al. 2017

Breast Cancer Res Treat

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PurposeWe investigated the prevalence of BRCA1/2 small mutations and large genomic rearrangements in high risk breast cancer patients who attended a genetic counseling clinic.MethodsIn total 478 patients were assessed for BRCA1/2 mutations by direct sequencing, of whom, 306 were identified as non-carriers of BRCA1/2 mutation and assessed for large rearrangement mutations by multiplex ligation-dependent probe amplification. Family history and clinicopathological characteristics of patients were evaluated.ResultsSixty-three mutation carriers (13.2%) were identified with BRCA1 mutations (6.3%) and BRCA2 mutations (6.9%), respectively. Mutation frequency was affected by familial and personal factors. Breast cancer patients with family history of breast and ovarian cancer showed the highest prevalence of BRCA1/2 mutations (67%), and triple-negative breast cancer (TNBC) patients showed high BRCA1 mutation prevalence (25%). The three probands of BRCA1 deletion (1%) represented both familial risk and personal or clinicopathological risk factors as two with TNBC and one with bilateral ovarian cancer.DiscussionThis is the largest study assessing large genomic rearrangement prevalence in Korea and BRCA1 deletion frequency was low as 1% in patients without BRCA1/2 small mutations. For clinical utility of large genomic rearrangement testing needs further study.

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“…The cancer risk associated with BRCA1 germline mutation is less clear for tumors other than breast, ovary, and fallopian tube cancers (BCLC, 1999;Brose et al, 2002;Thompson and Easton, 2002). Large studies have reported both a lack of association and small association with BRCA1 mutation in male breast and prostate cancer (Basham et al, 2002;Brose et al, 2002;Frank et al, 2002;Thompson and Easton, 2002). A recent editorial commenting on reports from two large and overlapping databases brings to light the difficulties in estimating/establishing other small cancer risks due to BRCA1 mutation (Gruber and Petersen, 2002).…”

Section: Brca1 and Brca2 Tumor Suppressionmentioning

confidence: 99%

The cancer connection: BRCA1 and BRCA2 tumor suppression in mice and humans

Moynahan

2002

Oncogene

108

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BRCA1 and BRCA2 mutations are estimated to be responsible for the great majority of familial breast and ovarian cancers. Much progress has been made toward the understanding of the function of these proteins through genetic, biochemical, and structural studies. The embryonic lethality encountered in the knockout mouse initially hindered the development of mouse models aimed at studying tumor suppression. However, mice that harbor hypomorphic Brca1 and Brca2 alleles and cre-mediated tissue-specific deletions for Brca1 and Brca2 have been generated. Mice deficient for either Brca1 or Brca2 sustain a wide range of carcinoma and mammary epithelium deleted for Brca1 or Brca2 is highly susceptible to mammary tumorigenesis. Mammary (and other) tumors occur at long latency as compared to oncogene-induced mouse tumors. p53 deficiency is highly cooperative with both Brca1 and Brca2 in promoting tumorigenesis. Analysis of Brca1-associated mammary tumors reveals significant similarities to BRCA1-associated breast cancer in regard to high tumor grade, hormone receptor negativity, a high incidence of p53 mutations and genetic instability.

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Clinical Characteristics of Individuals With Germline Mutations in BRCA1 and BRCA2: Analysis of 10,000 Individuals

Abstract: Specific features of personal and family history can be used to assess the likelihood of identifying a mutation in BRCA1 or BRCA2 in individuals tested in a clinical setting.

Cited by 566 publications

References 28 publications

Current guidelines for BRCA testing of breast cancer patients are insufficient to detect all mutation carriers

Current guidelines for BRCA testing of breast cancer patients are insufficient to detect all mutation carriers

Characteristics of BRCA1/2 mutations carriers including large genomic rearrangements in high risk breast cancer patients

The cancer connection: BRCA1 and BRCA2 tumor suppression in mice and humans

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