Opportunistic testing of <i>BRCA1</i>, <i>BRCA2</i> and mismatch repair genes improves the yield of phenotype driven hereditary cancer gene panels

Feliubadaló, Lídia; López‐Fernández, Adrià; Pineda, Marta; Dı́ez, Orland; Valle, Jesús Del; Gutiérrez-Enríquez, S.; Teulé, Àlex; González, Sara; Stjepanovic, Neda; Salinas, Mónica; Capellà, Gabriel; Brunet, Joan; Lázaro, Conxi; Balmañà, Judith

doi:10.1002/ijc.32304

Cited by 30 publications

(26 citation statements)

References 46 publications

(102 reference statements)

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“…Third, as reported previously (58)(59)(60)(61). a multigene panel for germline and/or somatic testing would probably be cost effective, providing a substantial rate of clinically actionable pathogenic variants (62). There is a potential benefit to be gained from rescreening with a multigene panel in patients who previously underwent noninformative genetic screening (63).…”

Section: Discussionmentioning

confidence: 80%

Germline and Somatic BRCA1/2 Mutations in 172 Chinese Women With Epithelial Ovarian Cancer

You

et al. 2020

Front. Oncol.

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Objective: Despite several nationwide cohort studies of germline BRCA1/2 mutations and several small cohort studies of somatic BRCA1/2 mutations in Chinese epithelial ovarian cancer (EOC) patients, little is known about the impact of these findings on survival outcomes in this population. In this study of 172 retrospectively recruited Chinese EOC patients, germline and somatic BRCA1/2 mutations and their value for predicting survival outcomes were evaluated. Methods: Unselected patients who visited the study center from January 1, 2011, to January 1, 2015, were recruited and asked to provide peripheral blood samples for this study if they were pathologically confirmed to have primary EOC. All patients received staging surgeries or debulking surgeries involving systemic platinum-based chemotherapy, and the patients were then followed up to December 1, 2017. DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) sections and peripheral blood and sequenced for somatic and germline testing, respectively. The demographic and clinicopathological characteristics of the patients were collected to analyze the distribution of BRCA mutations in subgroups. Survival outcomes were compared among various BRCA mutation statuses using univariate and multivariate models. Results: In 58 (33.7%) patients, 63 variants were identified, including variants of unknown significance (VUS) in 18 patients (10.5%) and pathogenic or likely pathogenic variants in a partially overlapping set of 41 patients (23.8%). Germline BRCA mutations, somatic BRCA mutations, BRCA1 mutations in general, and BRCA2 mutations in general were found in 35 (20.3%), 7 (4.1%), 28 (16.3%), and 13 (7.6%) patients, respectively. Five recurrent mutations were identified. Personal and family cancer histories as well as hereditary breast and ovarian cancer (HBOC) criteria were associated with deleterious BRCA mutations both overall and in the germline specifically, whereas only age at diagnosis of EOC was associated with somatic BRCA mutations. In univariate and Cox regression analyses, patients with BRCA1/2 mutations in general had significant improvements in progression-free survival (PFS) and overall survival (OS). You et al. Germline and Somatic BRCA1/2 Mutations in EOC Conclusions: In Chinese EOC patients, the distributions and risk factors associated with germline and somatic BRCA1/2 mutations were similar to those previously reported in international studies. Deleterious BRCA mutations in general were associated with improved survival outcomes in this cohort.

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Section: Discussionmentioning

confidence: 80%

Germline and Somatic BRCA1/2 Mutations in 172 Chinese Women With Epithelial Ovarian Cancer

You

et al. 2020

Front. Oncol.

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“…The sequence of all coding regions and exon-intron boundaries (±20) was obtained by NGS and was also used to determine putative copy number variations (CNVs), which were validated by MLPA analysis. Other pathogenic variants identified in the clinical testing workflow, according to the clinical cascades presented in Feliubadaló et al [32], are depicted in Table S1.…”

Section: Resultsmentioning

confidence: 99%

“…A total of 1021 hereditary cancer-suspected index cases, referred through our genetic counselling units, that underwent NGS panel testing based on clinical suspicion [32], were included in this study (Table 2). Genetic counselors followed international guidelines to request germline genetic tests under the suspicion of a hereditary cancer syndrome.…”

Section: Patients and Controlsmentioning

confidence: 99%

Exploring the Role of Mutations in Fanconi Anemia Genes in Hereditary Cancer Patients

Valle

Rofes

Moreno-Cabrera

et al. 2020

Cancers

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Fanconi anemia (FA) is caused by biallelic mutations in FA genes. Monoallelic mutations in five of these genes (BRCA1, BRCA2, PALB2, BRIP1 and RAD51C) increase the susceptibility to breast/ovarian cancer and are used in clinical diagnostics as bona-fide hereditary cancer genes. Increasing evidence suggests that monoallelic mutations in other FA genes could predispose to tumor development, especially breast cancer. The objective of this study is to assess the mutational spectrum of 14 additional FA genes (FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, FANCP, FANCQ, FANCR and FANCU) in a cohort of hereditary cancer patients, to compare with local cancer-free controls as well as GnomAD. A total of 1021 hereditary cancer patients and 194 controls were analyzed using our next generation custom sequencing panel. We identified 35 pathogenic variants in eight genes. A significant association with the risk of breast cancer/breast and ovarian cancer was found for carriers of FANCA mutations (odds ratio (OR) = 3.14 95% confidence interval (CI) 1.4–6.17, p = 0.003). Two patients with early-onset cancer showed a pathogenic FA variant in addition to another germline mutation, suggesting a modifier role for FA variants. Our results encourage a comprehensive analysis of FA genes in larger studies to better assess their role in cancer risk.

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“…Clinical validity for BRCA1/2 and PALB2 (BC/OvC), and BRIP1, RAD51C, RAD51D, MLH1, MSH2, MSH6 (OvC) has been established with subsequent surveillance and preventive clinical options. Therefore, HBOC germline panels including these genes are recommended (Evidence II, Recommendation A) (II, A) [8].…”

Section: Genetic Testing Methodologies In Hbocmentioning

confidence: 99%

SEOM clinical guidelines in hereditary breast and ovarian cancer (2019)

et al. 2019

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Mutations in BRCA1 and BRCA2 high penetrance genes account for most hereditary breast and ovarian cancer, although other new high-moderate penetrance genes included in multigene panels have increased the genetic diagnosis of hereditary breast and ovarian cancer families by 50%. Multigene cancer panels provide new challenges related to increased frequency of variants of uncertain significance, new gene-specific cancer risk assessments, and clinical recommendations for carriers of mutations of new genes. Although clinical criteria for genetic testing continue to be largely based on personal and family history with around a 10% detection rate, broader criteria are being applied with a lower threshold for detecting mutations when there are therapeutic implications for patients with breast or ovarian cancer. In this regard, new models of genetic counselling and testing are being implemented following the registration of PARP inhibitors for individuals who display BRCA mutations. Massive sequencing techniques in tumor tissue is also driving a paradigm shift in genetic testing and potential identification of germline mutations. In this paper, we review the current clinical criteria for genetic testing, as well as surveillance recommendations in healthy carriers, risk reduction surgical options, and new treatment strategies in breast cancer gene-mutated carriers.

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Opportunistic testing of BRCA1, BRCA2 and mismatch repair genes improves the yield of phenotype driven hereditary cancer gene panels

Cited by 30 publications

References 46 publications

Germline and Somatic BRCA1/2 Mutations in 172 Chinese Women With Epithelial Ovarian Cancer

Germline and Somatic BRCA1/2 Mutations in 172 Chinese Women With Epithelial Ovarian Cancer

Exploring the Role of Mutations in Fanconi Anemia Genes in Hereditary Cancer Patients

SEOM clinical guidelines in hereditary breast and ovarian cancer (2019)

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