scholarly journals Detection of Germline Mutations in a Cohort of 139 Patients with Bilateral Breast Cancer by Multi-Gene Panel Testing: Impact of Pathogenic Variants in Other Genes beyond BRCA1/2

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2415 ◽  
Author(s):  
Daniele Fanale ◽  
Lorena Incorvaia ◽  
Clarissa Filorizzo ◽  
Marco Bono ◽  
Alessia Fiorino ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Susceptibility ◽  
Bilateral Breast Cancer ◽  
Significant Proportion ◽  
Susceptibility Genes ◽  
Gene Panel ◽  
Panel Testing ◽  
Cancer Susceptibility Genes ◽  
Gene Panel Testing ◽  
Increased Risk

Patients with unilateral breast cancer (UBC) have an increased risk of developing bilateral breast cancer (BBC). The annual risk of contralateral BC is about 0.5%, but increases by up to 3% in BRCA1 or BRCA2 pathogenic variant (PV) carriers. Our study was aimed to evaluate whether all BBC patients should be offered multi-gene panel testing, regardless their cancer family history and age at diagnosis. We retrospectively collected all clinical information of 139 BBC patients genetically tested for germline PVs in different cancer susceptibility genes by NGS-based multi-gene panel testing. Our investigation revealed that 52 (37.4%) out of 139 BBC patients harbored germline PVs in high- and intermediate-penetrance breast cancer (BC) susceptibility genes including BRCA1, BRCA2, PTEN, PALB2, CHEK2, ATM, RAD51C. Nineteen out of 53 positively tested patients harbored a PV in a known BC susceptibility gene (no-BRCA). Interestingly, in the absence of an analysis performed via multi-gene panel, a significant proportion (14.4%) of PVs would have been lost. Therefore, offering a NGS-based multi-gene panel testing to all BBC patients may significantly increase the detection rates of germline PVs in other cancer susceptibility genes beyond BRCA1/2, avoiding underestimation of the number of individuals affected by a hereditary tumor syndrome.

Detection of Inherited Mutations in Brazilian Breast Cancer Patients Using Multi-Gene panel Testing

2021 ◽  
Author(s):  
Rodrigo Santa Cruz Guindalini ◽  
Danilo Vilela Viana ◽  
João Paulo Fumio Whitaker Kitajima ◽  
Vinícius Marques Rocha ◽  
Rossana Verónica Mendoza López ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Latin American ◽  
Cancer Susceptibility ◽  
Gene Panel ◽  
Breast Cancer Patients ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
Gene Panel Testing ◽  
Predisposition Genes

Abstract Genetic diversity of germline variants in breast cancer (BC) predisposition genes, is unexplored in miscegenated people, such as Latin American populations. We evaluated 1,662 Brazilian BC patients, who underwent hereditary multi-gene panel testing (20–38 cancer susceptibility genes), to determine the spectrum and prevalence of (likely) pathogenic variants (P/LP) and variants of uncertain significance (VUS). In total, 161 (9.7%) participants carried germline P/LP variants in BRCA1/2 and 162 (9.7%) in other cancer predisposition genes. Overall, 341 distinctive P/LP variants were identified in 22 genes, including BRCA1(28%), BRCA2(19%), TP53(11%), MUTYH heterozygous (10%), ATM(9%), CHEK2(6%), and PALB2(5%). The Brazilian variant TP53 R337H (c.1010G > A, p.Arg337His), detected in 1.6% of BC patients and 0.09% of reference controls (RC), was strongly associated with odds of disease (OR = 17.67; 95%CI:9.21–34.76; p < 0.001). Heterozygous MUTYH c.1187G > A and MUTYH c.536A > G, detected in 0.78% (0.90% RC) and 0.48% (0.40% RC) of the patients, respectively, were not associated with the odds of BC, the former with OR = 0.87 (95%CI:0.49–1.53; p = 0.63) and the latter with OR = 1.20 (95%CI:0.58–2.49; p = 0.63). Besides, 766 individuals (46.1%) had 1 or more VUS. Concluding, the use of multi-gene panel testing doubled the identification of mutation carriers in Brazilian BC patients. Special attention should be given to TP53 mutations.

scholarly journals Extended gene panel testing in lobular breast cancer

2021 ◽  
Author(s):  
Elke M. van Veen ◽  
D. Gareth Evans ◽  
Elaine F. Harkness ◽  
Helen J. Byers ◽  
Jamie M. Ellingford ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Testing ◽  
Detection Rate ◽  
Gene Panel ◽  
Lobular Breast Cancer ◽  
Germline Variants ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing ◽  
Increased Risk

AbstractPurpose: Lobular breast cancer (LBC) accounts for ~ 15% of breast cancer. Here, we studied the frequency of pathogenic germline variants (PGVs) in an extended panel of genes in women affected with LBC. Methods: 302 women with LBC and 1567 without breast cancer were tested for BRCA1/2 PGVs. A subset of 134 LBC affected women who tested negative for BRCA1/2 PGVs underwent extended screening, including: ATM, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51D, and TP53.Results: 35 PGVs were identified in the group with LBC, of which 22 were in BRCA1/2. Ten actionable PGVs were identified in additional genes (ATM(4), CDH1(1), CHEK2(1), PALB2(2) and TP53(2)). Overall, PGVs in three genes conferred a significant increased risk for LBC. Odds ratios (ORs) were: BRCA1: OR = 13.17 (95%CI 2.83–66.38; P = 0.0017), BRCA2: OR = 10.33 (95%CI 4.58–23.95; P < 0.0001); and ATM: OR = 8.01 (95%CI 2.52–29.92; P = 0.0053). We did not detect an increased risk of LBC for PALB2, CDH1 or CHEK2. Conclusion: The overall PGV detection rate was 11.59%, with similar rates of BRCA1/2 (7.28%) PGVs as for other actionable PGVs (7.46%), indicating a benefit for extended panel genetic testing in LBC. We also report a previously unrecognised association of pathogenic variants in ATM with LBC.

scholarly journals One in three highly selected Greek patients with breast cancer carries a loss-of-function variant in a cancer susceptibility gene

2019 ◽  
Vol 57 (1) ◽  
pp. 53-61 ◽  
Author(s):  
Florentia Fostira ◽  
Irene Kostantopoulou ◽  
Paraskevi Apostolou ◽  
Myrto S Papamentzelopoulou ◽  
Christos Papadimitriou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Gene Panel ◽  
Control Analysis ◽  
Loss Of Function ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing ◽  
Clinical Changes

BackgroundGene panel testing has become the norm for assessing breast cancer (BC) susceptibility, but actual cancer risks conferred by genes included in panels are not established. Contrarily, deciphering the missing hereditability on BC, through identification of novel candidates, remains a challenge. We aimed to investigate the mutation prevalence and spectra in a highly selected cohort of Greek patients with BC, questioning an extensive number of genes, implicated in cancer predisposition and DNA repair, while calculating gene-specific BC risks that can ultimately lead to important associations.MethodsTo further discern BC susceptibility, a comprehensive 94-cancer gene panel was implemented in a cohort of 1382 Greek patients with BC, highly selected for strong family history and/or very young age (<35 years) at diagnosis, followed by BC risk calculation, based on a case–control analysis.ResultsHerein, 31.5% of patients tested carried pathogenic variants (PVs) in 28 known, suspected or candidate BC predisposition genes. In total, 24.8% of the patients carried BRCA1/2 loss-of-function variants. An additional 6.7% carried PVs in additional genes, the vast majority of which can be offered meaningful clinical changes. Significant association to BC predisposition was observed for ATM, PALB2, TP53, RAD51C and CHEK2 PVs. Primarily, compared with controls, RAD51C PVs and CHEK2 damaging missense variants were associated with high (ORs 6.19 (Exome Aggregation Consortium (ExAC)) and 12.6 (Fabulous Ladies Over Seventy (FLOSSIES)), p<0.01) and moderate BC risk (ORs 3.79 (ExAC) and 5.9 (FLOSSIES), p<0.01), respectively.ConclusionStudying a large and unique cohort of highly selected patients with BC, deriving from a population with founder effects, provides important insight on distinct associations, pivotal for patient management.

Comparing and assessing the reported penetrance of cancer susceptibility genes for breast cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1520-1520
Author(s):  
Kanhua Yin ◽  
Danielle Braun ◽  
Ankur Tiwari ◽  
Jin Wang ◽  
Preeti Singh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
General Population ◽  
Case Control Study ◽  
Cancer Susceptibility ◽  
Susceptibility Genes ◽  
Case Control ◽  
Cancer Risks ◽  
Cancer Susceptibility Genes ◽  
Increased Risk ◽  
Control Study

1520 Background: It is critical for oncologists to be aware of unbiased and interpretable cancer risks (i.e., penetrance) in carriers with germline pathogenic variants in cancer susceptibility genes. However, relevant literature is large and varies significantly in study design, patient ascertainment, and types of risk estimates reported. This heterogeneity can cause inconsistent conclusions between studies and create barriers for clinicians to understand and apply them in practice. To further understand the current literature, we assessed penetrance studies associated with non-BRCA breast cancer susceptibility genes based on study design and ascertainment adjustment. Methods: We used a validated natural language processing-based abstract classifier to identify all penetrance studies regarding eleven genes: ATM, BARD1, CDH1, CHEK2, NBN, NF1, PALB2, PTEN, RECQL, STK11, and TP53. Relevant studies were then manually annotated as “with ascertainment adjustment” if a study was based on: (1) a general population; (2) a pedigree analysis or a family-based study with appropriate ascertainment adjustment; or (3) a hospital-based study or a panel testing analysis with well-matched cases and controls. Results: A total of 49 penetrance studies were identified, with a median of nine studies for each gene (range: 4-16). The case-control study was the dominant study type, accounting for over 80% in five genes, 50% in two genes, and 18% to 43% in the other four genes. The proportion of studies with ascertainment adjustment was generally low (mean: 33%) and varied widely between different genes (7% to 80%). Contradictory breast cancer risks (no increased risk vs. significantly increased risk) were found in eight genes (73%) (Table). The most common ascertainment bias identified was a case-control study with cases (patients) who had a strong family history but using general population controls. Conclusions: Ascertainment bias is common in penetrance studies, but few studies adjust for it appropriately. Clinicians should be aware of this issue, and new methods are warranted to select unbiased risk estimates, synthesize them, and provide the accurate general-population penetrance. [Table: see text]

BRIDGES, Breast Cancer Risk after Diagnostic Gene Sequencing, HORIZON2020

Impact ◽  
2020 ◽  
Vol 2020 (7) ◽  
pp. 12-15
Author(s):  
Peter Devilee ◽  
Marjanka Schmidt
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Gene Panel ◽  
Prophylactic Surgery ◽  
Panel Testing ◽  
Cancer Susceptibility Genes ◽  
Risk Estimates ◽  
Gene Panel Testing

"Breast cancer affects more than 360,000 women per year in the EU and causes more than 90,000 deaths. Identification of women at high risk of the disease can lead to early detection or disease prevention through intensive screening, therapeutic and/or lifestyle preventive measures, or prophylactic surgery. Breast cancer risk is determined by a combination of genetic and lifestyle risk factors. The advent of next generation sequencing has opened the opportunity for testing in many disease genes, and diagnostic gene panel testing is being introduced in many EU countries. However, the cancer risks associated with most variants in most genes are unknown. This leads to a major problem in appropriate counselling and management of women undergoing panel testing. The BRIDGES and B-CAST projects are jointly building a knowledge base that will allow identification of women at high-risk of specific subtypes of breast cancer, through comprehensive evaluation of DNA variants in known and suspected breast cancer genes. The effort exploits the huge resources established through the Breast Cancer Association Consortium (BCAC) and ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles). Existing datasets will be expanded by sequencing all known breast cancer susceptibility genes in >100,000 breast cancer cases and controls from population-based studies. Risk factor and tumour genome data have been collected for 10,000 cases. Jointly, the data will allow us to generate a comprehensive risk model with unprecedented discriminative power, that can provide personalised risk estimates. We will develop online tools to aid the interpretation of gene variants and provide risk estimates in a user-friendly format, to help genetic counsellors and patients worldwide to make informed clinical decisions for risk management. We will evaluate the acceptability and utility of comprehensive gene panel testing in the clinical genetics context."

scholarly journals Integrative genomic analysis implicates ERCC6 and its interaction with ERCC8 in susceptibility to breast cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Roxana Moslehi ◽  
Hui-Shien Tsao ◽  
Nur Zeinomar ◽  
Cristy Stagnar ◽  
Sean Fitzpatrick ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Susceptibility ◽  
Breast Cancer Susceptibility ◽  
Susceptibility Genes ◽  
Breast Cancer Susceptibility Gene ◽  
Genome Wide Association Studies ◽  
Integrative Genomics ◽  
Moderate Risk ◽  
Cancer Susceptibility Genes ◽  
Increased Risk

AbstractUp to 30% of all breast cancer cases may be inherited and up to 85% of those may be due to segregation of susceptibility genes with low and moderate risk [odds ratios (OR) ≤ 3] for (mostly peri- and post-menopausal) breast cancer. The majority of low/moderate-risk genes, particularly those with minor allele frequencies (MAF) of < 30%, have not been identified and/or validated due to limitations of conventional association testing approaches, which include the agnostic nature of Genome Wide Association Studies (GWAS). To overcome these limitations, we used a hypothesis-driven integrative genomics approach to test the association of breast cancer with candidate genes by analyzing multi-omics data. Our candidate-gene association analyses of GWAS datasets suggested an increased risk of breast cancer with ERCC6 (main effect: 1.29 ≤ OR ≤ 2.91, 0.005 ≤ p ≤ 0.04, 11.8 ≤ MAF ≤ 40.9%), and implicated its interaction with ERCC8 (joint effect: 3.03 ≤ OR ≤ 5.31, 0.01 ≤ pinteraction ≤ 0.03). We found significant upregulation of ERCC6 (p = 7.95 × 10–6) and ERCC8 (p = 4.67 × 10–6) in breast cancer and similar frequencies of ERCC6 (1.8%) and ERCC8 (0.3%) mutations in breast tumors to known breast cancer susceptibility genes such as BLM (1.9%) and LSP1 (0.3%). Our integrative genomics approach suggests that ERCC6 may be a previously unreported low- to moderate-risk breast cancer susceptibility gene, which may also interact with ERCC8.

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