Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing

Girard, Elodie; Eon-Marchais, Séverine; Olaso, Robert; A, Renault; Damiola, Francesca; Dondon, Marie-Gabrielle; Barjhoux, Laure; Goidin, Didier; Meyer, Vincent; Gal, Dorothée Le; Beauvallet, Juana; Mebirouk, Noura; Lonjou, Christine; Coignard, Juliette; Marcou, Morgane; Cavaciuti, Eve; Baulard, Céline; Bihoreau, Marie Thérèse; Cohen-Haguenauer, Odile; Leroux, Dominique; Penet, Clotilde; Fert‐Ferrer, Sandra; Colas, Chrystelle; Frébourg, Thierry; Eisinger, François; Adenis, Claude; Fajac, Anne; Gladieff, Laurence; Tinat, Julie; Floquet, Anne; Chiésa, Jean; Giraud, Sophie; Mortemousque, Isabelle; Soubrier, Florent; Audebert‐Bellanger, Séverine; Limacher, Jean Marc; Lasset, Christine; Lejeune-Dumoulin, S.; Dreyfus, Hélène; Bignon, Yves Jean; Longy, Michel; Pujol, Pascal; Vénat-Bouvet, Laurence; Bonadona, Valérie; Berthet, Pascaline; Luporsi, É.; Maugard, Christine M.; Noguès, Catherine; Delnatte, Capucine; Fricker, Jean Pierre; Gesta, Paul; Faivre, Laurence; Lortholary, Alain; Bruno, Benedetto; Caron, Olivier; Gauthier‐Villars, Marion; Coupier, Isabelle; Servant, Nicolas; Boland, Anne; Mazoyer, Sylvie; Deleuze, Jean; Stoppa‐Lyonnet, Dominique; Andrieu, Nadine; Lesueur, Fabienne

doi:10.1002/ijc.31921

Cited by 49 publications

(44 citation statements)

References 55 publications

(93 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the other hand, the genes with pathogenic variants associated with other syndromes included the Fanconi Anemia FANCM, Lynch syndrome MLH3, MSH2, MSH6; the colorectal adenoma MUTYH, the pancreatic and melanoma CDKN2A; and the ataxia telangiectasia gene ATM, as previously reported (15,(34)(35)(36)(37).…”

Section: Discussionmentioning

confidence: 55%

Latin American Study of Hereditary Breast and Ovarian Cancer LACAM: A Genomic Epidemiology Approach

et al. 2019

View full text Add to dashboard Cite

Purpose: Hereditary Breast and Ovarian Cancer (HBOC) syndrome is responsible for ∼5-10% of all diagnosed breast and ovarian cancers. Breast cancer is the most common malignancy and the leading cause of cancer-related mortality among women in Latin America (LA). The main objective of this study was to develop a comprehensive understanding of the genomic epidemiology of HBOC throughout the establishment Oliver et al. Latin American HBOC Study of The Latin American consortium for HBOC-LACAM, consisting of specialists from 5 countries in LA and the description of the genomic results from the first phase of the study. Methods: We have recruited 403 individuals that fulfilled the criteria for HBOC from 11 health institutions of Argentina, Colombia, Guatemala, Mexico and Peru. A pilot cohort of 222 individuals was analyzed by NGS gene panels. One hundred forty-three genes were selected on the basis of their putative role in susceptibility to different hereditary cancers. Libraries were sequenced in MiSeq (Illumina, Inc.) and PGM (Ion Torrent-Thermo Fisher Scientific) platforms. Results: The overall prevalence of pathogenic variants was 17% (38/222); the distribution spanned 14 genes and varied by country. The highest relative prevalence of pathogenic variants was found in patients from Argentina (25%, 14/57), followed by Mexico (18%, 12/68), Guatemala (16%, 3/19), and Colombia (13%, 10/78). Pathogenic variants were found in BRCA1 (20%) and BRCA2 (29%) genes. Pathogenic variants were found in other 12 genes, including high and moderate risk genes such as MSH2, MSH6, MUTYH, and PALB2. Additional pathogenic variants were found in HBOC unrelated genes such as DCLRE1C, WRN, PDE11A, and PDGFB. Conclusion: In this first phase of the project, we recruited 403 individuals and evaluated the germline genetic alterations in an initial cohort of 222 patients among 4 countries. Our data show for the first time in LA the distribution of pathogenic variants in a broad set of cancer susceptibility genes in HBOC. Even though we used extended gene panels, there was still a high proportion of patients without any detectable pathogenic variant, which emphasizes the larger, unexplored genetic nature of the disease in these populations.

show abstract

Section: Discussionmentioning

confidence: 55%

Latin American Study of Hereditary Breast and Ovarian Cancer LACAM: A Genomic Epidemiology Approach

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Four different truncating ATM mutations were seen in six cases (1% of non‐ BRCA cases). There is evidence that ATM protein‐truncating mutations are associated with a twofold to threefold increase in breast cancer risk . A meta‐analysis of 26 studies (including 4,076 cases and 2,389 controls) performed in 2009 reported an OR of 2.1 (95% CI 1.03–4.21) for breast cancer for carriers of truncating ATM mutations .…”

Section: Discussionmentioning

confidence: 99%

“…There is evidence that ATM protein-truncating mutations are associated with a twofold to threefold increase in breast cancer risk. [34][35][36][37] A meta-analysis of 26 studies (including 4,076 cases and 2,389 controls) performed in 2009 reported an OR of 2.1 (95% CI 1.03-4.21) for breast cancer for carriers of truncating ATM mutations. 36 In a more recent study of 9,639 patients with breast cancer in USA and 3,988 controls, ATM mutations were associated with threefold increased risk (95%CI = 1.7-5.7).…”

Section: Discussionmentioning

confidence: 99%

The spectrum of mutations predisposing to familial breast cancer in Poland

Cybulski

Kluźniak

Huzarski

et al. 2019

Intl Journal of Cancer

View full text Add to dashboard Cite

To optimize genetic testing, it is necessary to establish the spectrum of breast cancer‐predisposing mutations in particular ethnic groups. We studied 1,018 women with a strong family history for breast cancer (families with hereditary breast cancer; HBC) from genetically homogenous population of Poland, which is populated by ethnic Slavs, for mutations in 14 cancer susceptibility genes. Additionally, we compared the frequency of candidate pathogenic variants in breast cancer cases and controls. Germline mutations were detected in 512 of 1,018 probands with breast cancer (50.3%), including BRCA1/2 mutations detected in 420 families and non‐BRCA mutations seen in 92 families. Thirteen BRCA1/2 founder mutations represented 84% of all BRCA1/2‐positive cases. Seven founder mutations of CHEK2, PALB2, NBN and RECQL represented 73% of all non‐BRCA‐positive cases. Odds ratios for hereditary breast cancer were 87.6 for BRCA1, 15.4 for PALB2, 7.2 for CHEK2, 2.8 for NBN and 15.8 for RECQL. Odds ratios for XRCC2, BLM and BARD1 were below 1.3. In summary, we found that 20 founder mutations in six genes (BRCA1/2, CHEK2, PALB2, NBN and RECQL) are responsible for 82% of Polish hereditary breast cancer families. A simple test for these 20 mutations will facilitate genetic testing for breast cancer susceptibility in Poland. It may also facilitate genetic testing for breast cancer susceptibility in other Slavic populations and women of Slavic descent worldwide.

show abstract

“…A germline missense variant in POLH gene was observed in a 35-year-old breast cancer female whose uncle developed breast cancer at age of 43 years (33). However, according to a case-control study on investigating association between candidate genes and breast cancer susceptibility, individuals carrying rare germline missense variants in POLH showed decreased risk of breast cancer (34). In addition, another casecontrol study reported a common germline variant in POLH (c.1783A>G) that was associated with risk of melanoma in Caucasian origin population (35).…”

Section: Polhmentioning

confidence: 99%

Investigation on Gastric Cancer Susceptibility Genes in Chinese Early-onset Diffuse Gastric Cancer

Feng

Zhang

et al. 2020

Preprint

View full text Add to dashboard Cite

Abstract BackgroundDiffuse gastric cancer (DGC) is known as gastric cancer with diffuse type morphology. Early onset DGC is an indicator of suspicious hereditary diffuse gastric cancer (HDGC). HDGC patient are often less sensitive to chemotherapy and suffer from highly invasive late stage malignancy with poor prognosis. Such hereditary cancer syndrome is closely related to deleterious CDH1 germline variant. In addition, potential pathogenic germline variants in other candidate genes were also observed in HDGC families. However, the profile of gastric cancer (GC) susceptibility gene in Chinese HDGC patients is yet to be elucidated.MethodsTo investigate gastric cancer susceptibility genes in Chinese gastric cancer patients, we collected peripheral blood samples from 29 patients fulfilled both HDGC clinical diagnosis and genetic testing criteria updated on 2015 by IGCLC. Genomic DNA was extracted from peripheral blood followed by Whole Exome Sequencing (WES) with average sequencing depth of at least 100X. Gastric cancer predisposing SNV and Indel candidates were filtered based on population allele frequencies in public nucleotide polymorphism databases and pathogenic variant filtering process was performed to identify potential gastric cancer predisposing variant candidates. Immunohistochemistry was conducted on biopsies from patient who carries potential pathogenic CDH1 germline variant.ResultsIn general, 336296 germline non-synonymous variants were detected from 29 GC patients. According to the pathogenic variant filtering process, 25 germline variant candidates in 22 genes were identified as gastric cancer predisposing variant candidates. In addition, a novel splice-site variant, c.2165-1G>A (NM_004360.4), in CDH1 was detected in a Chinese early-onset HDGC patient who developed ovarian metastasis. Furthermore, IHC analysis on the ovarian cancer tissue from this patient demonstrated weakly to moderate staining of E-cadherin compared with positive control. Moreover, another two variants, CTNNA1 c.1975_1976del (NM_001903.2), APC c.-19+1G>A (NM_001127511.2), were suspicious of gastric cancer predisposing variants.ConclusionsThis study suggested that CDH1 c.2165-1G>A may act as a gastric cancer predisposing variant. In addition, to further investigate molecular mechanisms of early-onset gastric cancer, one may consider 22 genes observed in this study. Furthermore, the inconclusive results in this study warrant future investigation on gastric cancer susceptibility gene discovery that cohort selection may require more stringent conditions.

show abstract

Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing

Cited by 49 publications

References 55 publications

Latin American Study of Hereditary Breast and Ovarian Cancer LACAM: A Genomic Epidemiology Approach

Latin American Study of Hereditary Breast and Ovarian Cancer LACAM: A Genomic Epidemiology Approach

The spectrum of mutations predisposing to familial breast cancer in Poland

Investigation on Gastric Cancer Susceptibility Genes in Chinese Early-onset Diffuse Gastric Cancer

Contact Info

Product

Resources

About