Co-occurrence of germline pathogenic variants for different hereditary cancer syndromes in patients with Lynch syndrome  

作　　者：Rosario Ferrer-Avargues Maria Isabel Castillejo Estela Damaso Virginia Diez-Obrero Noemi Garrigos Tatiana Molina Alan Codoner-Alejos Angel Segura Ana Beatriz Sanchez-Heras Adela Castillejo Jose Luis Soto 

机构地区：[1]Foundation for the Promotion of Health and Biomedical Research of Valencia Region(FISABIO),FISABIO-Elche Health Department,Elche 032303,Spain [2]Molecular Genetics Unit.Elche University Hospital,Elche 032303,Spain [3]Department of Molecular Biopathology,Immunological Center of Alicante,San Juan-Alicante 03550,Spain [4]Medical Oncology Department,Cancer Genetic Counseling Unit.La Fe University Hospital,Valencia 46026,Spain [5]Medical Oncology Department,Cancer Genetic Counseling Unit.Elche University Hospital,Elche 03203,Spain

出　　处：《Cancer Communications》2021年第3期218-228,共11页癌症通讯（英文）

基　　金：supported by grants from the Foundation for the Promotion of Health and Biomedical Research in the Valencian Region,FISABIO(Grants:UGP-14-192 and UGP-16-146);the Carlos Ⅲ Health Institute(Grant AES:PI17/01082).

摘　　要：Background:Lynch syndrome(LS)is a hereditary condition characterized by a high risk of colorectal cancer,endometrial cancer,and other neoplasia associated with germline alterations in DNA mismatch repair genes.The classical genetic diagnostic strategy for LS consists of the Sanger sequencing of genes associated with the suspected syndrome.Next-generation sequencing(NGS)enables the simultaneous sequencing of a large number of hereditary cancer genes.Here,we aimed to study whether other germline pathogenic variants of hereditary cancer genes are present in patients with LS.Methods:A cohort of 84 probands with a previous genetic diagnosis of LS by Sanger sequencing was reanalyzed using NGS via a commercial panel of 94 hereditary cancer genes by hybrid capture.The American College of Medical Genetics and Genomics criteria were used to classify the clinical significance of the variants.The findings of NGS were confirmed by Sanger sequencing.When possible,genetic analyses of the new findings in the proband’s relativeswere also performed by Sanger sequencing.Results:We identified five families(6%),out of 84,with at least two germline pathogenic variants conferring to high or moderate risk in different dominant cancer-predisposing genes:[MLH1-BRCA2-NBN],[MLH1-BRCA1],[MSH2-ATM],[MSH6-NF1],and[MLH1-FANCA].Interestingly,only one out of these five families exhibited a clinical phenotype associated with the new pathogenic variants.The family with three pathogenic variants of the[MLH1-BRCA2-NBN]genes showed a high aggregation of tumors associated with LS and breast and ovarian cancer syndrome.Conclusions:Our results showed that the co-occurrence of more than one pathogenic variant in cancer-predisposing genes was remarkable among cases of LS.Inmost cases,no clinicial manifestations were associated with the secondary pathogenic variants.Further studies are needed to confirm these findings and elucidate their clinical impact.Reanalysis of LS families should be considered only in families with mixed clinical phenotypes.

关 键 词：cancer panel hereditary cancer lynch syndrome moderate penetrance genes multilocus inherited neoplasia alleles syndrome next-generation sequencing secondary findings 

分 类 号：R73[医药卫生—肿瘤]