Elucidating the molecular basis of MSH2-deficienttumors by combined germline and somatic analysis
Por:
Vargas-Parra, G, Gonzalez-Acosta, M, Thompson, B, Gomez, C, Fernandez, A, Damaso, E, Pons, T, Morak, M, del Valle, J, Iglesias, S, Velasco, A, Solanes, A, Sanjuan, X, Padilla, N, de la Cruz, X, Valencia, A, Holinski-Feder, E, Brunet, J, Feliubadalo, L, Lazaro, C, Navarro, M, Pineda, M and Capella, G
Publicada:
1 oct 2017
Resumen:
In a proportion of patients presenting mismatch repair (MMR)-deficient tumors, no germline MMR mutations are identified, the socalled Lynch-like syndrome (LLS). Recently, MMR-deficient tumors have been associated with germline mutations in POLE and MUTYH or double somatic MMR events. Our aim was to elucidate the molecular basis of MSH2-deficient LS-suspected cases using a comprehensive analysis of colorectal cancer (CRC)-associated genes at germline and somatic level. Fifty-eight probands harboring MSH2-deficient tumors were included. Germline mutational analysis of MSH2 (including EPCAM deletions) and MSH6 was performed. Pathogenicity of MSH2 variants was assessed by RNA analysis and multifactorial likelihood calculations. MSH2 cDNA and methylation of MSH2 and MSH6 promoters were studied. Matched blood and tumor DNA were analyzed using a customized next generation sequencing panel. Thirty-five individuals were carriers of pathogenic or probably pathogenic variants in MSH2 and EPCAM. Five patients harbored 4 different MSH2 variants of unknown significance (VUS) and one had 2 novel MSH6 promoter VUS. Pathogenicity assessment allowed the reclassification of the 4 MSH2 VUS and 6 probably pathogenic variants as pathogenic mutations, enabling a total of 40 LS diagnostics. Predicted pathogenic germline variants in BUB1, SETD2, FAN1 and MUTYH were identified in 5 cases. Three patients had double somatic hits in MSH2 or MSH6, and another 2 had somatic alterations in other MMR genes and/or proofreading polymerases. In conclusion, our comprehensive strategy combining germline and somatic mutational status of CRC-associated genes by means of a subexome panel allows the elucidation of up to 86% of MSH2-deficient suspected LS tumors.
Filiaciones:
Vargas-Parra, G:
CIBERONC, IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Ave Gran Via Hospitalet,199-203, Lhospitalet De Llobregat 08908, Spain
Gonzalez-Acosta, M:
CIBERONC, IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Ave Gran Via Hospitalet,199-203, Lhospitalet De Llobregat 08908, Spain
Thompson, B:
Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT USA
Univ Melbourne, Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia
Gomez, C:
CIBERONC, IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Ave Gran Via Hospitalet,199-203, Lhospitalet De Llobregat 08908, Spain
Fernandez, A:
CIBERONC, IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Ave Gran Via Hospitalet,199-203, Lhospitalet De Llobregat 08908, Spain
:
CIBERONC, IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Ave Gran Via Hospitalet,199-203, Lhospitalet De Llobregat 08908, Spain
Pons, T:
Spanish Natl Canc Res Ctr CNIO, Struct Biol & Biocomp Program, Madrid, Spain
Morak, M:
Klinikum Univ Munchen, Germany MGZ Med Genet Zentrum, Med Klin & Poliklin 4, Campus Innenstadt,Ziemssenstr, Munich, Germany
MGZ Med Genet Zentrum, Munich, Germany
del Valle, J:
CIBERONC, IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Ave Gran Via Hospitalet,199-203, Lhospitalet De Llobregat 08908, Spain
Iglesias, S:
CIBERONC, IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Ave Gran Via Hospitalet,199-203, Lhospitalet De Llobregat 08908, Spain
Velasco, A:
IdIBGI, Catalan Inst Oncol, Hereditary Canc Program, Girona, Spain
Solanes, A:
Hosp Badalona Germans Trias & Pujol, Catalan Inst Oncol, Hereditary Canc Program, Badalona, Spain
Sanjuan, X:
Hosp Univ Bellvitge IDIBELL, Pathol Dept, Barcelona, Spain
Padilla, N:
UAB, VHIR, Res Unit Translat Bioinformat, Barcelona, Spain
de la Cruz, X:
UAB, VHIR, Res Unit Translat Bioinformat, Barcelona, Spain
ICREA, Barcelona, Spain
Valencia, A:
Spanish Natl Canc Res Ctr CNIO, Struct Biol & Biocomp Program, Madrid, Spain
Holinski-Feder, E:
Klinikum Univ Munchen, Germany MGZ Med Genet Zentrum, Med Klin & Poliklin 4, Campus Innenstadt,Ziemssenstr, Munich, Germany
MGZ Med Genet Zentrum, Munich, Germany
Brunet, J:
IdIBGI, Catalan Inst Oncol, Hereditary Canc Program, Girona, Spain
Feliubadalo, L:
CIBERONC, IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Ave Gran Via Hospitalet,199-203, Lhospitalet De Llobregat 08908, Spain
Lazaro, C:
CIBERONC, IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Ave Gran Via Hospitalet,199-203, Lhospitalet De Llobregat 08908, Spain
Navarro, M:
CIBERONC, IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Ave Gran Via Hospitalet,199-203, Lhospitalet De Llobregat 08908, Spain
Hosp Badalona Germans Trias & Pujol, Catalan Inst Oncol, Hereditary Canc Program, Badalona, Spain
Pineda, M:
CIBERONC, IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Ave Gran Via Hospitalet,199-203, Lhospitalet De Llobregat 08908, Spain
Capella, G:
CIBERONC, IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Ave Gran Via Hospitalet,199-203, Lhospitalet De Llobregat 08908, Spain
Bronze, Green Published
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