Cancers (Jul 2020)
Comprehensive Constitutional Genetic and Epigenetic Characterization of Lynch-Like Individuals
- Estela Dámaso,
- Maribel González-Acosta,
- Gardenia Vargas-Parra,
- Matilde Navarro,
- Judith Balmaña,
- Teresa Ramon y Cajal,
- Noemí Tuset,
- Bryony A. Thompson,
- Fátima Marín,
- Anna Fernández,
- Carolina Gómez,
- Àngela Velasco,
- Ares Solanes,
- Sílvia Iglesias,
- Gisela Urgel,
- Consol López,
- Jesús del Valle,
- Olga Campos,
- Maria Santacana,
- Xavier Matias-Guiu,
- Conxi Lázaro,
- Laura Valle,
- Joan Brunet,
- Marta Pineda,
- Gabriel Capellá
Affiliations
- Estela Dámaso
- Hereditary Cancer Program, Catalan Institute of Oncology, Insititut d’Investigació Biomèdica de Bellvitge (IDIBELL), ONCOBELL Program, Avinguda de la Gran Via de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
- Maribel González-Acosta
- Hereditary Cancer Program, Catalan Institute of Oncology, Insititut d’Investigació Biomèdica de Bellvitge (IDIBELL), ONCOBELL Program, Avinguda de la Gran Via de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
- Gardenia Vargas-Parra
- Hereditary Cancer Program, Catalan Institute of Oncology, Insititut d’Investigació Biomèdica de Bellvitge (IDIBELL), ONCOBELL Program, Avinguda de la Gran Via de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
- Matilde Navarro
- Hereditary Cancer Program, Catalan Institute of Oncology, Insititut d’Investigació Biomèdica de Bellvitge (IDIBELL), ONCOBELL Program, Avinguda de la Gran Via de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
- Judith Balmaña
- High Risk and Cancer Prevention Group, Vall d’Hebron Institute of Oncology (VHIO), Carrer de Natzaret 115-117, 08035 Barcelona, Spain
- Teresa Ramon y Cajal
- Medical Oncology Department, Hospital de Santa Creu i Sant Pau, Carrer de Sant Quintí 89, 08041 Barcelona, Spain
- Noemí Tuset
- Genetic Counseling Unit, Hospital Arnau de Vilanova, Avinguda Alcalde Rovira Roure 80, 25198 Lleida, Spain
- Bryony A. Thompson
- Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Building 181 Grattan St, VIC 3010 Melbourne, Australia
- Fátima Marín
- Hereditary Cancer Program, Catalan Institute of Oncology, Insititut d’Investigació Biomèdica de Bellvitge (IDIBELL), ONCOBELL Program, Avinguda de la Gran Via de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
- Anna Fernández
- Hereditary Cancer Program, Catalan Institute of Oncology, Insititut d’Investigació Biomèdica de Bellvitge (IDIBELL), ONCOBELL Program, Avinguda de la Gran Via de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
- Carolina Gómez
- Hereditary Cancer Program, Catalan Institute of Oncology, Insititut d’Investigació Biomèdica de Bellvitge (IDIBELL), ONCOBELL Program, Avinguda de la Gran Via de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
- Àngela Velasco
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
- Ares Solanes
- Hereditary Cancer Program, Catalan Institute of Oncology, Insititut d’Investigació Biomèdica de Bellvitge (IDIBELL), ONCOBELL Program, Avinguda de la Gran Via de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
- Sílvia Iglesias
- Hereditary Cancer Program, Catalan Institute of Oncology, Insititut d’Investigació Biomèdica de Bellvitge (IDIBELL), ONCOBELL Program, Avinguda de la Gran Via de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
- Gisela Urgel
- Genetic Counseling Unit, Hospital Arnau de Vilanova, Avinguda Alcalde Rovira Roure 80, 25198 Lleida, Spain
- Consol López
- Medical Oncology Department, Hospital de Santa Creu i Sant Pau, Carrer de Sant Quintí 89, 08041 Barcelona, Spain
- Jesús del Valle
- Hereditary Cancer Program, Catalan Institute of Oncology, Insititut d’Investigació Biomèdica de Bellvitge (IDIBELL), ONCOBELL Program, Avinguda de la Gran Via de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
- Olga Campos
- Hereditary Cancer Program, Catalan Institute of Oncology, Insititut d’Investigació Biomèdica de Bellvitge (IDIBELL), ONCOBELL Program, Avinguda de la Gran Via de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
- Maria Santacana
- Pathology Department, Hospital Arnau de Vilanova, Institut de Recerca Biomèdica de Lleida (IRB Lleida), Avinguda Alcalde Rovira Roure 80, 25198 Lleida, Spain
- Xavier Matias-Guiu
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
- Conxi Lázaro
- Hereditary Cancer Program, Catalan Institute of Oncology, Insititut d’Investigació Biomèdica de Bellvitge (IDIBELL), ONCOBELL Program, Avinguda de la Gran Via de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
- Laura Valle
- Hereditary Cancer Program, Catalan Institute of Oncology, Insititut d’Investigació Biomèdica de Bellvitge (IDIBELL), ONCOBELL Program, Avinguda de la Gran Via de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
- Joan Brunet
- Hereditary Cancer Program, Catalan Institute of Oncology, Insititut d’Investigació Biomèdica de Bellvitge (IDIBELL), ONCOBELL Program, Avinguda de la Gran Via de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
- Marta Pineda
- Hereditary Cancer Program, Catalan Institute of Oncology, Insititut d’Investigació Biomèdica de Bellvitge (IDIBELL), ONCOBELL Program, Avinguda de la Gran Via de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
- Gabriel Capellá
- Hereditary Cancer Program, Catalan Institute of Oncology, Insititut d’Investigació Biomèdica de Bellvitge (IDIBELL), ONCOBELL Program, Avinguda de la Gran Via de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
- DOI
- https://doi.org/10.3390/cancers12071799
- Journal volume & issue
-
Vol. 12,
no. 7
p. 1799
Abstract
The causal mechanism for cancer predisposition in Lynch-like syndrome (LLS) remains unknown. Our aim was to elucidate the constitutional basis of mismatch repair (MMR) deficiency in LLS patients throughout a comprehensive (epi)genetic analysis. One hundred and fifteen LLS patients harboring MMR-deficient tumors and no germline MMR mutations were included. Mutational analysis of 26 colorectal cancer (CRC)-associated genes was performed. Pathogenicity of MMR variants was assessed by splicing and multifactorial likelihood analyses. Genome-wide methylome analysis was performed by the Infinium Human Methylation 450K Bead Chip. The multigene panel analysis revealed the presence of two MMR gene truncating mutations not previously found. Of a total of 15 additional MMR variants identified, five -present in 6 unrelated individuals- were reclassified as pathogenic. In addition, 13 predicted deleterious variants in other CRC-predisposing genes were found in 12 probands. Methylome analysis detected one constitutional MLH1 epimutation, but no additional differentially methylated regions were identified in LLS compared to LS patients or cancer-free individuals. In conclusion, the use of an ad-hoc designed gene panel combined with pathogenicity assessment of variants allowed the identification of deleterious MMR mutations as well as new LLS candidate causal genes. Constitutional epimutations in non-LS-associated genes are not responsible for LLS.
Keywords
- Lynch syndrome
- Lynch-like syndrome
- variant of unknown significance
- epimutation
- mismatch repair
- methylation