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Comprehensive Constitutional Genetic and Epigenetic Characterization of Lynch-Like Individuals

1
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
2
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
3
High Risk and Cancer Prevention Group, Vall d’Hebron Institute of Oncology (VHIO), Carrer de Natzaret 115-117, 08035 Barcelona, Spain
4
Medical Oncology Department, Hospital de Santa Creu i Sant Pau, Carrer de Sant Quintí 89, 08041 Barcelona, Spain
5
Genetic Counseling Unit, Hospital Arnau de Vilanova, Avinguda Alcalde Rovira Roure 80, 25198 Lleida, Spain
6
Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Building 181 Grattan St, VIC 3010 Melbourne, Australia
7
Hereditary Cancer Program, Catalan Institute of Oncology, Institut d’Investigació Biomèdica de Girona (IDIBGI), Carrer del Dr. Castany s/n, 17190 Salt, Girona, Spain
8
Pathology Department, Hospital Arnau de Vilanova, Institut de Recerca Biomèdica de Lleida (IRB Lleida), Avinguda Alcalde Rovira Roure 80, 25198 Lleida, Spain
9
Pathology Department, Bellvitge University Hospital, Insititut d’Investigació Biomèdica de Bellvitge (IDIBELL), Carrer de la Feixa Llarga s/n, 08907 L’Hospitalet de Llobregat, Barcelona, Spain
10
Department of Medical Sciences, School of Medicine, University of Girona, Carrer Emili Grahit 77, 17003 Girona, Spain
*
Authors to whom correspondence should be addressed.
Cancers 2020, 12(7), 1799; https://doi.org/10.3390/cancers12071799
Received: 4 May 2020 / Revised: 27 June 2020 / Accepted: 2 July 2020 / Published: 5 July 2020
(This article belongs to the Special Issue Lynch Syndrome)
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. View Full-Text
Keywords: Lynch syndrome; Lynch-like syndrome; variant of unknown significance; epimutation; mismatch repair; methylation; cancer genes panel; next generation sequencing Lynch syndrome; Lynch-like syndrome; variant of unknown significance; epimutation; mismatch repair; methylation; cancer genes panel; next generation sequencing
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Dámaso, E.; González-Acosta, M.; Vargas-Parra, G.; Navarro, M.; Balmaña, J.; Ramon y Cajal, T.; Tuset, N.; Thompson, B.A.; Marín, F.; Fernández, A.; Gómez, C.; Velasco, À.; Solanes, A.; Iglesias, S.; Urgel, G.; López, C.; del Valle, J.; Campos, O.; Santacana, M.; Matias-Guiu, X.; Lázaro, C.; Valle, L.; Brunet, J.; Pineda, M.; Capellá, G. Comprehensive Constitutional Genetic and Epigenetic Characterization of Lynch-Like Individuals. Cancers 2020, 12, 1799.

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