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Article

Germline and Somatic Whole-Exome Sequencing Identifies New Candidate Genes Involved in Familial Predisposition to Serrated Polyposis Syndrome

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Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Gastroenterology Department, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, 08036 Barcelona, Spain
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Moores Cancer Center, Department of Cellular and Molecular Medicine, Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA
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Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Pathology Department, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Tumor Bank-Biobank, Hospital Clínic, 08036 Barcelona, Spain
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Genetics Unit, Hospital Universitario de Móstoles, 28935 Madrid, Spain
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Gastroenterology Department, Hospital Donostia-Instituto Biodonostia, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Basque Country University (UPV/EHU), 20014 San Sebastián, Spain
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Gastroenterology Department, Complexo Hospitalario Universitario de Ourense, Instituto de Investigación Sanitaria Galicia Sur, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 32005 Ourense, Spain
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Digestive Disease Section, Hospital Universitario de Móstoles, 28935 Móstoles, Spain
*
Author to whom correspondence should be addressed.
Academic Editor: Luca Roncucci
Cancers 2021, 13(4), 929; https://doi.org/10.3390/cancers13040929
Received: 29 January 2021 / Revised: 18 February 2021 / Accepted: 19 February 2021 / Published: 23 February 2021
(This article belongs to the Special Issue New Insights into Colorectal Cancer)
Cancer is the second leading cause of death worldwide. Serrated polyposis syndrome (SPS) is characterized by the presence of serrated lesions in the colon and a higher colorectal cancer (CRC) risk. An important part of risk is due to the alteration of certain genes, which will be transmitted from one generation to another in the same family. Our main objective was to identify alterations of the human genome relevant to the hereditary predisposition to SPS, by focusing on families with several cases of this disease (familial SPS) and by using massive sequencing techniques to decode the genome. Our strategy allowed us to suggest the implication of 14 new genes in SPS predisposition. Identifying the inherited genetic factors involved in SPS can be useful to identify those families with medium-high CRC risk and, therefore, implement more targeted, intensive preventive measures for this group of patients.
The serrated polyposis syndrome (SPS) is the most common and yet underdiagnosed colorectal polyposis syndrome. It is characterized by multiple and/or large colonic serrated polyps and a higher associated risk for colorectal cancer (CRC). The main objective of this study was to identify new candidate genes involved in the germline predisposition to SPS/CRC. Thirty-nine SPS patients from 16 families (≥2 patients per family) were recruited without alterations in well-known hereditary CRC genes, and germline and somatic whole-exome sequencing were performed. Germline rare variants with plausible pathogenicity, located in genes involved in cancer development, senescence and epigenetic regulation were selected. Somatic mutational profiling and signature analysis was pursued in one sample per family, when possible. After data filtering, ANXA10, ASXL1, CFTR, DOT1L, HIC1, INO80, KLF3, MCM3AP, MCM8, PDLIM2, POLD1, TP53BP1, WNK2 and WRN were highlighted as the more promising candidate genes for SPS germline predisposition with potentially pathogenic variants shared within families. Somatic analysis characterized mutational profiles in advanced serrated polyps/tumors, revealing a high proportion of hypermutated samples, with a prevalence of clock-like mutational signatures in most samples and the presence of DNA mismatch repair-defective signatures in some cases. In conclusion, we identified new candidate genes to be involved in familial SPS. Further functional studies and replication in additional cohorts are required to confirm the selected candidates. View Full-Text
Keywords: serrated polyposis syndrome; genetic predisposition to disease; colorectal cancer; whole-exome sequencing; mutational signatures serrated polyposis syndrome; genetic predisposition to disease; colorectal cancer; whole-exome sequencing; mutational signatures
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MDPI and ACS Style

Soares de Lima, Y.; Arnau-Collell, C.; Díaz-Gay, M.; Bonjoch, L.; Franch-Expósito, S.; Muñoz, J.; Moreira, L.; Ocaña, T.; Cuatrecasas, M.; Herrera-Pariente, C.; Carballal, S.; Moreno, L.; Díaz de Bustamante, A.; Castells, A.; Bujanda, L.; Cubiella, J.; Rodríguez-Alcalde, D.; Balaguer, F.; Castellví-Bel, S. Germline and Somatic Whole-Exome Sequencing Identifies New Candidate Genes Involved in Familial Predisposition to Serrated Polyposis Syndrome. Cancers 2021, 13, 929. https://doi.org/10.3390/cancers13040929

AMA Style

Soares de Lima Y, Arnau-Collell C, Díaz-Gay M, Bonjoch L, Franch-Expósito S, Muñoz J, Moreira L, Ocaña T, Cuatrecasas M, Herrera-Pariente C, Carballal S, Moreno L, Díaz de Bustamante A, Castells A, Bujanda L, Cubiella J, Rodríguez-Alcalde D, Balaguer F, Castellví-Bel S. Germline and Somatic Whole-Exome Sequencing Identifies New Candidate Genes Involved in Familial Predisposition to Serrated Polyposis Syndrome. Cancers. 2021; 13(4):929. https://doi.org/10.3390/cancers13040929

Chicago/Turabian Style

Soares de Lima, Yasmin, Coral Arnau-Collell, Marcos Díaz-Gay, Laia Bonjoch, Sebastià Franch-Expósito, Jenifer Muñoz, Leticia Moreira, Teresa Ocaña, Miriam Cuatrecasas, Cristina Herrera-Pariente, Sabela Carballal, Lorena Moreno, Aránzazu Díaz de Bustamante, Antoni Castells, Luis Bujanda, Joaquín Cubiella, Daniel Rodríguez-Alcalde, Francesc Balaguer, and Sergi Castellví-Bel. 2021. "Germline and Somatic Whole-Exome Sequencing Identifies New Candidate Genes Involved in Familial Predisposition to Serrated Polyposis Syndrome" Cancers 13, no. 4: 929. https://doi.org/10.3390/cancers13040929

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