Article (Scientific journals)
Contribution of New Adenomatous Polyposis Predisposition Genes in an Unexplained Attenuated Spanish Cohort by Multigene Panel Testing
Lorca, Victor; Rueda, Daniel; Martin Morales, Lorena et al.
2019In Scientific Reports, 9 (1), p. 9814
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Keywords :
Cancer genetics; Genetic testing; Colorectal cancer
Abstract :
[en] Attenuated adenomatous polyposis (AAP) is a heterogeneous syndrome in terms of clinical manifestations, heritability and etiology of the disease. Genetic heterogeneity and low penetrance alleles are probably the best explanation for this variability. Certainly, it is known that APC and MUTYH are high penetrance predisposition genes for adenomatous polyposis, but they only account for 5-10% of AAP. Other new predisposition genes, such as POLE, POLD1, NTHL1, AXIN2 or MSH3, have been recently described and have been associated with AAP, but their relative contribution is still not well defined. In order to evaluate the genetic predisposition to AAP in a hospital based population, germline DNAs from 158 AAP subjects were screened for genetic variants in the coding regions and intron-exon boundaries of seven associated genes through a next-generation sequencing (NGS) custom gene panel. Splicing, segregation studies, somatic mutational screening and RNA quantitative expression assays were conducted for selected variants. In four of the probands the adenoma susceptibility could be explained by actionable mutations in APC or MUTYH, and one other patient was a double carrier of two truncating variants in both POLE and NTHL1. Furthermore, 16 additional patients harbored uncertain significance variants in the remaining tested genes. This report gives information about the contribution of the newly described adenomatous polyposis predisposition genes in a Spanish attenuated polyposis cohort. Our results highly support the convenience of NGS multigene panels for attenuated polyposis genetic screening and reveals POLE frameshift variants as a plausible susceptibility mechanism for AAP.
Disciplines :
Oncology
Genetics & genetic processes
Author, co-author :
Lorca, Victor;  Hospital Clínico San Carlos > Medical Oncology > Molecular Oncology Laboratory
Rueda, Daniel;  Hospital 12 de Octubre > Biochemistry > Hereditary Cancer Laboratory
Martin Morales, Lorena  ;  Université de Liège - ULiège > GIGA Stem Cells - Cancer Signaling
Fernandez-Aceñero, Maria Jesus;  Hospital Clínico San Carlos > Anatomical Pathology
Grolleman, Judith;  Radboud University Medical Center > Department of Human Genetics
Poves, Carmen;  Hospital Clínico San Carlos > Digestive System
Llovet, Patricia;  Hospital Clínico San Carlos Medical Oncology Molecular Oncology Laboratory > Medical Oncology > Molecular Oncology Laboratory
Tapial, Sandra;  Hospital 12 de Octubre > Biochemistry > Hereditary Cancer Laboratory
Garcia-Barberan, Vanesa;  Hospital Clínico San Carlos > Medical Oncology > Molecular Oncology Laboratory
Sanz, Julio;  Hospital Clínico San Carlos > Anatomical Pathology
Perez-Segura, Pedro;  Hospital Clínico San Carlos > Medical Oncology
de Voer, Ricarda M;  Radboud University Medical Center > Department of Human Genetics
Diaz-Rubio, Eduardo;  Hospital Clínico San Carlos > Medical Oncology
de la Hoya, Miguel;  Hospital Clínico San Carlos > Medical Oncology > Molecular Oncology Laboratory
Caldes, Trinidad;  Hospital Clínico San Carlos > Medical Oncology > Molecular Oncology Laboratory
Garre, Pilar;  Hospital Clínico San Carlos > Medical Oncology > Molecular Oncology Laboratory
More authors (6 more) Less
Language :
English
Title :
Contribution of New Adenomatous Polyposis Predisposition Genes in an Unexplained Attenuated Spanish Cohort by Multigene Panel Testing
Publication date :
July 2019
Journal title :
Scientific Reports
eISSN :
2045-2322
Publisher :
Nature Publishing Group, London, United Kingdom
Volume :
9
Issue :
1
Pages :
9814
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 27 May 2021

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