Contribution of New Adenomatous Polyposis Predisposition Genes in an Unexplained Attenuated Spanish Cohort by Multigene Panel Testing

• Published in: Scientific reports 2019-07, Vol.9 (1), p.9814-10, Article 9814
• Main Authors: Lorca, Víctor, Rueda, Daniel, Martín-Morales, Lorena, Fernández-Aceñero, María Jesús, Grolleman, Judith, Poves, Carmen, Llovet, Patricia, Tapial, Sandra, García-Barberán, Vanesa, Sanz, Julián, Pérez-Segura, Pedro, de Voer, Richarda M., Díaz-Rubio, Eduardo, de la Hoya, Miguel, Caldés, Trinidad, Garre, Pilar
• Format: Article
• Language: English
• Subjects: 45/22; 45/23; 45/29; 45/47; 45/77; 45/90; 631/208/2489/1512; 631/208/68; 692/4028/67/1504/1885; Adenoma; Adenomatous Polyposis Coli - genetics; Adult; Age; Aged; Aged, 80 and over; Cancer genetics; Cohort Studies; Colorectal cancer; DNA Mutational Analysis - methods; Etiology; Family medical history; Female; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Genes; Genetic counseling; Genetic diversity; Genetic Predisposition to Disease; Genetic screening; Genetic testing; Genetic variance; Genetics & genetic processes; Germ-Line Mutation; Génétique & processus génétiques; Heritability; Heterogeneity; High-Throughput Nucleotide Sequencing; Human health sciences; Humanities and Social Sciences; Humans; Laboratories; Life sciences; Male; Middle Aged; multidisciplinary; Mutation; Next-generation sequencing; Oncologie; Oncology; Patients; Pedigree; Penetrance; Polyps; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Sciences de la santé humaine; Sciences du vivant; Sequence Analysis, DNA; Sequence Analysis, RNA; Spain; Splicing; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-46403-5

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 MSH 3, 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.