Abstract
Germline variants in the APC gene cause familial adenomatous polyposis. Inherited variants in MutYH, POLE, POLD1, NTHL1, and MSH3 genes and somatic APC mosaicism have been reported as alternative causes of polyposis. However, ~30–50% of cases of polyposis remain genetically unsolved. Thus, the aim of this study was to investigate the genetic causes of unexplained adenomatous polyposis. Eight sporadic cases with >20 adenomatous polyps by 35 years of age or >50 adenomatous polyps by 55 years of age, and no causative germline variants in APC and/or MutYH, were enrolled from a cohort of 56 subjects with adenomatous colorectal polyposis. APC gene mosaicism was investigated on DNA from colonic adenomas by Sanger sequencing or Whole Exome Sequencing (WES). Mosaicism extension to other tissues (peripheral blood, saliva, hair follicles) was evaluated using Sanger sequencing and/or digital PCR. APC second hit was investigated in adenomas from mosaic patients. WES was performed on DNA from peripheral blood to identify additional polyposis candidate variants. We identified APC mosaicism in 50% of patients. In three cases mosaicism was restricted to the colon, while in one it also extended to the duodenum and saliva. One patient without APC mosaicism, carrying an APC in-frame deletion of uncertain significance, was found to harbor rare germline variants in OGG1, POLQ, and EXO1 genes. In conclusion, our restrictive selection criteria improved the detection of mosaic APC patients. In addition, we showed for the first time that an oligogenic inheritance of rare variants might have a cooperative role in sporadic colorectal polyposis onset.
Highlights
IntroductionMalpighi Hospital, University of Bologna, Bologna, Italy 5 Pathology Unit, S
1% of all the colorectal cancer (CRC) cases are due to familial adenomatous polyposis (FAP), an autosomal dominant CRC predisposition syndrome with a Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Bologna, Bologna, Italy 4 Center for Applied Biomedical Research (CRBA), S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy 5 Pathology Unit, S
To identify whether patients with Adenomatous Polyposis Coli (APC) mosaicism harbored a second hit in the APC gene, we first analyzed hot spot codons for somatic inactivating variants, finding a second hit in three out of four patients
Summary
Malpighi Hospital, University of Bologna, Bologna, Italy 5 Pathology Unit, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy 6 Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy chromosome region 5q21–22 [4]. Most inactivating APC germline variants are frameshift or nonsense; in addition, the APC gene could be inactivated through promoter hypermethylation or large deletions [6, 7]. A high frequency of de novo APC variants (10–25%), generally affecting the “mutation cluster region”(MCR; codons 1286–1513) [6], has been reported in FAP patients [8, 9]. Somatic mosaicism in the APC gene has been described in a small subset of FAP cases [10,11,12]
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