Somatic APCmosaicism and oligogenic inheritance in genetically unsolved colorectal adenomatous polyposis patients

Germline variants in the APCgene cause familial adenomatous polyposis. Inherited variants in MutYH, POLE, POLD1, NTHL1, and MSH3genes and somatic APCmosaicism 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 APCand/or MutYH, were enrolled from a cohort of 56 subjects with adenomatous colorectal polyposis. APCgene 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. APCsecond hit was investigated in adenomas from mosaic patients. WES was performed on DNA from peripheral blood to identify additional polyposis candidate variants. We identified APCmosaicism 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 APCmosaicism, carrying an APCin-frame deletion of uncertain significance, was found to harbor rare germline variants in OGG1, POLQ, and EXO1genes. In conclusion, our restrictive selection criteria improved the detection of mosaic APCpatients. 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.