Contribution of bi-allelic germline MUTYH mutations to early-onset and familial colorectal cancer and to low number of adenomatous polyps: case-series and literature review

In the absence of a polyposis phenotype, colorectal cancer (CRC) patients referred for genetic testing because of early-onset disease and/or a positive family history, typically undergo testing for molecular signs of Lynch syndrome in their tumors. In the absence of these signs, DNA testing for germline mutations associated with other known tumor syndromes is usually not performed. However, a few studies in large series of CRC patients suggest that in a small percentage of CRC cases, bi-allelic MUTYH germline mutations can be found in the absence of the MUTYH -associated polyposis phenotype. This has not been studied in the Dutch population. Therefore, we analyzed the MUTYH gene for mutations in 89 patients with microsatellite-low or stable CRC cancer diagnosed before the age of 40 years or otherwise meeting the Bethesda criteria, all of them without a polyposis phenotype. In addition, we studied a series of 693 non-CRC patients with 1–13 adenomatous colorectal polyps for the MUTYH hotspot mutations Y179C, G396D and P405L. No bi-allelic MUTYH mutations were observed. Our data suggest that the contribution of bi-allelic MUTYH mutations to the development of CRC in Dutch non-polyposis patients that meet clinical genetic referral criteria, and to the development of low number of colorectal adenomas in non-CRC patients, is likely to be low.