Prevalence of MUTYH Monoallelic Variants in Patients With Hereditary Cancer Using Multigene Panel Testing

The MUTYH gene is involved in DNA repair and is known for MAP (MUTYH-associated polyposis), an autosomal recessive disorder that predisposes individuals to colorectal cancer (CRC), with a lifetime risk ranging from 40% to 90%. Homozygosity or double heterozygosity (DH) for pathogenic variants (PVs) in MUTYH causes MAP, but several studies suggest that monoallelic PVs may also increase cancer risk, mainly CRC and breast cancer (BC).

We analyzed MUTYH status in a cohort of 130 patients referred to our familial cancer clinic for suspected hereditary cancer, describing their mutations and clinical features, and comparing the MUTYH mutation rate between our cancer cohort and a group of 150 healthy volunteers. We also described the genetic profile and clinical features of probands relatives, when possible.

10% of our cancer patients carried a MUTYH PV, while the gene was wild type in all the samples from the control group. The most frequent PVs were c.1187G>A (p.Gly396Asp) and c.536A>G (p.Tyr179cys). We found a double mutation (DM) in 6 patients, with one carrying a DM in MUTYH and the other 5 harboring mutations in MUTYH and other cancer susceptibility genes (CHEK2, BRIP1, MLH1, and BRCA1).

The higher MUTYH mutation rate observed in the cancer cohort compared with the control group; cancer recurrence observed in the heterozygous carriers and in both maternal and paternal family branches of patients harboring a DM suggests that MUTYH PVs may play a role in cancer predisposition and progression, even when monoallelic.