Abstract 356P
Background
MUTYH-associated polyposis (MAP) is a rare recessive condition typically characterized by the presence of 10-100 colorectal polyps and the elevated risk of colorectal cancer (CRC). CRCs arising in biallelic carriers of MUTYH mutation often contain KRAS G12C substitution and frequently arise without concomitant polyposis.
Methods
This study included 74 consecutive patients with colon polyposis and 3486 consecutive patients with CRC referred to the N.N. Petrov Institute of Oncology (St. Petersburg, Russia) for molecular testing. Normal DNA obtained from subjects with polyposis was analyzed by NGS using custom panel for hereditary cancer genes. CRC patients were screened for recurrent MUTYH pathogenic alleles p.Y179C, p.R245H and p.G396D. The status of the remaining allele in MUTYH-heterozygous CRC cases was analyzed by Sanger sequencing.
Results
Biallelic MUTYH mutations were identified in 8/74 (11%) patients with polyposis. MAP was the second most common hereditary polyposis syndrome after familial adenomatous polyposis (47/74, 64%), with Peutz-Jeghers syndrome being in the third place (3/74, 5%). MUTYH biallelic alterations were detected in 9/3486 (0.3%) consecutive CRC patients. Somatic KRAS G12C substitution was observed in 223/3486 (6%) CRCs. Germ-line MUTYH inactivation was identified in 7/223 (3%) KRAS G12C-positive CRCs vs. 2/3253 (0.06%) patients without this mutation (p < 0.00001).
Conclusions
Germ-line MUTYH biallelic mutations are significant contributors to the incidence of polyposis, while their impact in CRC morbidity is moderate. However, MUTYH gene analysis is highly feasible in CRC patients whose tumor harbors KRAS G12C substitution.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Russian Science Foundation, grant 20-15-00244.
Disclosure
All authors have declared no conflicts of interest.