We report a MUTYH variant, p.C306W (c.918C>G), with a tryptophan residue in place of native cysteine, that ligates the [4Fe4S] cluster in a patient with colonic polyposis and family history of early age colon cancer.
From the Colon Cancer Family Registry, we identified 10 carriers who had both a MUTYH mutation (6 with c.1187G>A p.(Gly396Asp), 3 with c.821G>A p.(Arg274Gln), and 1 with c.536A>G p.(Tyr179Cys)) and a MMR gene mutation (3 in MLH1, 6 in MSH2, and 1 in PMS2), 375 carriers of a single (monoallelic) MUTYH mutation alone, and 469 carriers of a MMR gene mutation alone.
Despite the relatively small sample size of the current study, our findings suggest that the MAP is not a frequent cause of colon cancer in Morocco as we had expected, and the molecular analysis of MYH gene should be restricted to patients displaying the classical phenotype of MAP.
In blinded specimens and colon cancer cell lines with defined mutations, ColoSeq correctly identified 28/28 (100%) pathogenic mutations in MLH1, MSH2, MSH6, PMS2, EPCAM, APC, and MUTYH, including single nucleotide variants (SNVs), small insertions and deletions, and large copy number variants.
Biallelic MUTYH exon 7 and 13 mutations are associated with a high frequency of somatic K-ras gene guanine to thymine transversion mutations at codon 12 position 1 in MUTYH-associated polyposis patients who have increased risk of colon cancer.
The ORs for the MUTYHGln324His and the APEX1 Asp148Glu were statistically significant for colon cancer (adjusted OR 3.95, 95%CI 1.28-12.20, p = 0.017 for MUTYHGln324His ; adjusted OR 3.04, 95%CI 1.38-6.71, p = 0.006 for APEX1 Asp148Glu).
Case-control studies of genetic polymorphisms in DNA repair enzymes suggest that the common variant Ser326Cys in OGG1 may be a risk factor for lung cancer, whereas a rare variant in OGG1 and germ line mutations in the corresponding mismatch repair gene MYH are risk factors for hereditary colon cancer.