We provide an overview of newly described genes and syndromes associated with predisposition to CRC and polyposis, including: polymerase proofreading-associated polyposis, NTHL1-associated polyposis, mismatch repair gene biallelic inactivation-related adenomatous polyposis (including MSH3- and MLH3-associated polyposes), GREM1-associated mixed polyposis, RNF43-associated serrated polyposis, and RPS20 mutations as a rare cause of hereditary nonpolyposis CRC.
In comparison to the non-obese controls, we observed significant DMRs in CRC for genes involved in tumorigenesis including <i>MLH3, MSH2</i>, <i>MSH6, SEPT9, GNAS</i>; and glucose transporter genes associated with obesity and diabetes including <i>SLC2A1/GLUT1,</i> and <i>SLC2A3/GLUT3</i> that were reported on methylation being modified in cancer tissues.
Lynch syndrome is one of the most common hereditary colorectal cancer (CRC) syndrome and is caused by germline mutations of MLH1, MSH2 and more rarely MSH6, PMS2, MLH3 genes.
Our different biochemical assays yielded no evidence that the eight MLH3 UVs tested are the cause of hereditary colorectal cancer, including Lynch syndrome.
MLH3 has been assumed to be less important in MMR than the other HNPCC susceptibility genes MSH2, MSH6, MLH1, and PMS2, and accordingly a low-risk gene for colorectal cancer (CRC).
Germ line and somatic mutations in MLH3 have been identified in a small fraction of colorectal cancers, but the role of MLH3 in colorectal cancer tumorigenesis remains controversial.
While our analyses do not exclude the existence of germline MLH3 mutations in patients with increased genetic risk factors for colorectal cancer susceptibility, they suggest such mutations are uncommon in this patient population.