Clinical and histopathologic characterization of SETD2-mutated colorectal cancer

With the advent of next-generation sequencing (NGS), identifying and better understanding genetic mutations in cancer pathways has become more feasible. A mutation now commonly reported in NGS panels is the SETD2 gene (H3K36 trimethyltransferase). However, its contributions to colorectal cancer (CRC) are not well described. In this study, we describe the clinicopathologic characteristics of SETD2-mutated CRC, determine common mutation sites on the SETD2 gene, and correlate these mutations with the loss of H3K36 trimethylation and the aberrant expression of beta-catenin. By searching pathology reports at our institution which included the 161-gene NGS panel from 2019 to 2021, we identify 24 individuals with SETD2-mutated CRC. All samples were evaluated for microsatellite status, H3K36 trimethylation, and beta-catenin via immunohistochemistry. In this cohort of 24 SETD2-mutated CRC individuals (a median age of 62.4 years [interquartile range: 49.1-73.6]), 10 (41.7%) patients presented at American Joint Committee on Cancer (AJCC) tumor stage II, seven (29.2%) at stage III, six (25%) at stage IV, and one (4.2%) at stage I. Most tumors studied were adenocarcinomas with no further specification (22, 92%), and most tumors were microsatellite stable (18, 82.5%). Thirty-three mutation locations were represented by 24 patients, with one patient having six mutations in the SETD2 gene and two patients having three mutations. The dominant mutation type is missense mutations (N = 29, 87.9%), and no mutation hotspots were found. Only two samples lost trimethylation of histone H3K36, both from individuals with multiple SETD2 mutations and aberrant nuclear beta-catenin expression. SETD2-mutated CRC is similar in clinical and histologic presentation to other commonly reported CRC. SETD2 mutations were missense dominantand showed no hotspots, and multiple mutations are likely necessary for loss of H3K36 trimethylation. These results warrant further study on determining a role of SETD2-histone H3K36 pathway in CRC.