MLH1-silenced and non-silenced subgroups of hypermutated colorectal carcinomas have distinct mutational landscapes.

摘要: Approximately 15% of colorectal carcinomas (CRC) exhibit a hypermutated genotype accompanied by high levels microsatellite instability (MSI-H) and defects in DNA mismatch repair. These tumors, unlike the majority carcinomas, are often diploid, frequent epigenetic silencing MLH1 repair gene, have better clinical prognosis. As an adjunct study to The Cancer Genome Atlas consortium that recently analyzed 224 cancers whole exome sequencing, we compared 35 CRC (15.6%) with those non-hypermutated genotype. We found 22 (63%) exhibited transcriptional frequency BRAF V600E gene mutations infrequent APC KRAS mutations, mutational pattern significantly different from their counterparts. However, remaining 13 (37%) lacked silencing, contained tumors highest mutation rates (“ultramutated” CRC), higher incidences but mutations. patterns were confirmed independent validation set 250 exome-sequenced CRC. Analysis mRNA microRNA expression signatures revealed had greatly reduced WNT signaling increased relative Our findings suggest include one subgroup fundamentally pathways malignancy than Examination status frequencies APC, KRAS, may provide useful diagnostic tool could supplement standard assays influence therapeutic decisions.