Exceptional Chemotherapy Response in Metastatic Colorectal Cancer Associated With Hyper-Indel-Hypermutated Cancer Genome and Comutation of <i>POLD1</i> and <i>MLH1</i>.

Abstract

A73-year-old woman with metastatic colon cancer experienced a complete response to chemotherapy with dose-intensified irinotecan that has been durable for 5 years. We sequenced her tumor and germ line DNA and looked for similar patterns in publicly available genomic data from patients with colorectal cancer. Tumor DNA was obtained from a biopsy before therapy, and germ line DNA was obtained from blood. Tumor and germline DNA were sequenced using a commercial panel with approximately 250 genes. Whole-genome amplification and exome sequencing were performed for <i>POLE</i> and <i>POLD1</i>. A <i>POLD1</i> mutation was confirmed by Sanger sequencing. The somatic mutation and clinical annotation data files from the colon (n = 461) and rectal (n = 171) adenocarcinoma data sets were downloaded from The Cancer Genome Atlas data portal and analyzed for patterns of mutations and clinical outcomes in patients with <i>POLE</i>- and/or <i>POLD1</i>-mutated tumors. The pattern of alterations included <i>APC</i> biallelic inactivation and microsatellite instability high (MSI-H) phenotype, with somatic inactivation of <i>MLH1</i> and hypermutation (estimated mutation rate > 200 per megabase). The extremely high mutation rate led us to investigate additional mechanisms for hypermutation, including loss of function of <i>POLE. POLE</i> was unaltered, but a related gene not typically associated with somatic mutation in colon cancer, <i>POLD1</i>, had a somatic mutation c.2171G>A[p.Gly724Glu]. Additionally, we noted that the high mutation rate was largely composed of dinucleotide deletions. A similar pattern of hypermutation (dinucleotide deletions, <i>POLD1</i> mutations, MSI-H) was found in tumors from The Cancer Genome Atlas. <i>POLD1</i> mutation with associated MSI-H and hyper-indel-hypermutated cancer genome characterizes a previously unrecognized variant of colon cancer that was found in this patient with an exceptional response to chemotherapy.