Abstract
Recent molecular profiling studies reported a new class of ultramutated colorectal cancers (CRCs), which are caused by exonuclease domain mutations (EDMs) in DNA polymerase ε (POLE). Data on the clinical implications of these findings as to whether these mutations define a unique CRC entity with distinct clinical outcome are lacking. We performed Sanger sequencing of the POLE exonuclease domain in 431 well-characterized patients with microsatellite stable (MSS) CRCs of a population-based patient cohort. Mutation data were analyzed for associations with major epidemiological, clinical, genetic, and pathological parameters including overall survival (OS) and disease-specific survival (DSS). In 373 of 431 MSS CRC, all exons of the exonuclease domain were analyzable. Fifty-four mutations were identified in 46 of these samples (12.3%). Besides already reported EDMs, we detected many new mutations in exons 13 and 14 (corresponding to amino acids 410–491) as well as in exon 9 and exon 11 (corresponding to aa 268–303 and aa 341–369). However, we did not see any significant associations of EDMs with clinicopathological parameters, including sex, age, tumor location and tumor stage, CIMP, KRAS, and BRAF mutations. While with a median follow-up time of 5.0 years, survival analysis of the whole cohort revealed nonsignificantly different adjusted hazard ratios (HRs) of 1.35 (95% CI: 0.82–2.25) and 1.44 (0.81–2.58) for OS and DSS indicating slightly impaired survival of patients with EDMs, subgroup analysis for patients with stage III/IV disease receiving chemotherapy revealed a statistically significantly increased adjusted HR (1.87; 95%CI: 1.02–3.44). In conclusion, POLE EDMs do not appear to define an entirely new clinically distinct disease entity in CRC but may have prognostic or predictive implications in CRC subgroups, whose significance remains to be investigated in future studies.
Highlights
Colorectal cancer (CRC) is the third most common cancer in men and the second most common cancer in women worldwide
Recent molecular profiling studies reported a new class of ultramutated colorectal cancers (CRCs), which are caused by exonuclease domain mutations (EDMs) in DNA polymerase e (POLE)
About 10–15% of CRCs arise through loss of function of DNA mismatch repair (MMR) genes leading to an inability to correct base mismatches, as well as insertions and deletions during DNA replication at repetitive sequences resulting in a hypermutation phenotype
Summary
Colorectal cancer (CRC) is the third most common cancer in men and the second most common cancer in women worldwide. Patients with high-frequency MSI follow a distinct clinical cause with significantly improved prognosis compared to microsatellite stable (MSS) tumors and potential differences in the response to chemotherapeutic agents [5] Besides these two major molecular types of CRC, two other well-defined alternative routes for CRC development have been described as follows: homozygous germline inactivation of the base excision repair gene mutY homologue (MUTYH) leading to a polyposis phenotype and the concomitant methylation of many gene loci resulting in the CpG island methylator phenotype (CIMP) [6]. While looking for potential molecular mechanisms driving genomic instability in these tumors, they identified recurrent somatic missense mutations in POLE as a likely cause Their suggestion of a causal role of POLE mutations in the constitution of an ultramutator phenotype CRC was backed by previous observations in mice being homozygous for a mutation in POLE that inactivates exonuclease activity. We investigated the type and frequency of POLE mutations in patients with MSS CRC of a well characterized population-based patient cohort study and analyzed the associations between the mutation status and all major CRC-related epidemiological, pathological, genetic and clinical parameters, including overall survival (OS) and disease-specific survival (DSS)
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