Background: Recent molecular profiling studies reported a new class of ultramutated colorectal cancers (CRC), which are likely caused by exonuclease domain (END) mutations in DNA polymerase ϵ (POLE). However, data on the clinical implications of these biological findings as to whether these mutations in analogy to endometrial cancer define a unique CRC entity with distinct clinical outcome is entirely lacking.

Methods: We performed Sanger sequencing of the POLE END in 431 well annotated microsatellite stable (MSS) CRCs of a population-based epidemiological case-control study (DACHS). Mutation data were correlated with major epidemiological, clinical, genetic and pathological parameters including overall and disease-specific survival.

Results: In 373 out of 431 MSS CRC all exons of POLE END were analyzable. 47 mutations in the END of POLE were identifiable in 41 of these samples (11%). Besides already reported mutations affecting the codons 459, 411 and 286, we found many new mutations in exons 13 and 14 (corresponding to codons 411-491 of the END) as well as in exon 12 (corresponding to codons 268-301 of the END), which have not been reported yet. However, we found no associations of POLE END mutations with clinicopathological parameters, including sex, age, tumor location and tumor stage, CIMP, RAS and BRAF mutations. Survival analysis by cox regression revealed adjusted (for sex, age, tumor location and therapy) HRs of 1.38 and 1.44 for disease-specific and overall survival indicating slightly impaired survival of patients with mutations in POLE END, however, these differences were not statistically significant. This was also true for the subgroups of different exons, known/new, potentially damaging/non-damaging mutations and the type of mutation.

Conclusions: In contrast to endometrial cancer, somatic POLE mutations do not appear to define a clinically strongly distinct disease entity in CRC.

Citation Format: Albrecht Stenzinger, Endris Volker, Nicole Pfarr, Roland Penzel, Lina Jansen, Esther Herpel, Wilfried Roth, Hendrik Bläker, Jenny Chang-Claude, Hermann Brenner, Michael Hoffmeister, Wilko Weichert. Mutations in polymerase ϵ as key molecular alteration of the novel ultramutator phenotype do not define a clinically distinct entity of colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1891. doi:10.1158/1538-7445.AM2014-1891