title: Mutations in POLE and survival of colorectal cancer patients--link to disease stage and treatment.
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.
authors.affiliation: Institute of Pathology, Heidelberg University Hospital, Germany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Stenzinger
authors.forename: Nicole
authors.initials: N
authors.lastname: Pfarr
authors.forename: Volker
authors.initials: V
authors.lastname: Endris
authors.forename: Roland
authors.initials: R
authors.lastname: Penzel
authors.forename: Lina
authors.initials: L
authors.lastname: Jansen
authors.forename: Thomas
authors.initials: T
authors.lastname: Wolf
authors.forename: Esther
authors.initials: E
authors.lastname: Herpel
authors.forename: Arne
authors.initials: A
authors.lastname: Warth
authors.forename: Frederick
authors.initials: F
authors.lastname: Klauschen
authors.forename: Matthias
authors.initials: M
authors.lastname: Kloor
authors.forename: Wilfried
authors.initials: W
authors.lastname: Roth
authors.forename: Hendrik
authors.initials: H
authors.lastname: Bläker
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
authors.forename: Michael
authors.initials: M
authors.lastname: Hoffmeister
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D004257:DNA Polymerase II / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005858:Germany / Q000453:epidemiology; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D009154:Mutation; D009367:Neoplasm Staging; D000075223:Poly-ADP-Ribose Binding Proteins; D011379:Prognosis; D016019:Survival Analysis
chemical_list: D000075223:Poly-ADP-Ribose Binding Proteins; D004257:DNA Polymerase II; C119525:POLE protein, human
keywords: Colorectal cancer; DACHS; MSS; POLE; mutation; polymerase ϵ; ultramutator phenotype