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Background  Mutations in the  POLE  gene result in an ultra-hypermutated phenotype in colorectal cancer (CRC); however, the molecular characterisation of epigenetic alterations remains unclear. We examined the genetic and epigenetic profiles of  POLE -mutant CRC to elucidate the clinicopathological features of the associated genetic and epigenetic alterations.    Results  Tumour tissues (1,013) obtained from a cohort of patients with CRC were analysed to determine associations between the proofreading domain mutations of  POLE  with various clinicopathological variables, microsatellite instability (MSI) status,  BRAF  and  KRAS  mutations, and the methylation status of key regions of  MLH1 ,  MGMT , and  SFRP2  promoters by calculating the methylation scores (range 0–6). Only four cases (0.4%) exhibited pathogenic  POLE  hotspot mutations (two p.P286R [c.857C > G], one p.V411L [c.1231G > C], and p.S459F [c.1376C > T] each), which were mutually exclusive to  BRAF  and  KRAS  mutations and MSI. CRC patients were divided into four subgroups: patients with  POLE  mutations (POLE, 0.4%,  n  = 4), patients with both MSI and extensive methylation in  MLH1  (MSI-M, 2.9%,  n  = 29), patients with MSI but no extensive methylation in  MLH1  (MSI-U, 3.6%,  n  = 36), and patients without MSI (non-MSI, 93.2%,  n  = 944). The POLE group was younger at diagnosis (median 52 years,  P  < 0.0001), with frequent right-sided tumour localisation (frequency of tumours located in the right colon was 100%, 93.1%, 36.1%, and 29.9% in POLE, MSI-M, MSI-U, and non-MSI, respectively;  P  < 0.0001), and was diagnosed at an earlier stage (frequency of stages I–II was 100%, 72.4%, 77.8%, and 46.6% in POLE, MSI-M, MSI-U, and non-MSI, respectively,  P  < 0.0001). The mean methylation score in POLE was not different from that in MSI-U and non-MSI, but the methylation signature was distinct from that of the other subgroups. Additionally, although the examined number of  POLE -mutant tumours was small, the number of CD8-positive cells increased in tumours with partial methylation in the  MLH1  gene.    Conclusions  CRC patients with  POLE  proofreading mutations are rare. Such mutations are observed in younger individuals, and tumours are primarily located in the right colon. Diagnosis occurs at an earlier stage, and distinct epigenetic alterations may be associated with CD8 cell infiltration.    Supplementary Information  The online version contains supplementary material available at 10.1186/s13148-021-01104-7.

Clinical and epigenetic features of colorectal cancer patients with somatic POLE proofreading mutations