The Clinicopathological Characteristics of POLE-mutated Colorectal Cancer and the Prognostic Value of POLE Status

Sir — Colorectal cancer (CRC) is one of the major causes of cancer-related morbidity and mortality worldwide [ [1] Sung H. Ferlay J. Siegel R.L. Laversanne M. Soerjomataram I. Jemal A. et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021; 71: 209-249https://doi.org/10.3322/caac.21660 Crossref PubMed Scopus (39195) Google Scholar ]. The Cancer Genome Atlas first identified the molecular cohort of POLE-mutated (POLEmut) in CRC [ [2] Cancer Genome Atlas NetworkComprehensive molecular characterization of human colon and rectal cancer. Nature. 2012; 487: 330-337https://doi.org/10.1038/nature11252 Crossref PubMed Scopus (6153) Google Scholar ]. It has been reported that patients with endometrial cancer and glioblastoma harbouring POLEmut exhibited excellent prognosis [ [3] Mehnert J.M. Panda A. Zhong H. Hirshfield K. Damare S. Lane K. et al. Immune activation and response to pembrolizumab in POLE-mutant endometrial cancer. J Clin Invest. 2016; 126: 2334-2340https://doi.org/10.1172/JCI84940 Crossref PubMed Scopus (283) Google Scholar , [4] Johanns T.M. Miller C.A. Dorward I.G. Tsien C. Chang E. Perry A. et al. Immunogenomics of hypermutated glioblastoma: a patient with germline POLE deficiency treated with checkpoint blockade immunotherapy. Cancer Discov. 2016; 6: 1230-1236https://doi.org/10.1158/2159-8290.CD-16-0575 Crossref PubMed Scopus (221) Google Scholar ]. In addition, an extraordinary response to immune checkpoint inhibitor was found in POLEmut endometrial cancers [ [5] Temko D. Van Gool I.C. Rayner E. Glaire M. Makino S. Brown M. et al. Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response. J Pathol. 2018; 245: 283-296https://doi.org/10.1002/path.5081 Crossref PubMed Scopus (62) Google Scholar ]. However, the clinicopathological characteristics and clinical outcomes of POLEmut CRC remain unclear. Therefore, we carried out a comprehensive survey on a large scale (27 cohorts incorporating 15 192 CRC patients) and multiple levels (including 12 subgroups) to investigate the clinicopathological characteristics of POLEmut CRC and to evaluate the prognostic value.