Clinicopathological and mutational analyses of colorectal cancer with mutations in the POLE gene

Abstract

Here, we investigated the clinicopathological and mutation profiles of colorectal cancer (CRC) with POLE mutations. Whole‐exome sequencing was performed in 910 surgically resected primary CRCs. Tumors exceeding 500 counts of nonsynonymous single nucleotide variants (SNVs) were classified as hypermutators, whereas the remaining were classified as nonhypermutators. The hypermutators were subdivided into 2 groups. CRCs harboring more than 20% C‐to‐A and less than 3% C‐to‐G transversions were classified as POLE category tumors, whereas the remaining were classified as common‐hypermutators. Gene expression profiling (GEP) analysis was performed in 892 (98.0%) tumors. Fifty‐seven (6.3%) and 10 (1.1%) tumors were classified common‐hypermutators and POLE category tumors, respectively. POLE category tumors harbored a significantly higher SNV count than common‐hypermutators, and all POLE category tumors were associated with exonuclease domain mutations, such as P286R, F367C, V411L, and S297Y, in the POLE gene. Patients with POLE category tumors were significantly younger than those with nonhypermutators and common‐hypermutators. All POLE mutations in the early‐onset (age of onset ≤50 years old) POLE category (7 tumors) were P286R mutations. GEP analysis revealed that PD‐L1 and PD‐1 gene expression levels were significantly increased in both common‐hypermutators and POLE category tumors compared with those in nonhypermutators. CD8A expression was significantly upregulated in POLE category tumors compared with that in nonhypermutators. Thus, we concluded that CRCs with POLE proofreading deficiency had characteristics distinct from those of other CRCs. Analysis of POLE proofreading deficiency may be clinically significant for personalized management of CRCs.

Immune landscape and biomarkers for immuno-oncology in colorectal cancers

“…Domingo et al [56] analyzed the frequency of somatic POLE mutations in 6,517 CRCs, and POLE mutations were detected in 1% of CRCs. CRCs with POLE mutations are associated with younger age at diagnosis, male sex, and proximal location [55,56]. Both POLE mutation and MSI-H/MMR-D status were associated with reduced risk of recurrence in a retrospective study [56].…”

“…Three-quarters of TMB-H CRCs are MSI-H, and the remaining one-quarter are MSS with somatic mutations in proofreading genes, mainly polymerase ε (POLE) and polymerase δ (POLD) [53]. In mutation analysis, MSI-H tumors show an insertiondeletion (indel)-predominant pattern, while POLE mutants show a single nucleotide variation-predominant pattern [54,55]. Domingo et al [56] analyzed the frequency of somatic POLE mutations in 6,517 CRCs, and POLE mutations were detected in 1% of CRCs.…”

Ultra‐mutated colorectal cancer patients withPOLEdriver mutations exhibit distinct clinical patterns

“…We extracted the data from these two articles, as presented in Table 2. Data from the Japanese research, 10 which included 910 CRC patients, only included patients from Japan; the article from the Lancet pooling data from clinical trials included 6277 non-Asian CRC patients. 11 We can conclude from the pooled the data that patients with POLE driver mutations are younger than 55 years old and are diagnosed at earlier stages (Japanese research vs. Lancet pooling research: 80.00% vs. 69.70%).…”

Mutated DNA Damage Repair Pathways Are Prognostic and Chemosensitivity Markers for Resected Colorectal Cancer Liver Metastases

“…Mice embryo studies have shown synthetic lethality of HRR and NHEJ pathways ( 45 , 46 ). Defective variants in POLD1 and POLE , essential genes in the BER pathway, are related to significantly higher mutational burden and malignancy through BER’s correlation to the MMR pathway ( 47 ). Co-mutations in the MMR and HRR pathways may also be related to hypermutated CRC with worse survival, via interruption of DNA binding and replication ( 48 ).…”