Recent advances in whole exome sequencing have generated evidence for new CRC-susceptibility genes including POLE, POLD1 and NTHL1¸ but many patients remain unexplained.
Mutation analysis of POLE gene in patients with early-onset colorectal cancer revealed a rare silent variant within the endonuclease domain with potential effect on splicing.
Prominent POLE-deficient somatic mutational signatures were seen in the CRCs, but in contrast, a mutational signature typical of concomitant tumoral loss of POLE and mismatch-repair function (POLE-exo<sup>*</sup> /MSI) was noted in the breast cancer.
Eleven of the 132 study subjects (8.3%) carried either a POLD1 or a POLE mutation: 7 of 68 (10.3%) subjects with multiple colorectal adenomas and 4 of 64 (6.2%) subjects with early-onset mismatch repair proficient colorectal cancer.
Refinement of estimates of CRC risk for POLD1 carriers is needed; however, clinical management recommendations could follow those made for POLE carriers.
Collectively, these data indicate that somatic POLE mutations are early, quite possibly initiating, events in the endometrial and colorectal cancers in which they occur.
Recently, germline and somatic mutations in the exonuclease domain of polymerase epsilon, catalytic subunit (POLE) gene have been reported in a small subset of microsatellite-stable and hypermutated colorectal carcinomas (CRCs), affecting the proofreading activity of the enzyme and leading to misincorporation of bases during DNA replication.
Mutations in the POLD1 and POLE genes encoding DNA polymerases δ (Polδ) and ɛ (Polɛ) cause hereditary colorectal cancer (CRC) and have been found in many sporadic colorectal and endometrial tumors.
In this study, using a multigene panel, we detected KRAS, NRAS, BRAF, PIK3CA, TP53, and POLE mutations in 90 CRCs and investigated their associations with clinicopathological parameters, including TB.
In addition to the POLEp.L424V recurrent mutation in a patient with polyposis, CRC and oligodendroglioma, six novel or rare POLD1 variants (four of them, p.D316H, p.D316G, p.R409W, and p.L474P, with strong evidence for pathogenicity) were identified in nonpolyposis CRC families.
The somatic POLEP286R mutation defines a unique subclass of colorectal cancer featuring hypermutation, representing a potential genomic biomarker for immunotherapy.
In addition, we evaluated the contribution of mutations in the exonuclease domain (exodom) of POLE and POLD1 genes that have recently been reported to confer CRC risk.
Commonly observed alterations across sporadic CRCs have allowed classification into a (1) hypermutated group that includes defective DNA mismatch repair with microsatellite instability and POLE mutations in ∼15%, containing multiple frameshifted genes and BRAF(V600E); (2) nonhypermutated group with multiple somatic copy number alterations and aneuploidy in ∼85%, containing oncogenic activation of KRAS and PIK3CA and mutation and loss of heterozygosity of tumor suppressor genes, such as APC and TP53; (3) CpG island methylator phenotype CRCs in ∼20% that overlap greatly with microsatellite instability CRCs and some nonhypermutated CRCs; and (4) elevated microsatellite alterations at selected tetranucleotide repeats in ∼60% that associates with metastatic behavior in both hypermutated and nonhypermutated groups.
Most of the approximately 13 high-penetrance genes that predispose to CRC primarily predispose to colorectal polyps, and each gene is associated with a specific type of polyp, whether conventional adenomas (APC, MUTYH, POLE, POLD1, NTHL1), juvenile polyps (SMAD4, BMPR1A), Peutz-Jeghers hamartomas (LKB1/STK11) and mixed polyps of serrated and juvenile types (GREM1).
We examined 1188 familial CRC and polyposis index patients for POLEp.(Leu424Val) and POLD1 p.(Ser478Asn) variants using competitive allele-specific PCR.
Recently, families with dominantly inherited colorectal adenomas and colorectal cancer were shown to have a causative heterozygous germline mutation in the proofreading exonuclease domain of POLE.
Further analysis of published data showed that the recently described group of hypermutant, microsatellite-stable CRCs is likely to be caused by somatic POLE mutations affecting the exonuclease domain.