POLEandPOLD1screening in 155 patients with multiple polyps and early-onset colorectal cancer

Abstract

Germline mutations in POLE and POLD1 have been shown to cause predisposition to colorectal multiple polyposis and a wide range of neoplasms, early-onset colorectal cancer being the most prevalent. In order to find additional mutations affecting the proofreading activity of these polymerases, we sequenced its exonuclease domain in 155 patients with multiple polyps or an early-onset colorectal cancer phenotype without alterations in the known hereditary colorectal cancer genes. Interestingly, none of the previously reported mutations in POLE and POLD1 were found. On the other hand, among the genetic variants detected, only two of them stood out as putative pathogenic in the POLE gene, c.1359 + 46del71 and c.1420G > A (p.Val474Ile). The first variant, detected in two families, was not proven to alter correct RNA splicing. Contrarily, c.1420G > A (p.Val474Ile) was detected in one early-onset colorectal cancer patient and located right next to the exonuclease domain. The pathogenicity of this change was suggested by its rarity and bioinformatics predictions, and it was further indicated by functional assays in Schizosaccharomyces pombe. This is the first study to functionally analyze a POLE genetic variant outside the exonuclease domain and widens the spectrum of genetic changes in this DNA polymerase that could lead to colorectal cancer predisposition.

Comprehensive Analysis of Hypermutation in Human Cancer

“…In addition, other sites were always spared from mutation, likely due to their importance to the cell. Mutations in POLE and POLD1 have only recently been described (Esteban-Jurado et al, 2017; Shinbrot et al, 2014), thus our method will be useful for the proper clinical classification. Further research and clinical follow-up are required to fully understand why some mutations in the exonuclease domain have weak mutagenic effects, yet occasionally mutations in the polymerase domain can be associated with hypermutation and putative loss of proofreading ability.…”

Pediatric High Grade Gliomas in the Context of Cancer Predisposition Syndromes

“…Recently, other components of the replication repair machinery have been reported to be associate with similar clinical and biological presentation and cancer hypermutations. These included mutations in MSH3 [ 1 ], deletions of the EPCAM gene, located just upstream of MSH2 [ 64 ] and mutations in DNA polymerases epsilon and delta 1 (POLE, POLD1) [ 29 , 77 ].…”

Gene aberration profile of tumors of adolescent and young adult females

“…A high tumor mutation burden (TMB), recently defined as > 10 SNVs/Mb [ 21 ], was found in two breast carcinomas (BR15-035T, TMB = 50.4 and BR15-045T, TMB = 16.4) and an ovarian carcinoma (OV15-005T, TMB = 250.9). Deleterious germline and somatic mutations, i.e ., nonsense and frameshift insertion/deletion (indel) alterations, in six hypermutator genes consisting of four mismatch repair (MMR) genes ( MLH1 , MSH2 , MSH6 , and PMS2 ) and two DNA polymerase genes with proofreading function, POLD and POLE , were examined as potentially responsible for high TMB, since their aberration is established as associated with high TMB in a variety of human cancers [ 21 - 24 ]. The case with ovarian cancer had a deleterious somatic mutation in MSH6 , a MMR gene, while the two cases with breast cancer lacked mutations in the six genes (Figure 1 , Supplementary Table 1 ).…”