In affected members of a family with susceptibility to colorectal cancer-12 (CRCS12; 615083), Palles et al. (2013) identified a heterozygous 1270C-G transversion in the POLE gene, resulting in a leu424-to-val (L424V) substitution at a highly conserved residue in the active site of the exonuclease (proofreading) domain. The mutant mRNA was stably expressed. Molecular modeling using yeast structures indicated that the L424V mutation will distort the packing of helices involved at the exonuclease active site, likely affecting nuclear activity. The mutation was identified by linkage analysis combined with whole-genome sequencing. Direct screening for this mutation in 3,805 individuals of European ancestry with a familial colorectal cancer, multiple adenomas, and early-onset disease resulted in the identification of 12 additional unrelated probands with the mutation. The mutation was not found in 6,721 control individuals or in 10,755 control exomes. The mutation segregated with the phenotype in each of the families; there was no evidence for a common ancestor. The phenotype was compatible with autosomal dominant inheritance of a high-penetrance predisposition to the development of colorectal adenomas and carcinomas, with a variable tendency to develop multiple and large tumors. The histologic features of the tumors were unremarkable, and all were microsatellite stable. Some tumors had additional somatic mutations, for example, in the APC (611731) or KRAS (190070) genes.
Valle et al. (2014) identified a de novo heterozygous L424V mutation in the POLE gene in a 28-year-old woman with polyposis and colorectal cancer. No loss of heterozygosity at the POLE chromosomal region was found in tumor DNA. This patient was ascertained from a cohort of 858 Spanish probands with familial/early-onset CRC who underwent screening of the POLE gene, thus accounting for 0.12% of the total.
Elsayed et al. (2015) identified heterozygosity for the c.1270C-G transversion (c.1270C-G, NM_006231.2) in the POLE gene, resulting in a L424V mutation, in 3 (0.25%) of 1,188 Dutch index patients with polyposis or familial colorectal cancer. In 1 patient, the mutation occurred de novo. Tumor tissue samples available from 3 patients from 2 families showed microsatellite instability and were found to have somatic mutations in the MSH2 (609309) and/or MSH6 (600678) genes. The findings indicated that POLE DNA analysis is warranted in microsatellite-unstable colorectal cancer, especially in the absence of a germline variant in DNA Mismatch repair genes.
