Colorectal Cancer, Susceptibility To, 12

A number sign (#) is used with this entry because susceptibility to the development of colorectal cancer-12 (CRCS12) is conferred by heterozygous mutation in the POLE gene (174762) on chromosome 12q24.

Description

Colorectal cancer-12 is an autosomal dominant disorder characterized by a high-penetrance predisposition to the development of colorectal adenomas and carcinomas, with a variable tendency to develop multiple and large tumors. Onset usually occurs before age 40 years. The histologic features of the tumors may be unremarkable (Palles et al., 2013) or show microsatellite instability (MSI) (Elsayed et al., 2015).

For a general phenotypic description and a discussion of genetic heterogeneity of colorectal cancer, see 114500.

Clinical Features

Palles et al. (2013) reported a large 3-generation family in which 8 individuals had various manifestations of a colorectal adenoma syndrome with predisposition to colorectal carcinoma. Affected individuals developed multiple adenomas or colorectal cancer as adults, between ages 23 and 61 years. Twelve additional pedigrees with the same disorder were subsequently identified. All showed autosomal dominant inheritance of a predisposition of multiple adenomas and/or colorectal cancer with onset usually before age 40 years. Histologic features of the tumors were unremarkable, but all were microsatellite stable.

Elsayed et al. (2015) reported 2 Dutch families and an unrelated Dutch patient with CRCS12 confirmed by genetic analysis. In the first family, a mother was diagnosed with an MSI colorectal tumor and 2 adenomas at age 40 years. She later developed multiple colorectal polyps as well as microsatellite-stable endometrial cancer at age 50. Her son was diagnosed with MSI adenocarcinoma at age 30. Tumor tissue from these patients showed loss of MSH2 (609309) and/or MSH6 (600678) protein expression, suggestive of Lynch syndrome (see, e.g., 120435), although there were no germline mutations in these genes. The mother's tumor showed a hypermutator phenotype, with multiple somatic mutations in several genes. In the second family, the proband was diagnosed with multiple polyps at age 34. An adenoma with cancer showed MSI associated with immunohistochemical loss of MSH2 and MSH6 protein staining, also in the absence of germline variants in these genes. The patient had a family history of colorectal and other forms of cancer, but DNA and tumor tissue samples from her relatives were not available. The unrelated Dutch patient was diagnosed with a microsatellite-stable colon cancer and polyposis at age 33. No tumor tissue was available for analysis. The MSI observed in some of these patients was in contrast to the microsatellite stability observed in the tumors from the family reported by Palles et al. (2013).

Bellido et al. (2016) reviewed phenotypic data on 47 patients from 20 families with the POLE L424V mutation, including a new case with a de novo occurrence. The mean number of colonic adenomas among 23 carriers available for ascertainment was 19.3, with a range of 1 to 68; 82% had 2 or more adenomas, and 74% had 5 or more. Colorectal cancer was diagnosed in 30 of 47 (64%) mutation carriers with mean age at first diagnosis 40.7 years. Brain tumors were present in 3 of 47 (6%) of carriers with a mean age at diagnosis of 30.6 years. Duodenal adenomas were present in 7 of 14 (50%). The authors recommended testing for mutations in POLE in patients with attenuated adenomatous polyposis and in other forms of CRC with or without oligopolyposis.

Inheritance

The transmission pattern of CRCS12 in the families reported by Palles et al. (2013) was consistent with autosomal dominant inheritance.

Molecular Genetics

In affected members of a family with susceptibility to colorectal cancer-12, Palles et al. (2013) identified a heterozygous missense mutation in the POLE gene (L424V; 174762.0001) affecting a highly conserved residue in the exonuclease (proofreading) domain. The mutation was identified by whole-genome sequencing. The L424V mutation was subsequently identified in 12 more families with early-onset colorectal adenomas and carcinomas. Some tumors had additional somatic mutations, for example, in the APC (611731) or KRAS (190070) genes. In addition to germline POLE mutations, Palles et al. (2013) identified somatic POLE mutations, many affecting the exonuclease domain, in 15 colorectal cancers from a large database. All of these tumors had additional somatic mutations, most commonly in the APC gene. These findings suggested that the mechanism of tumorigenesis in POLE-mutated tumors is decreased fidelity of replication-associated polymerase proofreading, leading to an increased mutation rate.

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 L424V mutation in the POLE gene 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 and/or MSH6 genes. The findings indicated that POLE DNA analysis is warranted in MSI colorectal cancer, especially in the absence of a germline variant in DNA mismatch repair genes.