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 is usually before age 40 years. The ... 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 is usually before age 40 years. The histologic features of the tumors are unremarkable (summary by Palles et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of colorectal cancer, see 114500.
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 ... 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.
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 ... 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.