Colorectal Cancer, Susceptibility To, 10

A number sign (#) is used with this entry because susceptibility to the development of colorectal cancer-10 (CRCS10) is conferred by heterozygous mutation in the POLD1 gene (174761) on chromosome 19q13.

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

Clinical Features

Palles et al. (2013) reported 2 large multigenerational families with a predisposition for the development of multiple colorectal adenomas and carcinomas between the ages of 26 and 68 years. In addition, 7 patients also developed endometrial carcinoma, and 1 patient had 2 primary brain tumors. All tumors showed microsatellite stability.

Valle et al. (2014) reported a woman who was diagnosed with colorectal cancer (CRC) without polyps at age 36 years. Her mother was diagnosed with endometrial cancer at age 52, and her maternal aunt was diagnosed with colorectal cancer without polyps at age 33 and endometrial cancer at age 56. There was no evidence of a mismatch-repair defect in this family.

Bellido et al. (2016) reviewed the data on 22 individuals from 8 families carrying pathogenic variants in POLD1. Colorectal cancer was diagnosed in 13 of 22 (59%), with a mean age of 35.9 years. Mutation carriers had a range of 0 to 45 polyps; among those with polyps, 64% had 2 or more and 56% had 5 or more polyps. Endometrial cancer was diagnosed in 8 of 14 (57%) female mutation carriers with a mean age at diagnosis of 51%. Breast cancer was seen in 2 carriers and brain tumor in 1, who had 2 tumors presenting simultaneously at age 26.

Inheritance

The transmission pattern of CRCS10 in the families reported by Palles et al. (2013) was consistent with autosomal dominant inheritance.

Mapping

In a metaanalysis of 2 previously published genomewide association (GWA) studies (Tomlinson et al., 2008; Tenesa et al., 2008) comprising 13,315 individuals, Houlston et al. (2008) found an association between susceptibility to colorectal cancer and SNP rs10411210 on chromosome 19q13.1 within the RHPN2 gene (617932) (p = 4.9 x 10(-8)). Pooling data from 8 independent case-control series comprising 27,418 individuals with the GWA series yielded a combined p value of 4.6 x 10(-9) for rs10411210.

Molecular Genetics

In affected members of 2 large multigenerational families with susceptibility to colorectal cancer-10, Palles et al. (2013) identified a heterozygous mutation in the POLD1 gene (S478N; 174761.0001). The mutation was identified by a combination of linkage analysis and whole-genome sequencing. The S489N mutation was also identified in a third affected family in the validation phase of the study. Tumor tissue from 2 of 6 mutation carriers showed additional somatic mutations, most commonly in the APC (611731), KRAS (190070), or FBXW7 (606278) genes. All tumors showed microsatellite stability. In addition to germline POLD1 mutations, Palles et al. (2013) identified somatic POLE mutations in 5 colorectal cancers from a large database. All of these tumors had additional somatic mutations. These findings suggested that the mechanism of tumorigenesis in POLD1-mutated tumors is decreased fidelity of replication-associated polymerase proofreading, leading to an increased mutation rate.

In a woman with CRCS10 without polyposis, Valle et al. (2014) identified a heterozygous missense mutation in the POLD1 gene (L474P; 174761.0004). The mutation was also present in the patient's maternal aunt, who had CRC and endometrial cancer, as well as in the patient's mother, who had endometrial cancer. There were no defects in mismatch repair in this family. The proband was ascertained from a cohort of 858 Spanish probands with familial/early-onset CRC who underwent screening of the POLD1 gene, thus accounting for 0.12% of the total.