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 ... 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.
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 ... 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.