POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance

Abstract

Purpose:Germ-line mutations in the exonuclease domains of POLE and POLD1 have been recently associated with polyposis and colorectal cancer (CRC) predisposition. Here, we aimed to gain a better understanding of the phenotypic characteristics of this syndrome to establish specific criteria for POLE and POLD1 mutation screening and to help define the clinical management of mutation carriers.Genet Med 18 4, 325–332.Methods:The exonuclease domains of POLE and POLD1 were studied in 529 kindred, 441 with familial nonpolyposis CRC and 88 with polyposis, by using pooled DNA amplification and massively parallel sequencing.Genet Med 18 4, 325–332.Results:Seven novel or rare genetic variants were identified. In addition to the POLE p.L424V recurrent mutation in a patient with polyposis, CRC and oligodendroglioma, six novel or rare POLD1 variants (four of them, p.D316H, p.D316G, p.R409W, and p.L474P, with strong evidence for pathogenicity) were identified in nonpolyposis CRC families. Phenotypic data from these and previously reported POLE/POLD1 carriers point to an associated phenotype characterized by attenuated or oligo-adenomatous colorectal polyposis, CRC, and probably brain tumors. In addition, POLD1 mutations predispose to endometrial and breast tumors.Genet Med 18 4, 325–332.Conclusion:Our results widen the phenotypic spectrum of the POLE/POLD1-associated syndrome and identify novel pathogenic variants. We propose guidelines for genetic testing and surveillance recommendations.Genet Med 18 4, 325–332.

DNA Polymerase ε Deficiency Leading to an Ultramutator Phenotype: A Novel Clinically Relevant Entity

“…As discussed, the specific alterations are distinct from those typically seen in cancers with MSI [1]. Rare germline mutations in POLD1 and POLE have been described in patients with polymerase proofreading‐associated polyposis, a clinical phenotype quite similar to that of MMR deficiency [11], [12]. While germline POLD1 mutations might be involved in familial cases, there is little evidence to suggest that somatic POLD1 mutations act as a driver of spontaneous CRC, as seen in POLE mutations.…”

NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 3.2017

“…45 Mutations in the POLD1 and POLE genes may be associated with polyposis and an increased risk for CRC. [46][47][48][49] Using whole-genome sequencing in combination with linkage and association analysis, heterozygous POLD1 and POLE germline variants were identified in multiple adenoma and/or CRC cases. 47 In an analysis of 858 Spanish patients with early-onset and/or familial CRC and/or colonic polyposis, only 1 patient was found to have a POLE mutation.…”

Current applications of molecular pathology in colorectal carcinoma

“…These genes, which encode protein subunits of DNA polymerase complexes, may play a role in the development of hypermutated, microsatellite-stable CRC [50]. Patients with a germline POLE p.L424V mutation or one of a handful of POLD1 mutations appear to be at risk of developing CRC, as well as tumors of the brain, breast, and endometrium [51,52]. Patients may develop an attenuated adenomatous polyposis, or may develop only a few polyps.…”

“…Missense mutations affecting the exonuclease domains of the polymerase genes POLE and POLD1 have recently been identified to be responsible for PPAP, which can present as a polyposis and/or a Lynch syndrome-like phenotype [51]. Individuals presenting with familial or early onset MMR-proficient CRC and/or APC-negative and MUTYH-negative polyposis should be screened for germline POLE or POLD1 exonuclease mutations.…”