December 2015, Vol. 4, No. 6

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Inherited Colorectal Cancer: POLE and POLD1

Cristi Radford, MS, CGC; Tuya Pal, MD, FACMG

Genetic Counseling

CristiRadford98pxThe association of POLE and POLD1 with colorectal cancer risk was demonstrated in 2013. Palles and colleagues studied families with a dominant pattern of inherited colorectal cancer and multiple adenomas through whole genome sequencing.1 Through these efforts, they identified germline mutations in POLE and POLD1 as high-penetrance genes predisposing to multiple colorectal adenomas and early-onset colo­rectal cancer. Subsequently, a Dutch study of 1188 patients with familial colorectal cancer polyposis identified 3 patients with POLE mutations.2 These patients, 2 of whom showed early-onset colorectal cancers, developed multiple colorectal adenomas. In 1 patient, the mutation was de Tuya,Pal98pxnovo, and unlike the cases described by Palles and colleagues,1 some of the tumors showed microsatellite instability with loss of MSH2/MSH6.2

Studies have continued to demonstrate an association of POLE/POLD1 in families consistent with dominant transmission of colorectal cancer. Spier and colleagues performed a targeted analysis of 8 polymerase genes, which included POLE/POLD1, in 266 unrelated patients with polyposis, or who fulfilled Amsterdam I or II criteria with microsatellite stable tumors.3 Again, mutations in POLE/POLD1 were found. Similarly, Bellido and colleagues analyzed POLE and POLD1 in 529 kindred with either familial nonpolyposis colorectal cancer or polyposis. Seven individuals were found to have mutations.4 These individuals had phenotypes consistent with autosomal dominant transmission and colorectal polyposis and colorectal cancer, and possible brain tumors. POLD1 mutations also showed an association with endometrial and breast tumors. To help determine the contribution of colo­rectal cancer risk genes in patients with early-onset familial colorectal cancer, Chubb and colleagues analyzed exome results for 626 unrelated patients with colorectal cancer aged <56 years who also had ≥1 first-degree relatives with colorectal cancer.5 Mutations were found in 24% (153 of 626) of individuals. Nine patients had mutations in POLE/POLD1, representing 0.5% of the familial colorectal cancer cases. Again, the pedigrees were similar, consisting of adenomas and colorectal cancer.

All of these studies provide evidence of a new inherited colorectal cancer syndrome, polymerase proofreading-associated polyposis (PPAP). As the name implies, the POLE and POLD1 genes encode proofreading subunits of polymerase enzyme complexes. It is clear the syndrome is inherited in an autosomal dominant fashion. However, given that the syndrome is newly identified, the number of reported cases is low, and the clinical phenotype is not well defined. The phenotype appears to overlap with the phenotypes of attenuated familial adenomatous polyposis, MUTYH-associated polyposis (MAP), and Lynch syndrome.3 Colorectal cancer tumors from carriers can be either microsatellite stable or unstable, and de novo mutations have been reported.2 It has been suggested to manage patients intermediately between MAP and Lynch with a colonoscopy every 1 to 2 years, and esophagogastroduodenoscopy (or upper endoscopy) every 3 years, beginning at age 20 to 25 years. For POLD1 carriers, endometrial screening should be considered, starting at age 40 years.1,4 PPAP should be on the differential diagnosis of individuals with phenotypes suggestive of an inherited colorectal cancer or polyposis syndrome. In addition, update testing—which includes analysis of the POLE/POLD1 genes in individuals with phenotypes consistent with Lynch syndrome or an inherited polyposis syndrome without a known mutation—could also be considered.


  1. Palles C, Cazier JB, Howarth KM, et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinoma. Nat Genet. 2013;45:136-144.
  2. Elsayed FA, Kets CM, Ruano D, et al. Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer. Eur J Hum Genet. 2015;23:1080-1084.
  3. Spier I, Holzapfel S, Altmüller J, et al. Frequency and phenotypic spectrum of germline mutations in POLE and seven other polymerase genes in 266 patients with colorectal adenomas and carcinomas. Int J Oncol. 2015;137:320-331.
  4. Bellido F, Pineda M, Aiza G, et al. 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 [published online July 2, 2015]. Genet Med.
  5. Chubb D, Broderick P, Frampton M, et al. Genetic diagnosis of high-penetrance susceptibility for colorectal cancer (CRC) is achievable for a high proportion of familial CRC by exome sequencing. J Clin Oncol. 2015;33:426-432.
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