POLD1 and POLE Analysis

Growing evidence indicates that mutations in POLD1 and POLE are associated with increased risk for colorectal cancer and polyposis and are autosomal dominantly inherited.  

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Growing evidence indicates that mutations in POLD1 and POLE are associated with increased risk for colorectal cancer and polyposis and are autosomal dominantly inherited.  

Disease Name 
Colorectal cancer
Polyposis
Disease Information 

Heterozygous pathogenic mutations in the POLD1 and POLE genes have been implicated in an emerging syndrome of hereditary colorectal cancer (CRC) and polyposis, called polymerase proofreading-associated polyposis (PPAP) by some.1 Exact cancer risks for mutation carriers have not yet been determined; however, published studies support POLD1 and POLE mutations as highly penetrant, conferring increased risk for early-onset CRC and/or multiple adenomas.

In POLD1 mutation carriers ascertained from several polyposis and CRC cohorts, polyp number ranged from 0-45 and age of onset in those affected ranged from 28-58 years. CRC was diagnosed in individuals between ages 29-53 years.2,3 In POLE mutation carriers ascertained from several polyposis and/or CRC cohorts, polyp number ranged from 0 to >100 and age of onset in those affected ranged from 16-74 years. CRC was diagnosed in individuals between ages 26-78 years.2-7  Associations between POLD1 and POLE mutations and elevated incidence of extra-intestinal tumors including endometrial cancer (EC) have been suggested, although data are currently limited.  Additionally, emerging data suggest that mutations in POLD1 may be associated with a more Lynch syndrome-like phenotype, while mutations in POLE may be associated with a stronger polyposis phenotype, but additional data are needed to confirm this.8

The polymerase delta 1 gene, POLD1, and polymerase epsilon gene, POLE, are DNA polymerases, which participate in DNA repair and replication.  The majority of POLD1 and POLE mutations identified in individuals with CRC and/or polyposis are located within the exonuclease (proofreading) domain of the DNA polymerase.9

Testing Benefits & Indication 

Genetic testing is useful to determine the cause of cancer and/or polyposis in symptomatic individuals and for testing of at-risk family members.  Genetic testing may help to identify those with increased risk for cancer and polyposis and offer early intervention measures for these individuals to significantly reduce their risk of cancer.  Recent studies have suggested surveillance regimens for mutation carriers that are similar to current recommendations for individuals with Lynch syndrome and familial adenomatous polyposis (FAP).6,8

A recent study by Bellido, et al. suggested the following initial guidelines for genetic testing:8

POLE

  • 20-100 adenomas
  • Family history that meets the Amsterdam I criteria (CRC only)
  • CRC and 5-20 adenomas, both diagnosed before age 50
  • CRC or 5-20 adenomas, and a first-degree relative with CRC before age 50
  • CRC or 5-20 adenomas and 2 or more first-or second-degree relatives with CRC, regardless of age

POLD1

  • 20-100 adenomas
  • Family history that meets the Amsterdam II criteria (only CRC and EC)
  • CRC before age 50 or EC before age 60, and 5-20 adenomas diagnosed before age 50
  • CRC or EC or 5-20 adenomas and a first-degree relative with CRC before age 50, or EC before age 60
  • CRC or EC or 5-20 adenomas and 2 or more first-or second-degree relatives with CRC or EC, regardless of age
Test Description 

POLD1 coding exons 1-26 and POLE coding exons 1-49 and well into the 5’ and 3’ ends of all the introns and untranslated regions are analyzed by sequencing. Clinically significant intronic findings beyond 5 base pairs are always reported. Intronic variants of unknown or unlikely clinical significance are not reported beyond 5 base pairs from the splice junction. Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using standardized methodology and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology, using long biotinylated oligonucleotide probes followed by polymerase chain reaction (PCR) and next generation sequencing (NGS). Sanger sequencing is performed for any regions missing or with insufficient read depth coverage for reliable heterozygous variant detection. Reportable small insertions and deletions, potentially homozygous variants, variants in regions complicated by pseudogene interference, and single nucleotide variant calls not satisfying 100x depth of coverage and 40% het ratio thresholds are verified by Sanger sequencing.10  Missense variants located outside of the exonuclease domains (POLD1 codons 311-541 and POLE codons 269-485) are not routinely reported.

Mutation Detection Rate 

Ambry’s POLD1 and POLE testing can detect >99.9% of described mutations in both genes, when present (analytic sensitivity).

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above on this page.

Turnaround Time 
TEST CODE TECHNIQUE CALENDAR DAYS
8877 POLD1 and POLE Gene Sequence Analysis 14 - 21 days

 

Specialty 
Genes 
POLD1
POLE
References 
  1. Church JM. Polymerase proofreading-associated polyposis: a new, dominantly inherited syndrome of hereditary colorectal cancer predisposition. Dis Colon Rectum. 2014; 57(3): 396-397.
  2. Palles C, et al. Germline mutations in the proof-reading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 2013; 45(2): 136-144.
  3. Valle V, et al. New insights in POLE and POLD1 germline mutations in familial colorectal cancer and polyposis. Hum Mol Genet. 2014; 23(13): 3506-3512.
  4. Elsayed FA, et al. Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer. Eur J Hum Genet. 2015; 23(8): 1080-1084.
  5. Smith CG, et al. Exome resequencing identifies potential tumor-suppressor genes that predispose to colorectal cancer. Hum Mutat. 2013; 34(7):1026-1034.
  6. Spier I, 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 Cancer. 2015; 137:320-331.
  7. Rohlin A, et al. A mutation in POLE predisposing to a multi-tumour phenotype. Int J Oncology. 2014; 45:77-81.
  8. Bellido F, 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. Genet Med. 2015. [Epub ahead of print].
  9. Briggs S and Tomlinson I. Germline and somatic polymerase ɛ and δ mutations define a new class of hypermutated colorectal and endometrial cancers. J Pathol. 2013; 320:148-153.
  10. Mu W, et al. Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J Mol Diagn. 2016. 18(6):923-932.