Associated disorders

The POLE gene is associated with autosomal dominant predisposition to polyposis and colorectal cancer. Other POLE-related conditions have been reported (OMIM: 174762).

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The POLE gene encodes the catalytic subunit of DNA polymerase epsilon, an enzyme that plays a critical role in DNA replication and repair.

POLE heterozygotes
MedGen UID: 430218

Clinical condition
Pathogenic variants in the POLD1 and POLE genes are associated with a recently defined, highly penetrant autosomal dominant colorectal cancer predisposition syndrome whose proposed name is polymerase proofreading-associated polyposis syndrome (PPAP) (PMID: 24509466, 26133394, 25529843, 26822575). Individuals with a single pathogenic POLE variant typically have a more attenuated colorectal phenotype, regularly presenting before the age of 60 with colorectal cancer (often microsatellite stable) or fewer than 100 adenomas (PMID: 25529843, 23263490, 24501277, 23585368). The clinical spectrum ranges from large polyps (>2 cm in diameter) to multiple adenomas resembling attenuated familial adenomatous polyposis (AFAP) to MUTYH-associated polyposis syndrome (MAP) (PMID: 25529843). Many cases may also have a family history of clustering of early-onset colorectal cancer similar to what is typically seen in Lynch syndrome (also called hereditary non-polyposis colorectal cancer, or HNPCC), although some have no such history (PMID: 25529843).

PPAP is associated with an increased risk of gastroduodenal (mostly duodenal) adenomas and malignancy; however, this risk appears limited to those with a POLE pathogenic variant (PMID: 26133394, 25529843, 24788313). Other reported extra-gastrointestinal findings observed in those with a pathogenic POLE variant include pilomatricomas, retroperitoneal fibrosis, lipoma, and fibromas (PMID: 25529843).

There is preliminary evidence suggesting women with PPAP may have an increased risk of endometrial cancer; however, this risk appears to be limited to those with a POLD1 pathogenic variant (PMID: 26133394, 25529843, 23263490, 26822575). The risk for other cancers may also be elevated; however, this evidence is limited and emerging (PMID: 23263490, 26133394, 25529843, 26822575). An individual with a POLE pathogenic variant will not necessarily develop cancer in their lifetime, but the risk of cancer is increased over the general population risk.

Gene information
The POLE gene plays a critical role in DNA replication and repair (Gene. Gene ID: 5426. http://www.ncbi.nlm.nih.gov/gene/5426 Accessed July 2016). POLE and POLD1 encode the catalytic and proofreading subunits of the polymerase enzyme complexes e (Pol d) and d (Pol e), respectively. These subunits are involved in synthesis regulation and cofactor binding (PMID: 25529843). If there is a pathogenic variant in this gene that prevents it from functioning normally, the risk of developing certain types of cancers is increased.

Hereditary predisposition to cancer due to pathogenic variants in the POLE gene has autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing the condition on to their offspring. Once a pathogenic mutation is detected in an individual, it is possible to identify at-risk relatives who can pursue testing for this specific familial variant. Most cases are inherited from a parent, but some cases can occur spontaneously (i.e., an individual with a pathogenic variant has parents who do not have it) (PMID: 25529843). An individual with a variant in POLE has a 50% risk of passing that variant on to offspring.

The POLE gene has preliminary evidence supporting a correlation with autosomal recessive facial dysmorphism, immunodeficiency, livedo, and short stature (FILS) syndrome (PMID: 23230001, 25948378). FILS is an autosomal recessive condition that is characterized by mild facial dysmorphism, immunodeficiency resulting in recurrent infections, livedo on the skin that is present at birth, and short stature. Malignancies have not been observed in affected individuals (PMID: 23230001, 25948378). For there to be a risk of FILS in offspring, a patient and their partner would each have to have a single pathogenic variant in POLE; in such a case, the risk of having an affected child is 25%.

Medical management and surveillance protocols for individuals with a pathogenic variant in POLE have been developed by the National Comprehensive Cancer Network (NCCN) (NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal. Version 1.2016 http://www.nccn.org/professionals/physician_gls/f_guidelines.asp):

  • Begin colonoscopy at 25-30 years of age
    • If negative, continue colonoscopy every 2-3 years thereafter.
    • If polyps are found, colonoscopy is recommended every 1-2 years with consideration of surgery if the polyp burden becomes unmanageable by colonoscopy.
  • Surgical evaluation, if appropriate.

Bellido et al. and Spier et al. have also proposed surveillance guidelines that include screening for gastroduodenal malignancies (PMID: 26133394, 25529843):

  • colonoscopies every 1–2 years starting at age 18–25 years
  • gastroduodenoscopy at least every three years (in the case of normal findings), beginning at 20–30 years of age
  • consideration of prophylactic colectomy (the timing and extent of such invasive interventions has yet to be determined) (PMID: 25529843)

Because endometrial cancer has so far only been reported in individuals with POLD1 pathogenic variants, no specific surveillance regarding endometrial cancer screening is currently suggested for those with a pathogenic variant in POLE (PMID: 26133394, 25529843).

An individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors, including personal medical history, family history, and any available genetic information that may result in a personalized plan for cancer prevention and surveillance.

Knowing if a pathogenic variant is present in POLE is advantageous. At-risk relatives can be identified, enabling pursuit of a diagnostic evaluation. Further, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant data regarding POLE are likely to become available in the near future. Awareness of this cancer predisposition encourages patients and their providers to inform at-risk family members, to diligently follow published screening protocols, and to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information.

Review date: July 2016

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
POLE NM_006231.3