Colon

Molecular

POLD1 / POLE


Editorial Board Member: Aaron R. Huber, D.O.
Deputy Editor-in-Chief: Catherine E. Hagen, M.D.
Neha Varshney, M.D.
Varsha Prakash, M.D., M.S.

Last author update: 20 July 2022
Last staff update: 20 July 2022

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PubMed Search: POLE POLD1 colon

Neha Varshney, M.D.
Varsha Prakash, M.D., M.S.
Page views in 2021: 159
Page views in 2022 to date: 638
Cite this page: Varshney N, Prakash V. POLD1 / POLE. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/colontumorpold1pole.html. Accessed December 3rd, 2022.
Definition / general
  • Germline missense pathogenic variants in the exonuclease domain (ED) of polymerases epsilon (POLE) and delta (POLD1) affect their proofreading capabilities, predisposing to multiple colorectal adenomas and carcinomas
  • Polymerase proof reading associated polyposis (PPAP) has autosomal dominant inheritance
  • POLE / POLD1 germline and rare somatic mutations are also associated with endometrial, brain, breast, ovarian, stomach, pancreas and skin tumors, among others
Essential features
  • Deleterious mutations in the proofreading exonuclease domain of POLE occur in approximately 7 - 12% of endometrial carcinomas, 1 - 2% of colorectal carcinomas and a small number of other cancer types
  • Identifying pathogenic mutations in the POLE gene is clinically important; such mutations are associated with a more favorable prognosis and can impact oncologic management
Terminology
  • DNA polymerase epsilon (POLE) and delta 1 (POLD1)
  • Polymerase proof reading associated polyposis (PPAP)
  • Colorectal cancer (CRC)
Epidemiology
  • Early onset CRCs with POLE mutations occur in (Oncotarget 2016;7:68638)
    • Age group < 50 years
    • M > F
    • Right side > left side
Sites
  • POLE is associated with the following malignancies:
    • Colon
    • Pancreas
    • Small intestine
    • Cutaneous melanoma
    • Endometrial
    • Ovarian
    • Brain
    • Lung
  • POLD1 is associated with the following malignancies:
    • Colon
    • Endometrial
    • Breast cancer
Pathophysiology
  • POLE and POLD1 genes encode the major catalytic and proofreading subunits of the Polε (polymerase epsilon) and Polδ (polymerase delta) enzyme complexes, respectively
  • Germline or somatic mutations in POLE / POLD1 proofreading domain cause deficiencies in DNA repair (Ann Transl Med 2021;9:129)
  • DNA repair deficiencies lead to the formation of a DNA hypermutated molecular phenotype (J Clin Invest 2018;128:4179)
  • Predisposition to multiple polyps (both adenomatous and serrated), which can lead to carcinogenesis in the future
Clinical features
  • POLE / POLD1 mutated cancers are primarily microsatellite stable (MSS) (Nat Rev Cancer 2016;16:71)
  • POLE mutated endometrial and CRCs also display MSI-H
  • POLE gene is located in 12q24.33 and encodes the proofreading (exonuclease) subunit of polymerase epsilon (POLE) with 2286 amino acids
  • Most common POLE mutations are identified in P286R/H, V411L and S459F tumor genome (Nat Rev Cancer 2016;16:71)
  • Somatic POLD1 mutations are also found (Nat Rev Cancer 2016;16:71)
  • Hereditary CRCs associated with mutations POLD1 and POLE are termed polymerase proofreading associated polyposis (PPAP) (Nat Genet 2013;45:136)
  • Combined POLE / POLD1 defects and mismatch repair explain unresolved suspected Lynch syndrome cancers (Eur J Hum Genet 2016;24:1089)
  • POLE mutated CRCs have hypermutated phenotypes despite MMR intact status; mutation burdens are higher than that in microsatellite unstable CRCs (Genet Med 2016;18:325)
  • POLE mutations can co-occur with somatic MLH1 mutation in endometrial carcinomas and ovarian endometrioid or clear cell carcinomas; this is due to the hypermutated state and genomic instability of the tumor
Diagnosis
  • Molecular testing for POLE specific site analysis (PCR, next gene sequencing)
Laboratory
  • When to consider testing: the following initial guidelines for POLE and POLD1 genetic testing have been suggested (Genet Med 2016;18:325)
    • 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 endometrial cancer [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
Prognostic factors
  • POLE / POLD1 mutations have beneficial clinical outcomes post immune checkpoint inhibitor (ICI) therapy in endometrial cancer, non small cell lung cancer, CRC and cervical carcinosarcoma (Nat Rev Cancer 2016;16:71)
  • POLE mutations are associated with better prognosis in endometrial cancer patients who underwent adjuvant treatment of chemotherapy or radiotherapy following surgery (J Natl Cancer Inst 2015;107:402)
  • POLE mutation is a good prognostic biomarker for patients with lung squamous cell carcinoma but not lung adenocarcinoma (Mol Cancer 2018;17:81)
Case reports
  • 29 year old Chinese man with advanced colon cancer harboring somatic POLE F367S mutation with microsatellite stability status (Onco Targets Ther 2021;14:1791)
  • 41 year old Chinese woman with a right sided colon adenocarcinoma who harbored a (p.P286R) POLE somatic mutation (BMC Gastroenterol 2020;20:255)
  • 45 and 54 year old men with advanced adenocarcinoma of the ileum and mixed neuroendocrine nonneuroendocrine neoplasm, both MSS and carrying a POLE mutation (Oncol Res Treat 2022;45:222)
Treatment
  • POLE / POLD is a recently described mutation so the guidelines regarding screening and management of POLE and POLD1 mutation carriers are not yet determined
  • POLE mutated tumors may also be eligible for immunotherapy (e.g., checkpoint inhibitors) given the strong correlation between these mutations and high tumor mutation burden (J Clin Invest 2016;126:2334)
  • Several POLE mutant cancers display increased tumor infiltrating lymphocyte density, a phenotype which shows better tumor immune response to immunotherapy
Microscopic (histologic) description
  • In a study, POLE mutated colorectal cancers frequently formed cribriform structures and intraluminal necrotic debris, which contained neutrophils and apoptotic bodies (Oncotarget 2016;7:68638)
  • Histologically, colonic adenocarcinoma and adenomas appear similar to sporadic cases
Negative stains
Videos

Understanding the cancer predisposing syndrome caused by defective POLE and POLD1

Board review style question #1
Which of the following is true about the POLE gene?

  1. POLE does not have an essential role in chromosomal DNA replication
  2. POLE gene is located in 12q24.33 and encodes the proofreading (exonuclease) subunit of polymerase epsilon (POLE) with 2286 amino acids
  3. POLE mutations harbor an unfavorable prognosis in endometrial cancer
  4. Mutations in the POLE gene do not have an increased risk for colon polyps or colon cancer
Board review style answer #1
B. POLE gene is located in 12q24.33 and encodes the proofreading (exonuclease) subunit of polymerase epsilon (POLE) with 2286 amino acids

Comment Here

Reference: POLD1 / POLE
Board review style question #2
Which of the following is associated with POLE / POLD1 mutation?

  1. Colon cancer
  2. Hepatocellular carcinoma
  3. Kaposi Sarcoma
  4. Salivary gland cancer
Board review style answer #2
A. Colon cancer

Comment Here

Reference: POLD1 / POLE
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