Colon
Molecular
POLD1 / POLE
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Last author update: 20 July 2022
Last staff update: 20 July 2022
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PubMed Search: POLE POLD1 colon
Table of Contents
Definition / general | Essential features | Terminology | Epidemiology | Sites | Pathophysiology | Clinical features | Diagnosis | Laboratory | Prognostic factors | Case reports | Treatment | Microscopic (histologic) description | Negative stains | Videos | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Varshney N, Prakash V. POLD1 / POLE. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/colontumorpold1pole.html. Accessed January 8th, 2025.
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
- POLE
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
- Tumors may show loss of staining for mismatch repair proteins (MLH1, PMS2, MSH2 or MSH6) via immunohistochemistry but germline testing fails to show evidence of a germline mutation (Eur J Hum Genet 2015;23:1080)
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?
- POLE does not have an essential role in chromosomal DNA replication
- POLE gene is located in 12q24.33 and encodes the proofreading (exonuclease) subunit of polymerase epsilon (POLE) with 2286 amino acids
- POLE mutations harbor an unfavorable prognosis in endometrial cancer
- 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
Comment Here
Reference: POLD1 / POLE
Board review style question #2
Which of the following is associated with POLE / POLD1 mutation?
- Colon cancer
- Hepatocellular carcinoma
- Kaposi Sarcoma
- Salivary gland cancer
Board review style answer #2
