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POLD1 and POLE Gene Mutations in Jewish Cohorts of Early-Onset Colorectal Cancer and of Multiple Colorectal Adenomas

Rosner, Guy M.D.1,2; Gluck, Nathan M.D., Ph.D.*,1,2; Carmi, Shai Ph.D.3; Bercovich, Dani Ph.D.4,5; Fliss-Issakov, Naomi Ph.D.1,2; Ben-Yehoyada, Merav Ph.D.1,2; Aharon-Caspi, Sivan M.S.1,2; Kellerman, Efrat Ph.D.4,5; Strul, Hana M.D.1,2; Shibolet, Oren M.D.1,2; Kariv, Revital M.D.1,2

doi: 10.1097/DCR.0000000000001150
Original Contributions: Colorectal Cancer
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BACKGROUND: Germline mutations in the DNA polymerase genes POLD1 and POLE confer high risk for multiple colorectal adenomas and colorectal cancer. However, prevalence and the clinical phenotype of mutation carriers are still not fully characterized.

OBJECTIVE: The purpose of this study was to assess the prevalence of germline mutations and to describe the genotype-phenotype correlation in POLD1 and POLE genes in Jewish subjects with multiple colorectal adenomas and/or early-onset mismatch repair proficient colorectal cancers.

DESIGN: This study is a comparison of genetic and clinical data from affected and control groups.

SETTINGS: The study was conducted at a high-volume tertiary referral center.

PATIENTS: The study cohort included 132 subjects: 68 with multiple colorectal adenomas and 64 with early-onset mismatch repair proficient colorectal cancers. The control group included 5685 individuals having no colorectal cancer or colorectal adenomas.

MAIN OUTCOME MEASURES: Study and control subjects were tested for POLD1 and POLE mutations and a clinical correlation was assessed.

RESULTS: Eleven of the 132 study subjects (8.3%) carried either a POLD1 or a POLE mutation: 7 of 68 (10.3%) subjects with multiple colorectal adenomas and 4 of 64 (6.2%) subjects with early-onset mismatch repair proficient colorectal cancer. Three mutations were detected, showing statistical significance in frequency between study and control groups (p < 0.001). Eight of the 11 mutation carriers were Ashkenazi Jews carrying the same POLD1 mutation (V759I), implicating it as a possible low-to-moderate risk founder mutation. Phenotype of mutation carriers was notable for age under 50 at diagnosis, a propensity toward left-sided colorectal cancer, and extracolonic tumors (64%, 100%, and 27% of cases).

LIMITATIONS: The study cohort was limited by its relatively small size.

CONCLUSIONS: Germline mutations in POLD1 and POLE were found to be relatively frequent in our Jewish cohorts. Further studies are needed to clarify the importance of POLD1 and POLE mutations and to define the most suitable surveillance program for Jewish and other POLD1 and POLE mutation carriers. See Video Abstract at

1 Department of Gastroenterology and Liver Diseases, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel

2 Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

3 Braun School of Public Health and Community Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel

4 Human Molecular Genetics and Pharmacogenetics, Migal-Galilee Bio-Technology Center, Kiryat Shmona, Israel

5 Tel-Hai Academic College, Kiryat Shmona, Israel

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Funding/Support: None reported.

Financial Disclosure: None reported.

Presented at the meeting of Digestive Disease Week, Washington, DC, May 16-19, 2015.

* Nathan Gluck and Guy Rosner contributed equally to this article.

Correspondence: Guy Rosner, M.D., Department of Gastroenterology and Liver Diseases, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel. E-mail:

© 2018 The American Society of Colon and Rectal Surgeons