RGD Reference Report - POLD1 and POLE Gene Mutations in Jewish Cohorts of Early-Onset Colorectal Cancer and of Multiple Colorectal Adenomas. - Rat Genome Database

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

Authors: Rosner, Guy  Gluck, Nathan  Carmi, Shai  Bercovich, Dani  Fliss-Issakov, Naomi  Ben-Yehoyada, Merav  Aharon-Caspi, Sivan  Kellerman, Efrat  Strul, Hana  Shibolet, Oren  Kariv, Revital 
Citation: Rosner G, etal., Dis Colon Rectum. 2018 Sep;61(9):1073-1079. doi: 10.1097/DCR.0000000000001150.
RGD ID: 151347647
Pubmed: PMID:30086056   (View Abstract at PubMed)
DOI: DOI:10.1097/DCR.0000000000001150   (Journal Full-text)


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 http://links.lww.com/DCR/A658.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Colorectal Neoplasms  IAGP 151347647DNA:nonsense mutation and missense mutation:CDS:p.195*, p.V759I (human)RGD 
Colorectal Neoplasms  IAGP 151347647DNA:missense mutation:CDS more ...RGD 
Colorectal Neoplasms  ISOPOLD1 (Homo sapiens)151347647; 151347647DNA:nonsense mutation and missense mutation:CDS:p.195*, p.V759I (human)RGD 
Colorectal Neoplasms  ISOPOLE (Homo sapiens)151347647; 151347647DNA:missense mutation:CDS more ...RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Neoplasm of the large intestine  IAGP 151347647DNA:nonsense mutation and missense mutation:CDS:p.195*, p.V759IRGD 
Objects Annotated

Genes (Rattus norvegicus)
Pold1  (DNA polymerase delta 1, catalytic subunit)
Pole  (DNA polymerase epsilon, catalytic subunit)

Genes (Mus musculus)
Pold1  (polymerase (DNA directed), delta 1, catalytic subunit)
Pole  (polymerase (DNA directed), epsilon)

Genes (Homo sapiens)
POLD1  (DNA polymerase delta 1, catalytic subunit)
POLE  (DNA polymerase epsilon, catalytic subunit)


Additional Information