NDLI: A novel POLE mutation associated with cancers of colon, pancreas, ovaries and small intestine

Content Provider	Springer Nature Link
Author	Hansen, Maren F. Johansen, Jostein Bjørnevoll, Inga Sylvander, Anna E. Steinsbekk, Kristin S. Sætrom, Pål Sandvik, Arne K. Drabløs, Finn Sjursen, Wenche
Copyright Year	2015
Abstract	In some families there is an increased risk for colorectal cancer, caused by heritable, but often unidentified genetic mutations predisposing to the disease. We have identified the likely genetic cause for disease predisposition in a large family with high burden of colorectal adenomas and carcinomas, in addition to extra-colonic cancers. This family had previously been tested for known cancer susceptibility genes, with negative results. Exome sequencing was used to identify a novel mutation, c.1373A>T (p.Tyr458Phe), in the gene for DNA polymerase epsilon catalytic subunit (POLE). This mutation is located in the active site of the exonuclease domain of the enzyme, and affects a residue that has previously been shown to be important for exonuclease activity. The first predisposing mutation identified in POLE (c.1270C>G, p.Leu424Val) was associated with colorectal cancer only, but another mutation with a broader tumour spectrum (c.1089C>A, p.Asn363Lys) has recently been reported. In the family described in the present study, carriers generally have multiple colorectal adenomas and cancer of colon, pancreas, ovaries and small intestine which represents an important broadening of the tumour spectrum of POLE mutation carriers. We also observe a large phenotypic variation among the POLE mutation carriers in this family, most likely explained by modifying variants in other genes. One POLE mutation carrier has a novel variant in EXO1 (c.458C>T, p.Ala153Val), which may contribute to a more severe phenotype. The findings in this study will have important implications for risk assessment and surveillance of POLE mutation carriers.
Starting Page	437
Ending Page	448
Page Count	12
File Format	PDF
ISSN	13899600
Journal	Familial Cancer
Volume Number	14
Issue Number	3
e-ISSN	15737292
Language	English
Publisher	Springer Netherlands
Publisher Date	2015-04-10
Publisher Place	Dordrecht
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Colorectal cancer Polymerase epsilon POLE Germline mutation Cancer Research Human Genetics Epidemiology Biomedicine general
Content Type	Text
Resource Type	Article
Subject	Genetics Cancer Research Genetics (clinical) Oncology

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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