Cytochrome P450 17A1 and Catechol O-Methyltransferase Polymorphisms and Age at Lynch Syndrome Colon Cancer Onset in Newfoundland
- Peter T. Campbell1,4,
- Laura Edwards3,
- John R. McLaughlin1,2,
- Jane Green3,
- H. Banfield Younghusband3 and
- Michael O. Woods3
- Authors' Affiliations:1Prosserman Centre for Health Research, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 2Division of Preventive Oncology, Cancer Care Ontario, Toronto, Ontario, Canada; 3Discipline of Genetics, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada; and 4Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington
- Requests for reprints:
Michael O. Woods, Discipline of Genetics, Faculty of Medicine, Health Sciences Centre, Room 4333, Memorial University of Newfoundland, 300 Prince Philip Drive, St. John's, Newfoundland and Labrador, Canada A1B 3V6. Phone: 709-777-7334; Fax: 709-777-7497; E-mail: mwoods{at}mun.ca.
Abstract
Purpose: Lynch syndrome is a cancer predisposition syndrome which includes colon cancer. It is caused by inherited defects in DNA mismatch repair genes. Sporadic colon cancers are influenced by exogenous hormones (e.g., postmenopausal hormones); we hypothesized that polymorphisms which influence endogenous hormones would therefore modify age at colon cancer onset among Lynch syndrome mutation carriers.
Experimental Design: We genotyped 146 Caucasian Lynch syndrome mutation carriers for a 5′-untranslated region polymorphism in cytochrome P450 17A1 (CYP17; c.−34T→C) and an exon 4 polymorphism in catechol O-methyltransferase (COMT; c.472G→A); 50 mutation carriers had developed colon or rectal cancer at last contact. We used χ2 tests to assess differences in counts. Kaplan-Meier survival curves and Cox proportional hazard models assessed age at onset of colorectal cancer stratified by CYP17 and COMT genotypes.
Results: Homozygous carriers of the CYP17 C allele were diagnosed with colorectal cancer 18 years earlier than homozygous carriers of the T allele. Hazard ratios identified that, relative to homozygous carriers of the T allele (T/T), carriers of one copy (T/C) and two copies (C/C) of the rare allele were, respectively, at 1.9-fold and 2.9-fold increased the risk of colon cancer at any age. The COMT rare allele suggested a nonstatistically significant trend of decreased colon cancer risk.
Conclusions: This study showed that a polymorphism in CYP17 (c.−34T→C) modifies age at onset of Lynch syndrome. Because of the high risk of colorectal cancer among this group, knowledge of the CYP17 genotype is warranted for genetic counseling and risk assessment. Future work should assess polymorphisms associated with steroid hormones in Lynch syndrome mutation carriers.
Footnotes
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↵5 Campbell PT, Newcomb P, Gallinger S, Cotterchio M, McLaughlin JR. Exogenous hormones and colorectal cancer risk in Canada: associations stratified by clinically defined familial risk. Cancer Causes Control. In press 2007.
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Grant support: Canadian Institutes of Health Research (CRT 43821) and the Newfoundland Cancer Treatment and Research Foundation. National Cancer Institute of Canada Doctoral Fellowship (no. 13523), with funds from the Canadian Cancer Society (P.T. Campbell). National Cancer Institute of Canada Post-Doctoral Fellowship (no. 13493), with funds from the Canadian Cancer Society (M.O. Woods).
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Accepted March 30, 2007.
- Received December 18, 2006.
- Revision received February 13, 2007.
