Cytochrome P450 17A1 and catechol O-methyltransferase polymorphisms and age at Lynch syndrome colon cancer onset in Newfoundland.
OBJECTIVE
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.


METHODS
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 chi(2) 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.
Campbell
Peter T
PT
Prosserman Centre for Health Research, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Division of Preventive Oncology, Cancer Care Ontario, Toronto, Ontario, Canada.
Edwards
Laura
L
McLaughlin
John R
JR
Green
Jane
J
Younghusband
H Banfield
HB
Woods
Michael O
MO
D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D003110:Colonic Neoplasms / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009523:Newfoundland and Labrador; D011110:Polymorphism, Genetic; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics*; D016896:Treatment Outcome
D013254:Steroid 17-alpha-Hydroxylase; D002394:Catechol O-Methyltransferase