Campbell Peter T, Edwards Laura, McLaughlin John R, Green Jane, Younghusband H Banfield, Woods Michael O
Prosserman Centre for Health Research, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Division of Preventive Oncology, Cancer Care Ontario, Toronto, Ontario, Canada.
Clin Cancer Res. 2007 Jul 1;13(13):3783-8. doi: 10.1158/1078-0432.CCR-06-2987.
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.
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.
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.
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.
林奇综合征是一种包括结肠癌在内的癌症易感性综合征。它由DNA错配修复基因的遗传性缺陷引起。散发性结肠癌受外源性激素（如绝经后激素）影响；我们推测，影响内源性激素的多态性会因此改变林奇综合征突变携带者患结肠癌的发病年龄。
我们对146名白种人林奇综合征突变携带者进行基因分型，检测细胞色素P450 17A1（CYP17；c.-34T→C）的5'-非翻译区多态性和儿茶酚-O-甲基转移酶（COMT；c.472G→A）的外显子4多态性；50名突变携带者在最后一次随访时已患结肠癌或直肠癌。我们使用卡方检验评估计数差异。Kaplan-Meier生存曲线和Cox比例风险模型评估按CYP17和COMT基因型分层的结直肠癌发病年龄。
CYP17 C等位基因的纯合携带者被诊断患结直肠癌的时间比T等位基因的纯合携带者早18年。风险比表明，相对于T等位基因（T/T）的纯合携带者，稀有等位基因的一个拷贝（T/C）和两个拷贝（C/C）的携带者在任何年龄患结肠癌的风险分别增加1.9倍和2.9倍。COMT稀有等位基因显示出结肠癌风险降低的非统计学显著趋势。
本研究表明，CYP17（c.-34T→C）的多态性会改变林奇综合征的发病年龄。由于该群体患结直肠癌的风险很高，因此在遗传咨询和风险评估中了解CYP17基因型是必要的。未来的工作应评估林奇综合征突变携带者中与类固醇激素相关的多态性。
