Postmenopausal hormone therapy and colorectal cancer risk in relation to somatic KRAS mutation status among older women.
Postmenopausal hormone therapy and colorectal cancer risk in relation to somatic KRAS mutation status among older women.
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DOI：
10.1158/1055-9965.epi-11-1168
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发表时间：
2012-04
期刊：
影响因子：
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通讯作者：
Cerhan JR
中科院分区：
文献类型：
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作者：
Limburg PJ;Limsui D;Vierkant RA;Tillmans LS;Wang AH;Lynch CF;Anderson KE;French AJ;Haile RW;Harnack LJ;Potter JD;Slager SL;Smyrk TC;Thibodeau SN;Cerhan JR
绝经后激素（PMH）治疗是一种有争议的结肠直肠癌（CRC）预防干预。由于结直肠癌的发生是一个异质性的过程，我们在以人群为基础的老年妇女队列中评估了PMH治疗与KRAS突变状态相关的结直肠癌发病率之间的关系（Iowa women’s Health Study [IWHS]）。1986年，IWHS随机招募了41836名年龄在55-69岁之间的女性。在基线时记录PMH治疗和其他暴露数据。对来自前瞻性鉴定的CRC病例（n = 507）的组织样本进行体细胞KRAS突变（外显子2，密码子12和13）分析。采用多变量Cox回归模型拟合估计相对危险度（RRs）和95%置信区间（ci）。PMH治疗与KRAS突变阴性（RR = 0.83; 95% CI = 0.66-1.06; p = 0.14）和KRAS突变阳性（RR = 0.82; 95% CI = 0.58-1.16; p = 0.27）肿瘤呈负相关，尽管观察到的风险估计无统计学意义。另外考虑解剖亚位点时，发现KRAS突变阴性的远端结直肠肿瘤的相关性最强（RR = 0.64; 95% CI = 0.43-0.96; p = 0.03）。据我们所知，我们提供了kras定义的与PMH治疗相关的CRC风险的第一份报告。这些数据表明，PMH治疗可能通过KRAS突变状态以外的机制降低结直肠癌风险，但对于KRAS突变阴性的肿瘤可能比突变阳性的肿瘤（至少在远端结直肠）提供更大的益处。这项前瞻性队列研究的发现为PMH治疗相关的CRC风险降低的分子生物学提供了新的见解。
Postmenopausal hormone (PMH) therapy represents a controversial colorectal cancer (CRC) preventive intervention. Since colorectal carcinogenesis is a heterogeneous process, we evaluated associations between PMH therapy and incident CRC in relation to KRAS mutation status in a population-based cohort of older women (Iowa Women’s Health Study [IWHS]). The IWHS enrolled 41,836 randomly selected women, ages 55–69 years, in 1986. PMH therapy and other exposure data were recorded at baseline. Tissue samples from prospectively identified CRC cases (n = 507) were analyzed for somatic KRAS mutations (exon 2, codons 12 and 13). Multivariable Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs). PMH therapy (ever vs. never) was inversely associated with KRAS mutation-negative (RR = 0.83; 95% CI = 0.66–1.06; p = 0.14) and KRAS mutation-positive (RR = 0.82; 95% CI = 0.58–1.16; p = 0.27) tumors, although the observed risk estimates were not statistically significant. When anatomic subsite was additionally considered, the strongest association was found for KRAS mutation-negative, distal colorectal tumors (RR = 0.64; 95% CI = 0.43–0.96; p = 0.03). To our knowledge, we provide the first report of KRAS-defined CRC risks associated with PMH therapy. These data suggest that PMH therapy may reduce CRC risk through mechanisms beyond KRAS mutation status, but might provide greater benefits for KRAS mutation-negative than mutation-positive tumors (at least in the distal colorectum). Findings from this prospective cohort study provide novel insights regarding the molecular biology of PMH therapy-related CRC risk reduction.