JAMA：基因突变或影响服用阿司匹林对结肠直肠癌的裨益

据6月26日发表在《美国医学会杂志》上的一则研究披露，在2项大型的研究中，服用阿司匹林与罹患结肠直肠癌的风险之间的关系受到了BRAF基因突变的影响，常规服用阿司匹林与野生型BRAF结肠直肠癌风险的降低有关，但与变异型BRAF结肠直肠癌风险的降低无关；这些结果提示，变异型BRAF结肠肿瘤细胞可能对阿司匹林的作用较不敏感。

结肠直肠癌是全球与癌症有关死亡的首要原因。根据文章的背景资料，随机对照的试验已经证明服用阿司匹林可降低结肠直肠癌的风险。试验证据表明，与BRAF-野生型（即自然界发生的某个基因的典型形式）肿瘤细胞相比，BRAF -变异的结肠细胞可能对阿司匹林的抗肿瘤作用较不敏感。

波士顿Dana-Farber癌症研究所的Reiko Nishihara, Ph.D.及其同事根据BRAF的变异状态对服用阿司匹林与结肠直肠癌风险的关系进行了检查。研究人员收集了在护士健康调查（从1980年开始）及卫生专业人员随访研究（从1986年开始）中的有关服用阿司匹林及跟踪随访的参与者的两年一次的问卷数据；对癌症发病率的数据的收集一直到2006年7月，对癌症死亡率的数据的收集一直到2012年1月。

在12万7865个人中，发现有1226起直肠及结肠癌事件可以得到其分子生物学的数据。研究人员发现，常规服用阿司匹林与BRAF-野生型癌症风险的显著下降（27%）有关。常规服用阿司匹林与BRAF-变异型癌症风险的降低没有关系。“服用阿司匹林与结肠直肠癌风险的关系会根据BRAF的变异状态而有明显的差异。”

文章的作者还观察到BRAF-野生型癌症的罹患风险会随着每周服用的阿司匹林片数的增加而降低；然而，对BRAF-变异型癌而言却没有明显的风险降低的趋势。 “每周服用阿司匹林的片数与患癌风险之间的关系随着BRAF变异的状态而有明显的差异。与那些报告没有服用阿司匹林者相比，在那些每周服用6-14片阿司匹林的人中及在那些每周服用超过14片阿司匹林的人中观察到的罹患BRAF野生型癌症风险有了显著的下降。”

此外，较长时间服用阿司匹林与BRAF野生型癌症罹患风险的显著下降有关，但服用阿司匹林的持续时间与BRAF变异型癌症罹患风险没有显著的关系。

“确认可通过阿司匹林预防的特定癌症亚型因为数个原因而变的重要。首先，它增进了我们对结肠直肠肿瘤发病的分子机制以及阿司匹林可能发挥其抗肿瘤作用的机制的理解。其次，研发对结肠直肠癌特定亚型的临床的、基因的或分子预测因子可能导致更有针对性的筛检或可用化疗进行预防的策略的发展。然而，鉴于不甚大的绝对风险差异，有必要进行进一步的研究来评估我们的结果的临床意义。最后，我们的数据就服用阿司匹林与某种特定亚型的结肠直肠癌风险的降低之间存在着因果关系提供了额外的支持。不断累积的证据支持阿司匹林具有抗结肠直肠癌的预防作用。”

Aspirin Use and Risk of Colorectal Cancer According to BRAF Mutation Status
Importance
Aspirin use reduces the risk of colorectal carcinoma. Experimental evidence implicates a role of RAF kinases in up-regulation of prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase 2), suggesting that BRAF-mutant colonic cells might be less sensitive to the antitumor effects of aspirin than BRAF–wild-type neoplastic cells.
Objective
To examine whether the association of aspirin intake with colorectal cancer risk differs according to status of tumor BRAF oncogene mutation.
Design and Setting
We collected biennial questionnaire data on aspirin use and followed up participants in the Nurses' Health Study (from 1980) and the Health Professionals Follow-up Study (from 1986) until July 1, 2006, for cancer incidence and until January 1, 2012, for cancer mortality. Duplication-method Cox proportional cause-specific hazards regression for competing risks data was used to compute hazard ratios (HRs) for colorectal carcinoma incidence according to BRAF mutation status.
Main Outcomes and Measures
Incidence of colorectal cancer cases according to tumor BRAF mutation status.
Results
Among 127 865 individuals, with 3 165 985 person-years of follow-up, we identified 1226 incident rectal and colon cancers with available molecular data. Compared with nonuse, regular aspirin use was associated with lower BRAF–wild-type cancer risk (multivariable HR, 0.73; 95% CI, 0.64 to 0.83; age-adjusted incidence rate difference [RD], −9.7; 95% CI, −12.6 to −6.7 per 100 000 person-years). This association was observed irrespective of status of tumor PTGS2 expression or PIK3CA or KRAS mutation. In contrast, regular aspirin use was not associated with a lower risk of BRAF-mutated cancer (multivariable HR, 1.03; 95% CI, 0.76 to 1.38; age-adjusted, incidence RD, 0.7; 95% CI, −0.3 to 1.7 per 100 000 person-years: P for heterogeneity = .037, between BRAF–wild-type vs BRAF-mutated cancer risks). Compared with no aspirin use, aspirin use of more than 14 tablets per week was associated with a lower risk of BRAF–wild-type cancer (multivariable HR, 0.43; 95% CI, 0.25 to 0.75; age-adjusted incidence RD, −19.8; 95% CI, −26.3 to −13.3 per 100 000 person-years). The relationship between the number of aspirin tablets per week and colorectal cancer risk differed significantly by BRAF mutation status (P for heterogeneity = .005).
Conclusions and Relevance
Regular aspirin use was associated with lower risk of BRAF–wild-type colorectal cancer but not with BRAF-mutated cancer risk. These findings suggest that BRAF-mutant colon tumor cells may be less sensitive to the effect of aspirin. Given the modest absolute risk difference, further investigations are necessary to determine clinical implications of our findings.