维生素可预防结直肠癌前病变复发风险？真相居然是……
虽然流行病学和临床前证据表明维生素D和钙可抑制结直肠癌发生，可能的机制包括诱导细胞分化和凋亡以及抑制细胞的生长和增殖，但是在一项随机双盲安慰剂对照临床试验（维生素D/钙预防息肉研究）中，45～75岁的参与者每天补充维生素D3和/或碳酸钙3～5年并未显著降低复发性结直肠腺瘤的风险，亦未证据显示其在亚组中有预防作用，只提示可能使低体重指数参与者的风险降低。那么，维生素D3或钙剂补充到底能不能预防结直肠腺瘤？或许这一问题能在分子和基因层面找到答案，因为维生素D和钙信号通路相关基因的单核苷酸多态性（SNP）与循环25-羟维生素D水平相关。
SNP是指不同物种、个体基因组DNA序列同一位置上的单个核苷酸存在差别的现象。有这种差别的基因座、DNA序列等可作为基因组作图的标志。人基因组上平均约每1000个核苷酸即可能出现1个SNP的变化，其中有些SNP可能与疾病有关，但可能大多数与疾病无关。SNP是研究人类家族和动植物品系遗传变异的重要依据。
2016年12月15日，《美国医学会杂志·肿瘤学》在线发表美国达特茅斯学院、英国伦敦国王学院、美国埃默里大学、美国退伍军人事务部佛蒙特白河汇医疗中心、美国德克萨斯大学MD安德森癌症中心、美国北卡罗来纳大学的随机临床研究报告，探讨了7种维生素D和钙信号通路基因（VDR、GC、DHCR7、CYP2R1、CYP27B1、CYP24A1、CASR）中的常见SNP变异是否改变维生素D3或钙补充对结直肠腺瘤复发的影响。
该研究在美国11个临床中心进行的随机双盲安慰剂对照临床试验中，检测了2259位患者的41个候选SNP。入组标准包括新诊断为结直肠腺瘤但经结肠镜切除后无结直肠息肉残留。干预措施为每天口服补充维生素D3（1000IU）或碳酸钙（1200mg元素钙）或两者或安慰剂。研究的治疗阶段于2013年8月31日结束，分析于2014年7月28日～2016年10月19日进行。评定结局为随访期间出现≥1个腺瘤或晚期腺瘤（估计直径≥1cm；或有绒毛组织学发现，高度不典型增生或癌），根据校正风险比和95%置信区间估算治疗效果与基因型的相关性和相互作用，计算独立SNP有效数量以校正多重检测。
结果发现，在2259例随机化患者中，完成试验并有基因型数据可供分析的非西班牙裔白人共1702例（男性1101例，平均年龄58.1±6.8岁）。
补充维生素D3仅对晚期腺瘤而非全部腺瘤的复发风险有影响，根据连锁不平衡分析，受到维生素D受体（VDR）的2个SNP基因型（rs7968585和rs731236）显著影响（D'=0.98；r²=0.6）。
对于rs7968585，在占26%的AA基因型患者中，补充维生素D3将复发风险减少64%（风险比：0.36，95%置信区间：0.19～0.69，P=0.002；绝对风险从14.4%减至5.1%）；在占74%的G或GG基因型患者中，补充维生素D3将复发风险增加41%（风险比：1.41，95%置信区间：0.99～2.00，P=0.05；绝对风险从7.7%增至11.1%，相互作用P＜0.001）。基因型与补充钙无显著相互作用。
该研究结果表明，补充维生素D3预防晚期结直肠腺瘤的好处可能会根据维生素D受体基因型不同而变化。也就是说，服用维生素D的“好消息”是对晚期腺瘤有预防作用，“坏消息”是该预防作用因人而异。
对于想要谋求腺瘤预防效果的人群，医生暂时还不能贸然给予维生素D。需要注意的是，现在的研究证据还不够强，即便在分子层面，SNP也只是基因个体差异的一部分，还有其他很多干扰因素有待查证。在精准医学背景下，肿瘤的预防也需要更加个体化。未来的研究需要深入了解结直肠癌发生的复杂机制，以确定维生素D到底有无预防作用、预防作用的大小、在哪些人群中有预防作用。
相关阅读
JAMA Oncol. 2016 Dec 15. [Epub ahead of print]
Vitamin D Receptor Genotype, Vitamin D3 Supplementation, and Risk of Colorectal Adenomas: A Randomized Clinical Trial.
Barry EL, Peacock JL, Rees JR, Bostick RM, Robertson DJ, Bresalier RS, Baron JA.
Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire; King's College London, London, England; Rollins School of Public Health, Winship Cancer Institute, Emory University, Atlanta, Georgia; VA Medical Center, White River Junction, Vermont; The University of Texas MD Anderson Cancer Center, Houston; University of North Carolina School of Medicine, Chapel Hill.
IMPORTANCE: Despite epidemiological and preclinical evidence suggesting that vitamin D and calcium inhibit colorectal carcinogenesis, daily supplementation with these nutrients for 3 to 5 years was not found to significantly reduce the risk of recurrent colorectal adenomas in a recent randomized clinical trial.
OBJECTIVE: To investigate whether common variants in 7 vitamin D and calcium pathway genes (VDR, GC, DHCR7, CYP2R1, CYP27B1, CYP24A1, and CASR) modify the effects of vitamin D3 or calcium supplementation on colorectal adenoma recurrence.
DESIGN, SETTING, AND PARTICIPANTS: We examined 41 candidate single-nucleotide polymorphisms (SNPs) in 2259 participants in a randomized, double-blind, placebo-controlled trial conducted at 11 clinical centers in the United States. Eligibility criteria included a recently diagnosed adenoma and no remaining colorectal polyps after complete colonoscopy. The study's treatment phase ended on August 31, 2013, and the analysis for the present study took place from July 28, 2014, to October 19, 2016.
INTERVENTIONS: Daily oral supplementation with vitamin D3 (1000 IU) or calcium carbonate (1200 mg elemental calcium) or both or neither.
MAIN OUTCOMES AND MEASURES: The outcomes assessed were the occurrence of 1 or more adenomas or advanced adenomas (estimated diameter, ≥1 cm; or with villous histologic findings, high-grade dysplasia, or cancer) during follow-up. Treatment effects and genotype associations and interactions were estimated as adjusted risk ratios (RRs) and 95% confidence intervals (CIs). The effective number of independent SNPs was calculated to correct for multiple testing.
RESULTS: Among the 2259 participants randomized, 1702 were non-Hispanic whites who completed the trial and had genotype data for analysis (1101 men; mean [SD] age 58.1 [6.8] years). The effect of vitamin D3 supplementation on advanced adenomas, but not on adenoma risk overall, significantly varied according to genotype at 2 VDR SNPs (rs7968585 and rs731236) in linkage disequilibrium (D' = 0.98; r² = 0.6). For rs7968585, among individuals with the AA genotype (26%), vitamin D3 supplementation reduced risk by 64% (RR, 0.36; 95% CI, 0.19-0.69; P = .002; absolute risk decreased from 14.4% to 5.1%). Among individuals with 1 or 2 G alleles (74%), vitamin D3 supplementation increased risk by 41% (RR, 1.41; 95% CI, 0.99-2.00; P = .05; absolute risk increased from 7.7% to 11.1%; P < .001 for interaction). There were no significant interactions of genotypes with calcium supplementation.
CONCLUSIONS AND RELEVANCE: Our findings suggest that benefits from vitamin D3 supplementation for the prevention of advanced colorectal adenomas may vary according to vitamin D receptor genotype.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00153816.
PMID: 27978548
DOI: 10.1001/jamaoncol.2016.5917
