Keum NaNa, Liu Li, Hamada Tsuyoshi, Qian Zhi Rong, Nowak Jonathan A, Cao Yin, da Silva Annacarolina, Kosumi Keisuke, Song Mingyang, Nevo Daniel, Wang Molin, Chan Andrew T, Meyerhardt Jeffrey A, Fuchs Charles S, Wu Kana, Ogino Shuji, Nishihara Reiko, Zhang Xuehong
Department of Nutrition, Harvard T.H. Chan School of Public Health, Building 2, 3rd Floor, 665 Huntington Avenue, Boston, MA, 02115, USA.
Department of Food Science and Biotechnology, Dongguk University, Goyang, South Korea.
Cancer Causes Control. 2019 Jun;30(6):637-649. doi: 10.1007/s10552-019-01165-3. Epub 2019 Apr 8.
A preventive potential of high calcium intake against colorectal cancer has been indicated for distal colon cancer, which is inversely associated with high-level CpG island methylator phenotype (CIMP), high-level microsatellite instability (MSI), and BRAF and PIK3CA mutations. In addition, BRAF mutation is strongly inversely correlated with KRAS mutation. We hypothesized that the association between calcium intake and colon cancer risk might vary by these molecular features.
We prospectively followed 88,506 women from the Nurses' Health Study and 47,733 men from the Health Professionals Follow-up Study for up to 30 years. Duplication-method Cox proportional cause-specific hazards regression was used to estimate multivariable hazard ratios (HRs), and 95% confidence intervals (95% CIs) for the associations between calcium intake and the risk of colon cancer subtypes. By Bonferroni correction, the α-level was adjusted to 0.01.
Based on 853 colon cancer cases, the inverse association between dietary calcium intake and colon cancer risk differed by CIMP status (p = 0.01). Per each 300 mg/day increase in intake, multivariable HRs were 0.84 (95% CI 0.76-0.94) for CIMP-negative/low and 1.12 (95% CI 0.93-1.34) for CIMP-high. Similar differential associations were suggested for MSI subtypes (p = 0.02), with the corresponding HR being 0.86 (95% CI 0.77-0.95) for non-MSI-high and 1.10 (95% CI 0.92-1.32) for MSI-high. No differential associations were observed by BRAF, KRAS, or PIK3CA mutations.
The inverse association between dietary calcium intake and colon cancer risk may be specific to CIMP-negative/low and possibly non-MSI-high subtypes.
高钙摄入对远端结肠癌具有预防潜力，远端结肠癌与高水平的CpG岛甲基化表型（CIMP）、高水平微卫星不稳定性（MSI）以及BRAF和PIK3CA突变呈负相关。此外，BRAF突变与KRAS突变呈强烈负相关。我们推测钙摄入量与结肠癌风险之间的关联可能因这些分子特征而异。
我们对护士健康研究中的88,506名女性和健康专业人员随访研究中的47,733名男性进行了长达30年的前瞻性随访。采用重复法Cox比例病因特异性风险回归来估计多变量风险比（HR）以及钙摄入量与结肠癌亚型风险之间关联的95%置信区间（95%CI）。通过Bonferroni校正，将α水平调整为0.01。
基于853例结肠癌病例，饮食钙摄入量与结肠癌风险之间的负相关因CIMP状态而异（p = 0.01）。摄入量每增加300毫克/天，CIMP阴性/低水平者的多变量HR为0.84（95%CI 0.76 - 0.94），CIMP高水平者为1.12（95%CI 0.93 - 1.34）。MSI亚型也显示出类似的差异关联（p = 0.02），非MSI高水平者的相应HR为0.86（95%CI 0.77 - 0.95），MSI高水平者为1.10（95%CI 0.92 - 1.32）。BRAF、KRAS或PIK3CA突变未观察到差异关联。
饮食钙摄入量与结肠癌风险之间的负相关可能特定于CIMP阴性/低水平以及可能的非MSI高水平亚型。
