Zhu Yun, Wang Peizhong Peter, Zhai Guangju, Bapat Bharati, Savas Sevtap, Woodrow Jennifer R, Sharma Ishor, Li Yuming, Zhou Xin, Yang Ning, Campbell Peter T, Dicks Elizabeth, Parfrey Patrick S, Mclaughlin John R
Division of Community Health and Humanities, Faculty of Medicine, Memorial University of Newfoundland, St John's, NL A1B 3V6, Canada.
School of Public Health, Tianjin Medical University, Tianjin, 300070, China.
Br J Cancer. 2017 Sep 5;117(6):898-906. doi: 10.1038/bjc.2017.242. Epub 2017 Aug 1.
Increased serum levels of vitamin D and calcium have been associated with lower risks of colorectal cancer (CRC) incidence and mortality. These inverse associations may be mediated by the vitamin D receptor (VDR) and the calcium-sensing receptor (CASR). We investigated genetic variants in VDR and CASR for their relevance to CRC prognosis.
A population-based cohort of 531 CRC patients diagnosed from 1999 to 2003 in Newfoundland and Labrador, Canada, was followed for mortality and cancer recurrence until April 2010. Germline DNA samples were genotyped with the Illumina Omni-Quad 1 Million chip. Multivariate Cox models assessed 41 tag single-nucleotide polymorphisms and relative haplotypes on VDR and CASR in relation to all-cause mortality (overall survival, OS) and disease-free survival (DFS).
Gene-level associations were observed between VDR and the DFS of rectal cancer patients (P=0.037) as well as between CASR and the OS of colon cancer patients (P=0.014). Haplotype analysis within linkage blocks of CASR revealed the G-G-G-G-G-A-C haplotype (rs10222633-rs10934578-rs3804592-rs17250717-A986S-R990G-rs1802757) to be associated with a decreased OS of colon cancer (HR, 3.15; 95% CI, 1.66-5.96). Potential interactions were seen among prediagnostic dietary calcium intake with the CASR R990G (P=0.040) and the CASR G-T-G-G-G-G-C haplotype for rs10222633-rs10934578-rs3804592-rs17250717-A986S-R990G-rs1802757 (P=0.017), with decreased OS time associated with these variants limited to patients consuming dietary calcium below the median, although the stratified results were not statistically significant after correction for multiple testing.
Polymorphic variations in VDR and CASR may be associated with survival after a diagnosis of CRC.
血清维生素D和钙水平升高与结直肠癌（CRC）发病率和死亡率降低相关。这些反向关联可能由维生素D受体（VDR）和钙敏感受体（CASR）介导。我们研究了VDR和CASR中的基因变异与CRC预后的相关性。
对1999年至2003年在加拿大纽芬兰和拉布拉多诊断出的531例CRC患者进行基于人群的队列研究，随访其死亡率和癌症复发情况直至2010年4月。用Illumina Omni-Quad 100万芯片对种系DNA样本进行基因分型。多变量Cox模型评估了VDR和CASR上的41个标签单核苷酸多态性和相对单倍型与全因死亡率（总生存期，OS）和无病生存期（DFS）的关系。
观察到VDR与直肠癌患者的DFS之间存在基因水平关联（P = 0.037），以及CASR与结肠癌患者的OS之间存在基因水平关联（P = 0.014）。对CASR连锁块内的单倍型分析显示，G-G-G-G-G-A-C单倍型（rs10222633-rs10934578-rs3804592-rs17250717-A986S-R990G-rs1802757）与结肠癌患者OS降低相关（HR，3.15；95%CI，1.66 - 5.96）。在诊断前饮食钙摄入量与CASR R990G（P = 0.040）以及rs10222633-rs10934578-rs3804592-rs17250717-A986S-R990G-rs1802757的CASR G-T-G-G-G-G-C单倍型之间观察到潜在相互作用，与这些变异相关的OS时间缩短仅限于饮食钙摄入量低于中位数的患者，尽管在多重检验校正后分层结果无统计学意义。
VDR和CASR的多态性变异可能与CRC诊断后的生存期相关。
