Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
Department of Preventive Medicine, USC Norris Comprehensive Cancer Center.
J Natl Cancer Inst. 2019 Feb 1;111(2):146-157. doi: 10.1093/jnci/djy099.
Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.
We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.
The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.
This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.
先前的全基因组关联研究（GWAS）已经确定了 42 个与结直肠癌（CRC）风险相关的位点（P < 5×10-8）。扩展的联盟努力有助于发现更多的易感性位点，可能会捕捉到无法解释的家族风险。
我们采用发现-复制设计进行了欧洲血统 CRC 病例和对照的 GWAS，随后在多民族样本中检查了新发现（累积 n = 163315）。在发现阶段（36948 例病例/30864 例对照），我们使用逻辑回归识别了风险等位基因频率为 1%或更高的与 CRC 风险相关的遗传变异，然后进行固定效应逆方差加权荟萃分析。所有达到全基因组统计学意义（双侧 P < 5×10-8）的新独立变异均在单独的欧洲血统样本中进行了复制检验（12952 例病例/48383 例对照）。接下来，我们研究了在东亚人、非裔美国人和西班牙裔中发现的变异的可推广性（12085 例病例/22083 例对照）。最后，我们研究了新风险变异对家族相对风险的贡献，并研究了多基因风险评分的预测能力。所有统计检验均为双侧。
发现 GWAS 在 P < 5×10-8 处确定了 11 个与 CRC 相关的变异，其中 9 个（位于 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13）在 P 值小于.05 时独立复制。多民族随访支持发现结果的可推广性。这些结果表明，常见风险等位基因解释家族相对风险的增加了 14.7%，从 10.3%（95%置信区间[CI] = 7.9%至 13.7%；已知变体）增加到 11.9%（95%CI = 9.2%至 15.5%；已知和新变体）。多基因风险评分确定了 4.3%的人群，其患 CRC 的比值比至少为 2.0。
本研究深入了解了常见遗传变异对 CRC 病因学的影响，并提高了个体化筛查的风险预测能力。
