Cumulative Burden of Colorectal Cancer Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer
Cumulative Burden of Colorectal Cancer Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer
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DOI：
10.1053/j.gastro.2019.12.012
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发表时间：
2020-04-01
期刊：
影响因子：
29.4
通讯作者：
Hayes, Richard B.
中科院分区：
文献类型：
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作者：
Archambault, Alexi N.;Su, Yu-Ru;Hayes, Richard B.
背景与目的：早发性结直肠癌（CRC，年龄小于50岁）的发病率正在上升；然而，由于没有CRC家族史，这一人群缺乏统一的预防建议。我们的目的是确定由95种CRC相关的常见遗传风险变异形成的多基因风险评分（PRS）是否与早发性CRC的风险相关。方法：我们研究了12197名年龄小于50岁的参与者和95865名年龄大于50岁的参与者与加权PRS相关的CRC风险。PRS是根据截至2019年1月的大规模全基因组关联研究中与CRC相关的单核苷酸多态性计算的。参与者来自3个提供临床和基因分型数据的大型联盟：结肠癌家族登记处、结直肠癌跨学科研究和结直肠癌遗传学和流行病学联盟，并且都是遗传上确定的欧洲血统。研究结果在72573名参与者的独立队列中得到了重复。结果：早发性癌症的PRS与CRC的每标准差的总体相关性显著，与晚发性癌症相比更强（相互作用P = 0.01）；当我们比较最高PRS四分位数与最低PRS四分位数时，早发性CRC的风险增加3.7倍（95% CI 3.28-4.24），而晚发性CRC的风险增加2.9倍（95% CI 2.80-3.04）。这种关联在没有一级CRC家族史的参与者中最强（相互作用P = 5.61 x 10(-5)）。当我们比较该组中最高和最低四分位数时，早发性CRC的风险增加了4.3倍（95% CI 3.61-5.01），而晚发性CRC的风险增加了2.9倍（95% CI 2.70-3.00）。敏感性分析与这些发现一致。结论：在一项PRS标准差与CRC的相关性分析中，我们发现CRC相关常见遗传变异的累积负担与早发性癌症相关，并且与早发性癌症的相关性比晚发性癌症更强，特别是在没有CRC家族史的情况下。对PRS以及环境和生活方式风险因素的分析，可能会确定哪些年轻人将从预防措施中受益。
BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC. METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants. RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 x 10(-5)). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings. CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.