Genome-wide association study and Mendelian randomization analyses provide insights into the causes of early-onset colorectal cancer

孟德尔随机化 医学 结直肠癌 全基因组关联研究 穆提 遗传学 遗传关联 肿瘤科 癌症 生物信息学 单核苷酸多态性 内科学 种系突变 基因 基因型 突变 生物 遗传变异
作者
Ruhina Shirin Laskar,Conghui Qu,Jeroen R. Huyghe,Tabitha A. Harrison,Richard B. Hayes,Yin Cao,Peter T. Campbell,Robert S. Steinfelder,Fazlur Rahman Talukdar,Hermann Brenner,Shuji Ogino,S. Brendt,D. Timothy Bishop,Daniel D. Buchanan,Andrew T. Chan,Michelle Cotterchio,Stephen B. Gruber,Andrea Gsur,Bethany Van Guelpen,Mark A. Jenkins,Temitope O. Keku,Brigid M. Lynch,Loı̈c Le Marchand,Richard M. Martin,Kathryn McCarthy,Vı́ctor Moreno,Rachel Pearlman,Mingyang Song,Konstantinos K. Tsilidis,Pavel Vodička,Michael O. Woods,Kana Wu,Li Hsu,Marc J. Gunter,Ulrike Peters,Neil Murphy
出处
期刊:Annals of Oncology [Elsevier]
被引量:7
标识
DOI:10.1016/j.annonc.2024.02.008
摘要

Abstract

Background

The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. Colorectal cancer (CRC) has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC.

Patients and methods

We conducted a genome-wide association study meta-analysis of 6,176 EOCRC cases and 65,829 controls from Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), Colorectal Transdisciplinary study (CORECT), Colon Cancer Family Registry (CCFR), and UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample Mendelian randomization (MR).

Results

We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (OR=1.80 [95%CI=1.47-2.22]) but show that most of the common genetic susceptibility was from non-coding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC susceptibility genes, and in addition to pathways such as TGFβ, SMAD, BMP, and PI3K signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors - such as body fat percentage, waist circumference, waist to hip ratio, basal metabolic rate, and fasting insulin – higher alcohol drinking and lower education attainment, with increased EOCRC risk.

Conclusion

Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk stratify individuals for personalized screening strategies or other interventions.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
刚刚
tree完成签到,获得积分10
4秒前
4秒前
5秒前
1111111111完成签到,获得积分10
8秒前
9秒前
9秒前
9秒前
孤烟发布了新的文献求助10
10秒前
烟花应助啦啦哗啦啦哗采纳,获得10
11秒前
11秒前
我爱学习发布了新的文献求助10
12秒前
13秒前
zlh发布了新的文献求助10
13秒前
14秒前
123456qi完成签到,获得积分10
15秒前
二十八发布了新的文献求助10
17秒前
正直无颜发布了新的文献求助10
17秒前
18秒前
18秒前
五月天发布了新的文献求助30
19秒前
称心的映菱完成签到,获得积分10
19秒前
阿木完成签到,获得积分10
19秒前
随机子应助学霸土豆采纳,获得10
19秒前
小周同学完成签到,获得积分10
20秒前
许十五完成签到,获得积分10
20秒前
20秒前
21秒前
香蕉觅云应助LIKUN采纳,获得10
21秒前
赘婿应助畜生采纳,获得30
21秒前
24秒前
于禾发布了新的文献求助10
24秒前
25秒前
25秒前
26秒前
沉静若山发布了新的文献求助10
26秒前
不懂发布了新的文献求助10
26秒前
27秒前
28秒前
小木又寸发布了新的文献求助10
29秒前
高分求助中
Evolution 3rd edition 1500
保险藏宝图 1000
Lire en communiste 1000
Mantiden: Faszinierende Lauerjäger Faszinierende Lauerjäger 700
PraxisRatgeber: Mantiden: Faszinierende Lauerjäger 700
Mathematics and Finite Element Discretizations of Incompressible Navier—Stokes Flows 500
A new species of Coccus (Homoptera: Coccoidea) from Malawi 500
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3184739
求助须知:如何正确求助?哪些是违规求助? 2835049
关于积分的说明 8002768
捐赠科研通 2497447
什么是DOI,文献DOI怎么找? 1332826
科研通“疑难数据库(出版商)”最低求助积分说明 636714
邀请新用户注册赠送积分活动 604085