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
窝窝头发布了新的文献求助10
刚刚
刚刚
已而遂晴发布了新的文献求助10
刚刚
刚刚
田向露发布了新的文献求助10
1秒前
义气发布了新的文献求助10
1秒前
1秒前
2秒前
Little_可爱发布了新的文献求助10
2秒前
科研通AI2S应助niu采纳,获得10
3秒前
wt发布了新的文献求助10
3秒前
小赞完成签到,获得积分10
3秒前
3秒前
yfxf发布了新的文献求助10
3秒前
3秒前
慕青应助呆萌从蓉采纳,获得10
4秒前
4秒前
5秒前
Jasper应助euphoria采纳,获得10
5秒前
寒冷志泽发布了新的文献求助50
6秒前
6秒前
英姑应助Uith采纳,获得10
6秒前
好甜口完成签到,获得积分10
7秒前
科研通AI2S应助义气采纳,获得10
7秒前
Alex发布了新的文献求助10
7秒前
Nicole发布了新的文献求助10
9秒前
新时代好青年完成签到,获得积分10
10秒前
CBL发布了新的文献求助10
10秒前
希望天下0贩的0应助卿十采纳,获得30
10秒前
wt完成签到,获得积分10
11秒前
哎呀我去完成签到,获得积分10
11秒前
12秒前
12秒前
乔苏惠娜完成签到,获得积分10
13秒前
害羞的裘完成签到 ,获得积分10
13秒前
13秒前
林子恒发布了新的文献求助10
13秒前
13秒前
robinhood完成签到,获得积分10
13秒前
高分求助中
Evolution 3rd edition 1500
Lire en communiste 1000
Mantiden: Faszinierende Lauerjäger Faszinierende Lauerjäger 700
PraxisRatgeber: Mantiden: Faszinierende Lauerjäger 700
A new species of Coccus (Homoptera: Coccoidea) from Malawi 500
2-Acetyl-1-pyrroline: an important aroma component of cooked rice 500
Ribozymes and aptamers in the RNA world, and in synthetic biology 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 3181189
求助须知:如何正确求助?哪些是违规求助? 2831405
关于积分的说明 7984596
捐赠科研通 2493399
什么是DOI,文献DOI怎么找? 1330143
科研通“疑难数据库(出版商)”最低求助积分说明 635934
版权声明 602954