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.
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