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The Association and Risk Prediction of the Ubiquitination Pathway Genetic Variants and Lung Cancer Incidence: A
Jianing Mao1, Lingyun Leng1, Tianyi Zhu1
1Department of Epidemiology, School of Public Health; Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China.
Summary
Genetic variants in the ubiquitin-proteasome system (UPS) are linked to lung cancer risk. A specific MGRN1 variant may increase risk by downregulating MGRN1, a potential tumor suppressor.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- The ubiquitin-proteasome system (UPS) plays a crucial role in cellular protein degradation and is implicated in cancer development.
- While UPS dysregulation is linked to tumorigenesis, population-level data on UPS genetic variants and lung cancer risk are scarce.
Purpose of the Study:
- To investigate the association between genetic variants in UPS-related genes and lung cancer risk in a population-based cohort.
- To evaluate the potential of identified genetic variants to improve lung cancer risk prediction models.
Main Methods:
- A two-stage genetic association study was conducted, analyzing 70,801 single nucleotide polymorphisms (SNPs) from 750 UPS-related genes.
- Discovery stage involved 612 lung cancer cases and 901 controls; significant SNPs were validated in an independent cohort of 2718 individuals.
- Functional analyses, including expression quantitative trait loci (eQTL) and enhancer-promoter interaction studies, were performed.
Main Results:
- Over 2,500 SNPs were initially associated with lung cancer risk, with six validated in the independent cohort.
- The MGRN1 rs11640681 A>G variant showed a significant association with increased lung cancer risk (ORvalidation = 1.32, P = 0.011).
- This variant may downregulate MGRN1 expression, which was found to be higher in normal lung tissue than NSCLC and associated with better patient survival.
Conclusions:
- Genetic variants in the UPS pathway contribute to non-small cell lung cancer (NSCLC) risk.
- The MGRN1 rs11640681 G allele may increase NSCLC risk by reducing MGRN1 expression, suggesting MGRN1 acts as a tumor suppressor.
- These findings offer insights into NSCLC etiology and identify potential biomarkers for risk stratification.
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