Cancer
UGT2B10 haplotypes within the substrate binding and enzyme activity functional pockets are associated with lung cancer Maher Alsaadi* Maher Alsaadi Mohammed S Orloff Heather Robeson
Background.
Smoking accounts for 80-90% of lung cancer cases, yet only 10-15% of smokers develop the disease, indicating the complexity of genetic factors involved. Smoking-related carcinogens can damage the lungs, but genetic mutations greatly increase lung cancer risk. The UDP glucuronosyltransferase 2B10 (UGT2B10) gene helps remove tobacco-specific carcinogens, and reduced activity of this gene raises serum nicotine levels in smokers. While associations between UGT2B10 SNPs and lung cancer have been reported, the full extent of genetic/allelic heterogeneity remains unexplained. Our goal was to investigate the relationship between UGT2B10 haplotype and lung cancer.
Methods.
A total of 154 tissue samples, including lung cancer and normal tissue, were genotyped for the exon 1 of UGT2B10. In this cohort 69 matched pairs of non-small cell lung cancer (NSCLC) tissues and their corresponding normal tissues, and 16 unmatched samples were analyzed. Allelic and genotypic association analyses were performed using PLINK 1.9 and Haploview 4.2. Linkage disequilibrium (LD) analysis and moving window haplotype analysis were used to assess haplotype structures and LD patterns. UGT2B10 protein stability and enzyme activity were studied for significant haplotypes containing relevant missense mutations by AlphaFold and Alpha Missense.
Results.
Twenty-one of the 26 SNPs that passed quality control spanned the UGT2B10 domain containing multiple structural pockets (P1–P20), which are critical for substrate binding and enzyme activity. The haplotype analysis revealed three significant haplotypes P= 0.01 to 0.04. These haplotypes contained alleles that mapped to multiple pockets including P1 (which affects substrate interactions), suggesting their role in substrate interactions and enzyme efficiency.
Conclusion.
These genetic variations may influence UGT2B10 function, affecting toxic/nicotine metabolism and NSCLC pathogenesis.