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Study Links Lung Cancer Risk to Genetic Variants Implicated in Alternative Splicing

NEW YORK — Researchers from China have cataloged and analyzed splicing quantitative trait loci (sQTLs) in human lung tissue. Combining the results with a genome-wide association study of non-small cell lung cancer, they identified several candidate risk genes and novel risk loci for the disease, the most common type of lung cancer.

Alternative splicing can result in different mRNAs from the same gene. According to the researchers, aberrant splicing patterns are common among diseases, including lung cancer; however, the effect of lung sQTLs on NSCLC risk has been largely underexplored.

"Alternative splicing contributes to the functional diversity and complexity of tissue proteins. The identification of sQTLs could help to understand the functional effects of genetic variants on complex traits and diseases," they wrote in a study published in the American Journal of Human Genetics on Thursday.

For its study, a team led by researchers from Nanjing Medical University in China recruited 116 NSCLC patients of Chinese ancestry who had not received chemotherapy or radiotherapy yet.

Next, they performed whole-genome sequencing on peripheral blood samples and RNA sequencing and splicing quantification on normal lung tissue samples from these patients and performed sQTL analysis. They identified 1,385 sQTL-harboring genes (sGenes) containing 378,210 significant variant-intron pairs.

The sQTLs were enriched in actively transcribed regions, genetic regulatory elements, and splicing factor binding sites, they noted. Some of the proteins binding to these sites are known to be involved in NSCLC risk: for example, RBM5, a component of the spliceosome A complex, could inhibit the development of NSCLC by modulating the alternative splicing of apoptosis-related genes.

Moreover, the sQTLs were largely distinct from expression quantitative trait loci (eQTLs) and showed significant enrichment in potential risk loci of NSCLC.

Subsequently, the researchers integrated their sQTL findings with a previously published NSCLC genome-wide association study (GWAS) of 13,327 individuals with cancer and 13,328 without in Chinese populations, using a splice-transcriptome-wide association study (spTWAS). Their results identified alternative splicing events in 19 genes significantly associated with NSCLC risk.

They picked an sQTL variant, rs35861926, in one of these genes for a functional study to confirm its biological mechanism. Their findings showed that this allele promoted skipping of exon 20 in the FARP1 gene and reduced the expression level of the long transcript FARP1-011.

FARP1 is a Rac guanine nucleotide exchange factor upregulated in EpCam-positive cells of human lung adenocarcinomas. The gene is also responsible for Rac1-mediated migration and invasion in lung cancer cells upon activation of receptor tyrosine kinases, but its role in the development of NSCLC had been unknown.

The findings showed that decreased expression levels of FARP1-011 inhibited the proliferation and migration of lung adenocarcinoma cells, which could explain the decrease in lung adenocarcinoma risk.

The study's findings indicated "that alternative splicing can be considered more broadly in post-GWAS functional analyses," the authors concluded.

One of the limitations was that they only considered cis-sQTLs in their study. Moreover, since they used bulk RNA sequencing data, they could not detect cell-type-specific sQTLs.

While they performed functional validation for FARP1, they added that the biological functions of other genes should be further evaluated in the future.