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Gene & Protein in Disease Association of GST1 with lung cancer

1. Introduction non-coding variants in cancer by integrating whole-
genome and transcriptome data from cancer samples.
Lung cancer stands as the most prevalent form of
carcinogenesis and the primary cause of cancer-related Of particular interest is the differential expression of
fatalities worldwide. In India, it accounts for 5.9% of all xenobiotic metabolism genes (XMGs) and DNA repair
cancer cases and contributes to 8.1% of cancer-related genes (DRGs) in the airway bronchial epithelium of healthy
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deaths. Tobacco smoke plays a significant role in the etiology smokers compared to non-smokers, as well as with smokers
of lung cancer, with smoking causing approximately 90% with lung cancer. 14-16 Xenobiotic metabolism and DNA
of all lung cancer deaths. According to the report from repair proteins have been known to play crucial roles in
2,3
the National Cancer Registry Programme of India, there determining the level of carcinogenic load in the lungs and
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were 1,392,179 cancer patients in the country in 2020, the capacity to repair DNA damage inflicted by this load.
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with lung cancer being among the top five common types. Effective clearance of cigarette smoke toxic metabolites by
The Indian Council of Medical Research projects that by xenobiotic metabolism proteins is essential for preventing
2025, India is likely to experience a more than seven-fold the accumulation of toxic products and subsequent DNA
increase in lung cancer cases. damage. 15,18,19 In addition, DNA repair proteins must
remain vigilant in correcting such damage to prevent the
Interestingly, susceptibility to cigarette smoke-related replication of damaged DNA. Therefore, it is reasonable
lung cancer varies considerably, even among individuals to hypothesize that alterations in the expression of XMGs
exposed to similar pack-years of smoking. Epidemiological and DRGs, potentially due to the presence of regulatory
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research reveals that only 15 – 20% of smokers develop SNVs (rSNVs), may cause less effective metabolism of
lung cancer, suggesting differential genetic susceptibility. cigarette smoke xenobiotics and/or inefficient repair of
5-7
This observation is supported by evidence from familial DNA damage induced by cigarette smoke.
clustering of the disease, segregation studies, microarray
analyses, and single nucleotide variant (SNV)-based Based on this hypothesis, our team has identified
association studies. Both high-penetrance, rare genetic 22 gene expression-correlated DNAse hypersensitive
variants, and low-penetrance, high-frequency variants sequence rSNVs from the regulatory regions of seven
have been identified, and these genetic variants tend to XMGs and seven DRGs. These rSNVs possess the strong
differ between populations. Molecular genetic studies potential to modulate the transcription of target genes and
show that lung cancer cells acquire multiple genetic and are primarily situated in the cis-expression quantitative
epigenetic changes, including copy number alterations and trait locus (eQTL) regions of the associated genes. We
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aberrant promoter hypermethylation, probably as a result identified risk variants for each rSNV, which, on exposure
of increasing genomic instability. However, a deeper to cigarette smoke, could potentially modulate gene
8,9
insight into the molecular basis of these risk signatures expression and contribute to lung cancer development.
often remains elusive. Conversely, individuals with the protective variants may
be less susceptible to this damage.
The advent of next-generation sequencing and genome-
wide SNV genotyping has been pivotal in advancing To test this hypothesis, we conducted a pilot case–control
personalized treatment for lung cancer. Genome- association study with three promoter SNVs (selected
wide association studies in populations with relatively from the list of 22) in an eastern Indian cohort. The study
homogeneous ancestry have recognized around 45 loci revealed an association between the rs3764821 SNV of the
associated with lung cancer. However, such comprehensive ALDH3B1 and the rs3748523 SNV of the RAD52 gene with
7,10
association studies have not been conducted in countries cigarette smoke-related lung cancer, thereby strengthening
like India, where lung cancer incidence is on the rise. our hypothesis and validating our SNV identification and
prioritization pipeline. We aim to further validate the
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Notably, significant differences in gene expression
have been observed between smokers with lung cancer other identified SNVs in the same population through
case–control association studies, which may help define a
and both healthy smokers and healthy non-smokers,
as demonstrated through microarray and RNA-seq population-specific genetic signature of risk variants that
analyses. 11,12 SNVs related to human traits and diseases, contribute to cigarette smoke-related lung cancer. This
including cancer, are now believed to modulate the activity strategy may also facilitate the development of precision
of cis-regulatory elements of target genes, contributing to medicine-based personalized treatments, the creation of
differences in gene expression. Some SNVs are known to effective cigarette control laws, and the implementation of
create entirely new regulatory elements, thereby altering genetic counseling for disease prevention.
target gene expression. Extensive research has been In this study, we focused on assessing the genetic
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conducted to develop algorithms for identifying regulatory association between cigarette smoke-related lung cancer

Volume 3 Issue 3 (2024) 2 doi: 10.36922/gpd.3928