REV3L single nucleotide variants lead to increased susceptibility towards non-small cell lung cancer in the population of Jammu and Kashmir

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Background

The region of Jammu and Kashmir (J&K) in India lies in the Himalayan belt between Latitude 32.17″ and 36.58″ North and Longitude 73.26″ and 80.30″ East [1] , having population of diverse ethnic background, such as Gujjar, Bakarwal, Dogra, Kashmiri and Pahari. This region has long been considered as an endemic cancer zone with a peculiar cancer profile [2] . Lung cancer, which globally accounted for 18% of cancer related deaths in 2020, is a major cancer type in Indian populations; especially in the male population (India State-Level Disease Burden Initiative Cancer Collaborators, 2016) [3] . A recent study has reported lung cancer as the second most common cancer in the J&K region, with 23.5% of all new cancer cases reported in 2017 [4] . Although several studies have evaluated mutations in the key genes, such as genes involved in cell cycle, cell growth, DNA damage repair and many other pathways with reference to different cancers in the population of J&K 5678 , none have evaluated the role of Translesion Synthesis (TLS) polymerase in any cancer type. As the DNA is continuously getting altered by both endogenous as well as exogenous factors, organisms have developed various repair and DNA damage tolerance (DDT) mechanisms to preserve their genome. Any disruption in these pathways, therefore, has a potential to cause malignancy [1213] , which may lead to cancer 91011 .

TLS polymerases, the key players of DDT pathway consist of a family of five specialized polymerases; polymerase κ, ζ, η, ι and Rev1 121314 . Due to their error prone nature, most of these TLS polymerases, including pol ζ have been found associated with different cancer types [15] . DNA pol ζ is a heterodimer; consisting of Rev3, the catalytic subunit and Rev7, the accessory subunit. Pol ζ mediated lesion bypass involves binding of Rev1 to the replication complex, which then recruits DNA pol ζ to the damaged site. The lesion bypass allows the replication process to continue, thereby preventing the more deleterious effect of blocked replication forks which may lead to chromosome instability in cells. Hence, pol ζ along with other TLS polymerases may be considered as suppressors of spontaneous tumorigenesis [1617] .

Various genetic and environmental factors have been associated with increased risk of developing lung cancer 9101121] . In the present study, we looked at the association of rs1002481 (T > A), rs462779 (G>A), rs465646 (G>A), and rs11153292 (G>A) single nucleotide variants (SNVs) in the REV3L (Protein reversion less 3-like) gene, which encodes the Rev3 subunit of pol ζ with non-small cell lung cancer (NSCLC) in the population of Jammu and Kashmir. The selection of these variants was based on available literature 181920212223 . SNV rs1002481 is an intronic variant located on Intron 7, rs462779 is an exonic variant located on exon 15, rs465646 is located on 3′ UTR region of REV3L and rs11153292 is an intronic variant located on Intron 6.