Lung cancer has highest mortality rate among cancers for both males and females, whereas males are more affected than females in leukemia by the ratio 1:5:1:0 [
1]. Both the cancers are aggressive in nature, and this is one of the major global health concern worldwide. Lung cancer constitutes 12.9% of all newly diagnosed cancer cases and 19.4% of all cancer associated deaths globally [
2,
3] took place. Lung Cancer is the major cause of cancer related deaths in India accounting for 63,000 newly diagnosed patients each year with 52,000 deaths, and thereby contributing to 9.3% of all cancer associated deaths [
4,
5]. Furthermore, lung cancer in Kashmir region (J&K) was reported to be the second most common malignancy in hospital based study. [
6]. While in Jammu region (J&K), unpublished data from our research group found that lung cancer and breast cancer are most commonly occurring cancers followed by esophageal cancer.
Lung cancer and Leukemia are multifactorial in nature, where both genetic and non-genetic factors like environmental pollution, occupational exposure and smoking mainly contribute to its etiology [
7]. Single nucleotide polymorphism (SNP) genotyping and Genome wide association studies (GWAS) in Japanese population have revealed that chromosome 5p15.33 is the strong candidate region associated with lung cancer [
8]. Genetic variant rs2853677 of telomere maintenance gene
TERT is located in an intronic region of chromosome 5p15.33 (chr5:1,253,147-1,295,069) [
9]. Telomeres are actually caps located at the terminal end of the linear chromosomes, which acts as an important factor in maintaining the genomic stability. In humans, telomeres comprise of guanine rich hexa nucleotide (TTAGGG) repeats. The stability of the telomeres solely depends on the integrity of the associated telomere maintenance proteins, which always work in coordinated manner, referred to as the shelterin complex [
10]. Shelterin complex comprises of different factors like Telomeric Repeat Binding Factor 1 (TRF1), Telomeric Repeat Binding Factor 2 (TRF2), TRF1-Interacting Nuclear Factor 2 (TIN2), Protection of Telomeres 1 (POT1), Tripeptidyl Peptidase 1 (TPP1) and Repressor Activator Protein 1 (RAP1) [
11]. Among the binding factors TRF1 and TRF2 bind to the double stranded telomeric DNA segment as homodimers. TRF1 inhibits the action of telomerase thus acts as negative regulator of telomere length [
12] and the stability of T loop is maintained by TRF2. Mutation in TRF2 results in the activation of Ataxia Telangiectasia Mutated (ATM) protein mediated DNA damage signal which leads to end-to-end telomere fusion and telomere homologous recombination, leading to typical process of telomere sister-chromatid exchange (T-SCE) [
13]. However, repressor activator protein 1 (RAP1) directly binds to TRF2 protein which is crucial for efficient binding of TRF2 protein to the telomeric DNA. Another important factor POT1 protects the chromosome ends from fusion and a typical recombination and helps in the recruitment of telomerase to the telomeric DNA, thus contributing to the protection of telomeres [
14]. TRF-interacting nuclear factor 2 (TIN2) protein mainly binds with other shelterin proteins like TRF1, TRF2 and TPP1, acting as a critical component of the shelterin complex and bridging all these proteins of the shelterin complex together for efficient working. [
12]. Shelterin proteins possibly regulate telomere elongation by enrolling Telomerase, which is a ribonucleoprotein complex consisting of reverse transcriptase (
TERT) and RNA subunit (
TERC). Telomerase is inactive and suppressed in most of the normal somatic cells. During the S phase of cell cycle, it gets activated and stimulates the replication process of telomeric DNA, which is not replicated, by DNA polymerase during replication [
15].
In the present study, we conducted an association study of variant rs2853677 of TERT gene and susceptibility to non-small cell lung carcinoma and leukemia in population of Jammu and Kashmir. The critical reason to identify these associations is to understand the genetic heterogeneity of non-small cell lung cancer and leukemia and possibility of using the newly identified genetic variant of telomere maintenance gene (TERT) as prognostic biomarker for diagnosis of non-small cell lung cancer and leukemia.