TERTPolymorphism rs2736100-C Is Associated with EGFR Mutation–Positive Non–Small Cell Lung Cancer

Abstract

Purpose Epidermal growth factor receptor (EGFR) mutation-positive (EGFRmut+) non-small cell lung cancer (NSCLC) may be a unique orphan disease. Previous studies suggested that the telomerase reverse transcriptase (TERT) gene polymorphism is associated with demographic and clinical features strongly associated with EGFR mutations, e.g. adenocarcinoma histology, never-smoking history and female gender. We aim to test the association between TERT polymorphism and EGFRmut+ NSCLC. Experimental Design We conducted a genetic association study in Chinese NSCLC patients (n=714) and healthy controls (n=2,520), between the rs2736100 polymorphism and EGFRmut+ NSCLC. We further tested the association between the EGFR mutation status and mean leukocyte telomere length (LTL). The potential function of rs2736100 in lung epithelial cells was also explored. Results The rs2736100-C allele was significantly associated with EGFRmut+ NSCLC (OR=1.52, 95%CI=1.28–1.80, p=1.6×10−6) but not EGFRmut− NSCLC (OR=1.07, 95%CI=0.92–1.24, p=0.4). While NSCLC patients as a whole have significantly longer LTL compared to healthy controls (p≤10−13), the EGFRmut+ patients have even longer LTL compared to EGFRmut-patients (p=0.008). Meanwhile, rs2736100 was significantly associated with TERT mRNA expression in both normal and tumor lung tissues. All results remained significant after controlling for age, gender, smoking status and histology (p<0.05 for all tests). Moreover, the rs2736100 DNA sequence has an allele-specific affinity to nuclear proteins extracted from lung epithelial cells, which led to an altered enhancer activity of the sequence in vitro. Conclusion Our study suggests that telomerase and telomere function may be essential for carcinogenesis of EGFRmut+ NSCLC. Further investigation for the underlying mechanism is warranted.

The association between the TERT rs2736100 AC genotype and reduced risk of upper tract urothelial carcinomas in a Han Chinese population

“…The relationship between the rs2736100 SNP and cancer susceptibility has been extensively explored [4, 5, 20–32, 35, 40, 41]. We and others previously analyzed the rs2736100 association with lung cancer risk, and observed a significantly elevated risk in C variant-carriers [20].…”

“…We and others previously analyzed the rs2736100 association with lung cancer risk, and observed a significantly elevated risk in C variant-carriers [20]. Recently, rs2736100-C was further identified to be more intimately associated with female, non-smoking, EGFR-mutation-positive lung adenocarcinoma [40]. In addition, the rs2736100-C has also been shown to be a risk allele for malignant glioma, colorectal carcinoma, cervical, pancreatic, bladder, and ovarian cancer, acute myeloid and lymphocytic leukemia, and others.…”

“…In a few of studies, the effect of rs2736100 alleles on TERT expression or telomerase activity was analyzed, but the results were discrepant. Wei et al observed that the luciferase reporter driven by C allele-containing sequences exhibited a higher activity than that by A allele-carrying fragments in one lung cancer cell line; they also showed significantly higher TERT mRNA levels coupled with longer telomere in lung cancer patients harboring CC genotypes than those with AA or AC variant [40]. In contrast, however, in patients with acute lymphoblastic leukemia, leukemic cells derived from CC- and AC-allele-carriers expressed lower levels of telomerase activity and had shorter telomere compared to those with the AA genotype [26].…”

“…We found that approximately 50% of RPCs and 20% of UCs carried TERT promoter mutations [2, 3, 39]. Because the cancer-risk alleles of the TERT SNPs may contribute to cancer susceptibility by their regulatory effect on TERT expression and telomerase activity [26, 40], it is worth assessing a relationship between TERT risk-alleles and TERT promoter mutations, which likely provides insights into cooperative roles of germline variants and somatic mutations of the TERT gene in oncogenesis.…”

An Overview of Genetic Polymorphism and Lung Cancer Risk

“…EGFR is activated by inflame deletion mutations in exon 19 and a point mutation in exon 21 (e.g., L858R) in 40-55% of ADC cases in the East Asian population and in 5-15% of ADC cases in the American population [26]. The association for the TERT SNP rs2736100 SNP in TERT intron 2 was reported to be stronger in ADC with an EGFR mutation than in ADC without an EGFR mutation [27].…”