Telomere length and TERT polymorphisms of as biomarkers in asbestos-related diseases

Abstract

Background: Malignant mesothelioma (MM), primarily caused by asbestos exposure, is considered a telomerase-dependant cancer. The reactivation of the enzymatic complex telomerase results in maintaining short yet stable telomere length in cancer cells. The catalytic subunit hTERT plays a critical role in this process. Previous studies have noted a connection between shorter leukocyte telomere length in pleural effusion and an increased risk of cancer development. Additionally, asbestos exposure has been identified as a risk factor for shorter telomere length. However, these findings have not yet been applied to MM. The objective of this study is to investigate whether telomere length in leukocytes and genetic polymorphisms in the hTERT gene could serve as a potential biomarkers for the risk of developing asbestos-related diseases and as biomarkers of progression and chemotherapy response rate in MM.

Methods: We conducted two retrospective studies: a case-control study and a longitudinal observational study. Telomere length was assessed in 79 patients with MM (211 samples, taken at various time points during MM chemotherapy treatment) and in 79 cases with pleural plaques (PP). Furthermore, a total of 340 patients with MM, 340 cases with PP and 94 control group subjects were genotyped for hTERT polymorphisms. Logistic regression and survival analysis were used as statistical methods for our analysis.

Results: Our analysis revealed that patients with MM had significantly shorter telomeres (p <0.001) than cases with PP. Carriers of at least one polymorphic allele rs2736098 had a significantly higher risk of developing MM (carriers of one polymorphic allele: odds ratio (OR) = 1.63; 95% confidence interval (CI) = 1.20 – 2.21; p = 0.002; adjustment for age: OR = 1.49; CI = 1.06 – 2.10; p = 0.023; carriers of at least one polymorphic allele: OR = 1.46; CI = 1.09 – 1.96; p = 0.011). However, the presence of at least one polymorphic allele rs2736100, along with age adjustment, significantly decreased the risk of developing MM (carriers of at least one polymorphic allele: OR = 0.66; CI = 0.46-0.95; p = 0.026; carriers of two polymorphic alleles: OR = 0.56; CI = 0.35 – 0.90; p = 0.017). On the other hand, carriers of two polymorphic alleles rs10069690 displayed a significantly higher risk for MM development (OR = 2.28; CI = 1.24 – 4.22; p = 0.008). We found no significant connection between telomere length and chemotherapy response rate in patients with MM (p > 0.05). Good chemotherapy response was observed in patients with MM who had at least one polymorphic allele of rs10069690 (carriers of one polymorphic allele: OR = 1.81; CI = 1.03 – 3.17; p = 0.039; adjustment for age: OR = 2.08; CI = 1.13 – 3.84; p = 0.019; carriers of at least one polymorphic allele: OR = 1.72; CI = 1.00 – 2.93; p = 0.048; adjustment for age: OR = 2.04; CI = 1.13 – 3.67; p = 0.017). Regarding progression-free survival (PFS) in MM patients, we did not find any significant influence of telomere length (p > 0.05). However, carrying two polymorphic alleles of rs2736100 was significantly associated with longer PFS in patients with MM (HR = 0.68; CI = 0.47 – 0.98; p = 0.038).

Conclusions: Telomere length and hTERT polymorphisms may serve as a biomarker for the risk of developing asbestos-related diseases. While telomere length did not show an association with MM chemotherapy response, genetic variability in hTERT may be used as a predictive biomarker for chemotherapy response rate in patients with MM. Additionally, in this paper, we did not observe a significant connection between telomere length and MM progression. Lastly, hTERT polymorphism may be considered as a biomarker for the progression of MM.