Assessing the Relationship Between Leukocyte Telomere Length and Cancer Risk/Mortality in UK Biobank and TCGA Datasets With the Genetic Risk Score and Mendelian Randomization Approaches.

Yixin Gao,Ping Zeng,Xiang Zhou,Shuiping Huang,Yongyue Wei,Huashuo Zhao

doi:10.3389/fgene.2020.583106

Abstract

BackgroundTelomere length is an important indicator of tumor progression and survival for cancer patients. Previous work investigated the associations between genetically predicted telomere length and cancers; however, the types of cancers investigated in those studies were relatively limited or the telomere length-associated genetic variants employed often came from genome-wide association studies (GWASs) with small sample sizes.MethodsWe constructed the genetic risk score (GRS) for leukocyte telomere length based on 17 associated genetic variants available from the largest telomere length GWAS up to 78,592 individuals. Then, a comprehensive analysis was undertaken to evaluate the association between the constructed GRS and the risk or mortality of a wide range of cancers [i.e., 37 cancers in the UK Biobank and 33 cancers in The Cancer Genome Atlas (TCGA)]. We further applied the two-sample Mendelian randomization (MR) to estimate the causal effect of leukocyte telomere length on UK Biobank cancers via summary statistics.ResultsIn the UK Biobank dataset, we found that the GRS of leukocyte telomere length was associated with a decreased risk of nine types of cancer (i.e., significant association with multiple myeloma, chronic lymphocytic leukemia, kidney/renal cell cancer, bladder cancer, malignant melanoma, basal cell carcinoma, and prostate cancer and suggestive association with sarcoma/fibrosarcoma and Hodgkin’s lymphoma/Hodgkin’s disease). In addition, we found that the GRS was suggestively associated with an increased risk of leukemia. In the TCGA dataset, we observed suggestive evidence that the GRS was associated with a high death hazard of rectum adenocarcinoma (READ), sarcoma (SARC), and skin cutaneous melanoma (SKCM), while the GRS was associated with a low death hazard of kidney renal papillary cell carcinoma (KIRP). The results of MR further supported the association for leukocyte telomere length on the risk of malignant melanoma, Hodgkin’s lymphoma/Hodgkin’s disease, chronic lymphocytic leukemia and multiple myeloma.ConclusionOur study reveals that telomere played diverse roles in different types of cancers. However, further validations in large-scale prospective studies and deeper investigations of the biologic mechanisms are warranted.

Highlights

Telomere is a special structure with a 6-bp TTAGGG repeat sequence and plays an important role in genomic stability by protecting DNA against damage and fusion 0 (de Lange, 2005)
It has been proposed that telomere shortening can generally give rise to end-to-end chromosome fusions and attenuates DNA damage response, increasing genomic instability and initiating carcinogenesis (Wu et al, 2003). These findings indicate that telomere plays a dual role in cancer development, and such role seems to depend on the types of cancers and the balance of the proliferation and senescence of cells in cancers
Our study reveals that telomere played diverse roles in different types of cancers; further validations in large-scale prospective studies and deeper investigations of the biologic mechanisms are warranted

Summary

Introduction

Telomere is a special structure with a 6-bp TTAGGG repeat sequence and plays an important role in genomic stability by protecting DNA against damage and fusion 0 (de Lange, 2005). Due to the inability of DNA polymerase to fully extend the 3 end of DNA strand, the telomere becomes progressively shorter during each round of cell division. In stem and progenitor cells, the length of telomere is maintained by enzyme telomerase (Hackett and Greider, 2002; Shawi and Autexier, 2008). It is shown that enzyme telomerase is activated in almost all human tumors; such an activation can result in the continuous division of cancer cells and is the key component of the tumorigenic phenotype of human cancer cells (Stewart and Weinberg, 2006; O’Sullivan and Karlseder, 2010). Telomere length is an important indicator of tumor progression and survival for cancer patients. Previous work investigated the associations between genetically predicted telomere length and cancers; the types of cancers investigated in those studies were relatively limited or the telomere length-associated genetic variants employed often came from genome-wide association studies (GWASs) with small sample sizes

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