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; Yongyue Wei; Xiang Zhou; Shuiping Huang; Huashuo Zhao; Ping Zeng

doi:10.3389/fgene.2020.583106

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

Front Genet. 2020 Oct 23:11:583106. doi: 10.3389/fgene.2020.583106. eCollection 2020.

Authors

Yixin Gao¹, Yongyue Wei², Xiang Zhou^{3

4}, Shuiping Huang^{1

5}, Huashuo Zhao^{1

5}, Ping Zeng^{1

5}

Affiliations

¹ Department of Epidemiology and Biostatistics, School of Public Health, Xuzhou Medical University, Xuzhou, China.
² Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.
³ Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, United States.
⁴ Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI, United States.
⁵ Center for Medical Statistics and Data Analysis, School of Public Health, Xuzhou Medical University, Xuzhou, China.

Abstract

Background: 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; 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.

Methods: We 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.

Results: In 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.

Conclusion: Our 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.

Keywords: Mendelian randomization; TCGA; UK Biobank; cancer; genetic risk score; leukocyte telomere length.

Abstract

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