Abstract 3408: Telomere length and TERT promoter mutations in cutaneous melanoma

Abstract

Abstract Telomeres at chromosomal ends are comprised of multiple short repeat sequences. In humans TTAGGG repeats account for telomere length ranging 10-15 kb. Telomere sequences are mainly double stranded that end in a single stranded G-rich tail of 150-200 nucleotides. Telomeres in somatic cells undergo gradual shortening due to inherent limitations of DNA replication and limited levels of specialized enzyme telomerase that adds the repeats at chromosomal ends to maintain homeostasis. We previously reported somatic mutations in the core promoter of the telomerase reverse transcriptase (TERT) gene that lead to increased transcription of catalytic subunit and tumor specific telomerase reactivation. Telomere length per se is associated with risk in different cancers. In this study, we measured leukocyte telomere length using real-time PCR in 1469 melanoma patients and compared with that in 1158 matched healthy controls. The melanoma patients had statistically significantly longer telomeres than matched controls (t-test; P 6X10^-10). Mendelian randomization, carried out using two polymorphisms represented by rs1317082 and rs7726159 that associated with telomere length in genome wide association studies, showed association between increased telomere length and melanoma risk with an odds ratio of 2.3 (95% confidence interval 1.8-2.8). When measured in blood tissues from a melanoma family with the germline -57A>C TERT promoter mutation, the carriers had longer telomeres (median 1.12) than the non-carriers (median 0.87). The TERT promoter mutations create binding motifs for E-twenty six (ETS) transcription factors and in stem cell the presence of the promoter mutations resulted in continued TERT expression and telomerase activity following differentiation into adult cells. Individuals with the germline TERT promoter mutations develop melanoma with an early age of onset and rapid progression to metastases; two individuals in the family who lived past median age of onset developed several other malignancies, besides melanoma. Thus, dysregulated telomerase leads to a severe phenotype. In an analogy, we hypothesize that association of longer rather than shorter telomeres with an increased risk of melanoma reflects stochastic increased telomerase levels due to common genetic variation. In contrast, the telomere length was shorter in tumors from unrelated melanoma patients with (121) than without (170) somatic TERT promoter mutations (P 1X10^-5), which reflects the selection of the mutations at telomere crisis. Thus, a dynamic but controlled system evolved around telomere homeostasis when dysregulated leads to an increased cancer risk and affects tumor progression. Citation Format: Sivaramakirishna Rachakonda, Barbara Heidenreich, Eduardo Nagore, Rajiv Kumar. Telomere length and TERT promoter mutations in cutaneous melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3408. doi:10.1158/1538-7445.AM2017-3408