Telomere lengths in patients with a high burden of melanomas

Summary: Abstract Body: Both short and long telomere lengths have been implicated in cancer susceptibility due to its role in genomic stability. While prior studies have found longer blood telomere lengths to be associated with increased risk for melanoma, the role of telomere length in patients with an extreme burden of melanoma remains unexplored. Understanding this relationship can provide insights into mechanisms driving melanoma development in high-burden cases. From 2017 to 2022, 94 patients with an extreme number of melanomas (mean 5.26±2.29, range 3–16) without known germline mutations were enrolled, and genomic DNA from saliva samples were subjected to whole genome sequencing. Telomere lengths were calculated using TelSeq and compared to an age-matched cohort of patients with keratinocyte cancers but no history of melanoma. Contrary to prior findings in melanoma incidence cohorts, these high-burden melanoma patients demonstrated substantially shorter weighted mean telomere lengths compared to controls (0.46 vs 1.24 kb, p<0.0001, Wilcoxon Rank Sum Test). This reduction was most pronounced in the shortest telomere fraction (0.32 vs 0.94 kb, p<0.0001), though longer telomeres were also decreased relative to controls (0.65 vs 1.62 kb, p<0.0001). When separating our high-burden melanoma cohort into groups of patients with 3-4 melanomas versus 5 or more melanomas, we found a non-significant slight trend towards shorter telomeres in patients with 5 or more melanomas compared to those with 3-4 (0.45 vs 0.48 kb, p=0.303). These findings challenge the established paradigm of long telomeres in melanoma risk and suggest that telomere shortening, which can lead to genomic instability and compromised DNA damage response, may be a distinct mechanism driving melanoma development in patients with extreme melanoma burden. This suggests that there is a context dependent role for telomeres in melanoma risk. Audris Chiang¹, Haniyah Shareef¹, Shufeng Li¹, Warren Chan¹, Nicole Urman¹, Aatman Shah¹, Shaundra Eichstadt¹, Jeanie Ramos¹, Kiana Yekrang¹, Irene Bailey¹, Ying Ni², Joshua Arbesman³, Susan Swetter¹, Kavita Sarin¹ 1. Dermatology, Stanford University, Stanford, CA, United States. 2. Immunotherapy & Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH, United States. 3. Cancer Biology, Cleveland Clinic, Cleveland, OH, United States. Pigmentation, Melanoma, and Melanoma Immune Surveillance