Telomere Length and the Risk of Cutaneous Malignant Melanoma in Melanoma-Prone Families with and without CDKN2A Mutations

Laura S Burke,Laurie Burdette,Alisa M Goldstein,Stephen Chanock,Sharon A Savage,Meredith Yeager,Lisa Mirabello,Margaret A Tucker,Jennifer Prescott,William Wheeler,Xiaohong R Yang,Immaculata De Vivo,Ruth M Pfeiffer,Paula L Hyland

doi:10.1371/journal.pone.0071121

Abstract

IntroductionRecent evidence suggests a link between constitutional telomere length (TL) and cancer risk. Previous studies have suggested that longer telomeres were associated with an increased risk of melanoma and larger size and number of nevi. The goal of this study was to examine whether TL modified the risk of melanoma in melanoma-prone families with and without CDKN2A germline mutations.Materials and MethodsWe measured TL in blood DNA in 119 cutaneous malignant melanoma (CMM) cases and 208 unaffected individuals. We also genotyped 13 tagging SNPs in TERT.ResultsWe found that longer telomeres were associated with an increased risk of CMM (adjusted OR = 2.81, 95% CI = 1.02–7.72, P = 0.04). The association of longer TL with CMM risk was seen in CDKN2A- cases but not in CDKN2A+ cases. Among CMM cases, the presence of solar injury was associated with shorter telomeres (P = 0.002). One SNP in TERT, rs2735940, was significantly associated with TL (P = 0.002) after Bonferroni correction.DiscussionOur findings suggest that TL regulation could be variable by CDKN2A mutation status, sun exposure, and pigmentation phenotype. Therefore, TL measurement alone may not be a good marker for predicting CMM risk.

Highlights

Recent evidence suggests a link between constitutional telomere length (TL) and cancer risk
The association of longer TL with Cutaneous malignant melanoma (CMM) risk was seen in CDKN2A- cases but not in CDKN2A+ cases
When CDKN2A+ and CDKN2A- cases were separately compared to unaffected individuals, we found that the association of longer TL with CMM risk was seen in CDKN2A- cases (OR = 3.34, 95% confidence intervals (CIs) = 1.12–10.00, P = 0.03; comparing longest to shortest TL) but not in CDKN2A+ cases (OR = 1.00, 95% CI = 0.42–2.38, P = 0.99) (Table 4)

Summary

Introduction

Recent evidence suggests a link between constitutional telomere length (TL) and cancer risk. Germline CDKN2A mutations are associated with a high risk of CMM, the penetrance of this gene is incomplete and varies by age and geographical location. [6] phenotypic manifestations such as age at diagnosis, presence/number of DN, number of melanomas, and cosegregation of pancreatic cancer vary significantly among mutation carriers even within a single family These findings suggest that other factors modify the effect of CDKN2A. Telomeres are located at the ends of chromosomes, and consist of tandem nucleotide repeats (TTAGGG)n, the telomerase enzyme, the shelterin protein complex, and many other accessory proteins. Telomerase is upregulated in the majority of cancers [9] and in the immortalization of skin keratinocytes. [10] Previous studies have shown that genetic variation in TERT was associated with melanoma risk. [11] Recently, a germline mutation in the promoter of TERT was identified in a melanoma-prone family that caused a 2–4 fold increase of TERT transcription. [12] Multiple mutations in the TERT promoter were found in primary melanoma tissues with high frequency (33%),[12,13] suggesting that the dysregulation of TERT may play an important role in the genesis of melanoma

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