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J Natl Cancer Inst. 2014 Dec 13;107(2). pii: dju408. doi: 10.1093/jnci/dju408. Print 2015 Feb.

Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma.

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Affiliations of authors: QIMR Berghofer Medical Research Institute, Brisbane, Australia (LGA, ALP, MG, PJ, JMP, JS, VB, SW, KDR, MSS, GWM, NGM, NKH); Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK (CDRE, TMK, DJA); Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark (KW, AMG); Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK (MH, HSn, DTB, JANB); Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD (JC, KMB); Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias (IUOPA) Universidad de Oviedo, Oviedo, Spain (VQ, AJR, CLO); Cancer Genomics Research Laboratory, NCI Frederick, SAIC-Frederick Inc., Frederick MD (XZ, KJ); Department of Dermatology, Leiden University Medical Centre, Leiden, the Netherlands (RvD, NAG); Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden (HO, CI, ÅB, GJ); Translational Genomics Institute, Phoenix, AZ (JMT); University of Sydney at Westmead Millennium Institute, Westmead, Sydney, NSW, Australia (EAH, HSc, GJM); Melanoma Institute Australia, North Sydney, NSW, Australia (EAH, HSc, GJM).



The shelterin complex protects chromosomal ends by regulating how the telomerase complex interacts with telomeres. Following the recent finding in familial melanoma of inactivating germline mutations in POT1, encoding a member of the shelterin complex, we searched for mutations in the other five components of the shelterin complex in melanoma families.


Next-generation sequencing techniques were used to screen 510 melanoma families (with unknown genetic etiology) and control cohorts for mutations in shelterin complex encoding genes: ACD, TERF2IP, TERF1, TERF2, and TINF 2. Maximum likelihood and LOD [logarithm (base 10) of odds] analyses were used. Mutation clustering was assessed with χ(2) and Fisher's exact tests. P values under .05 were considered statistically significant (one-tailed with Yates' correction).


Six families had mutations in ACD and four families carried TERF2IP variants, which included nonsense mutations in both genes (p.Q320X and p.R364X, respectively) and point mutations that cosegregated with melanoma. Of five distinct mutations in ACD, four clustered in the POT1 binding domain, including p.Q320X. This clustering of novel mutations in the POT1 binding domain of ACD was statistically higher (P = .005) in melanoma probands compared with population control individuals (n = 6785), as were all novel and rare variants in both ACD (P = .040) and TERF2IP (P = .022). Families carrying ACD and TERF2IP mutations were also enriched with other cancer types, suggesting that these variants also predispose to a broader spectrum of cancers than just melanoma. Novel mutations were also observed in TERF1, TERF2, and TINF2, but these were not convincingly associated with melanoma.


Our findings add to the growing support for telomere dysregulation as a key process associated with melanoma susceptibility.

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