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

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  • Lauren G Aoude
  • Antonia L Pritchard
  • Carla Daniela Robles-Espinoza
  • Karin Wadt
  • Mark Harland
  • Jiyeon Choi
  • Michael Gartside
  • Víctor Quesada
  • Peter Johansson
  • Jane M Palmer
  • Andrew J Ramsay
  • Xijun Zhang
  • Kristine Jones
  • Judith Symmons
  • Elizabeth A Holland
  • Helen Schmid
  • Vanessa Bonazzi
  • Susan Woods
  • Ken Dutton-Regester
  • Mitchell S Stark
  • Helen Snowden
  • Remco van Doorn
  • Grant W Montgomery
  • Nicholas G Martin
  • Thomas M Keane
  • Carlos López-Otín
  • Anne-Marie Gerdes
  • Håkan Olsson
  • Christian Ingvar
  • Ake Borg
  • Nelleke A Gruis
  • Jeffrey M Trent
  • Göran Jönsson
  • D Timothy Bishop
  • Graham J Mann
  • Julia A Newton-Bishop
  • Kevin M Brown
  • David J Adams
  • Nicholas K Hayward
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BACKGROUND: 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.

METHODS: 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).

RESULTS: 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.

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

Original languageEnglish
JournalNational Cancer Institute. Journal (Online)
Volume107
Issue number2
Pages (from-to)dju408
ISSN1460-2105
DOIs
Publication statusPublished - Feb 2015

    Research areas

  • Adult, Aged, Codon, Nonsense, DNA, Neoplasm, Female, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Male, Melanoma, Middle Aged, Pedigree, Point Mutation, Sequence Analysis, DNA, Skin Neoplasms, Telomere, Telomere-Binding Proteins, Telomeric Repeat Binding Protein 2

ID: 45089177