Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/118198
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Type: Journal article
Title: Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma
Author: Aoude, L.
Pritchard, A.
Robles-Espinoza, C.
Wadt, K.
Harland, M.
Choi, J.
Gartside, M.
Quesada, V.
Johansson, P.
Palmer, J.
Ramsay, A.
Zhang, X.
Jones, K.
Symmons, J.
Holland, E.
Schmid, H.
Bonazzi, V.
Woods, S.
Dutton-Regester, K.
Stark, M.
et al.
Citation: JNCI Journal of the National Cancer Institute, 2014; 107(2):dju408-1-dju408-7
Publisher: Oxford University Press
Issue Date: 2014
ISSN: 0027-8874
1460-2105
Statement of
Responsibility: 
Lauren G. Aoude, Antonia L. Pritchard, Carla Daniela Robles-Espinoza, Karin Wadt, Mark Harland ... Susan Woods ... et al.
Abstract: 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 TINF2. Maximum likelihood and LOD [logarithm (base 10) of odds] analyses were used. Mutation clustering was assessed with χ2 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.
Keywords: Telomere; Humans; Melanoma; Skin Neoplasms; Genetic Predisposition to Disease; Telomere-Binding Proteins; Telomeric Repeat Binding Protein 2; DNA, Neoplasm; Codon, Nonsense; Pedigree; Sequence Analysis, DNA; Germ-Line Mutation; Point Mutation; Adult; Aged; Middle Aged; Female; Male
Rights: © The Author 2014. Published by Oxford University Press. All rights reserved.
RMID: 0030037253
DOI: 10.1093/jnci/dju408
Appears in Collections:Medicine publications

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