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

Aoude, Lauren G., Pritchard, Antonia L., Robles-Espinoza, Carla Daniela, Wadt, Karin, Harland, Mark, Choi, Jiyeon, Gartside, Michael, Quesada, Victor, Johansson, Peter, Palmer, Jane M., Ramsay, Andrew J., Zhang, Xijun, Jones, Kristine, Symmons, Judith, Holland, Elizabeth A., Schmid, Helen, Bonazzi, Vanessa, Woods, Susan, Dutton-Regester, Ken, Stark, Mitchell S., Snowden, Helen, van Doom, Remco, Montgomery, Grant W., Martin, Nicholas G., Keane, Thomas M., Lopez-Otin, Carlos, Gerdes, Anne-Marie, Olsson, Hakan, Ingvar, Christian, Borg, Ake, Gruis, Nelleke A., Trent, Jeffrey M., Jonsson, Goran, Bishop, D. Timothy, Mann, Graham J., Newton-Bishop, Julia A., Brown, Kevin M., Adams, David J. and Hayward, Nicholas K. (2015) Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma. Journal of the National Cancer Institute, 107 2: 1-7. doi:10.1093/jnci/dju408

Attached Files (Some files may be inaccessible until you login with your UQ eSpace credentials)
Name Description MIMEType Size Downloads

Author Aoude, Lauren G.
Pritchard, Antonia L.
Robles-Espinoza, Carla Daniela
Wadt, Karin
Harland, Mark
Choi, Jiyeon
Gartside, Michael
Quesada, Victor
Johansson, Peter
Palmer, Jane M.
Ramsay, Andrew J.
Zhang, Xijun
Jones, Kristine
Symmons, Judith
Holland, Elizabeth A.
Schmid, Helen
Bonazzi, Vanessa
Woods, Susan
Dutton-Regester, Ken
Stark, Mitchell S.
Snowden, Helen
van Doom, Remco
Montgomery, Grant W.
Martin, Nicholas G.
Keane, Thomas M.
Lopez-Otin, Carlos
Gerdes, Anne-Marie
Olsson, Hakan
Ingvar, Christian
Borg, Ake
Gruis, Nelleke A.
Trent, Jeffrey M.
Jonsson, Goran
Bishop, D. Timothy
Mann, Graham J.
Newton-Bishop, Julia A.
Brown, Kevin M.
Adams, David J.
Hayward, Nicholas K.
Title Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma
Formatted title
Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma
Journal name Journal of the National Cancer Institute   Check publisher's open access policy
ISSN 1460-2105
Publication date 2015-02-01
Year available 2015
Sub-type Article (original research)
DOI 10.1093/jnci/dju408
Volume 107
Issue 2
Start page 1
End page 7
Total pages 7
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Collection year 2016
Language eng
Formatted 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 TINF 2. 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Medicine Publications
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 19 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 17 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Fri, 19 Jun 2015, 19:30:19 EST by System User on behalf of Discipline of Molecular and Cellular Pathology