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

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 & 19 others Helen Snowden, Remco Van Doorn, Grant W. Montgomery, Nicholas G. Martin, Thomas M. Keane, Carlos López-Otín, Anne Marie Gerdes, Hakan 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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numberdju408
JournalJournal of the National Cancer Institute
Volume107
Issue number2
DOIs
StatePublished - Feb 1 2015
Externally publishedYes

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Nonsense Codon
Melanoma
Mutation
Genes
Telomere
Cluster Analysis
Population Control
Cutaneous Malignant Melanoma
Germ-Line Mutation
Telomerase
Point Mutation
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Aoude, L. G., Pritchard, A. L., Robles-Espinoza, C. D., Wadt, K., Harland, M., Choi, J., ... Hayward, N. K. (2015). Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma. Journal of the National Cancer Institute, 107(2), [dju408]. https://doi.org/10.1093/jnci/dju408

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, Víctor; 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 Doorn, Remco; Montgomery, Grant W.; Martin, Nicholas G.; Keane, Thomas M.; López-Otín, Carlos; Gerdes, Anne Marie; Olsson, Hakan; Ingvar, Christian; Borg, Ake; Gruis, Nelleke A.; Trent, Jeffrey M.; Jönsson, Göran; Bishop, D. Timothy; Mann, Graham J.; Newton-Bishop, Julia A.; Brown, Kevin M.; Adams, David J.; Hayward, Nicholas K.

In: Journal of the National Cancer Institute, Vol. 107, No. 2, dju408, 01.02.2015.

Research output: Contribution to journalArticle

Aoude, LG, Pritchard, AL, Robles-Espinoza, CD, Wadt, K, Harland, M, Choi, J, Gartside, M, Quesada, V, Johansson, P, Palmer, JM, Ramsay, AJ, Zhang, X, Jones, K, Symmons, J, Holland, EA, Schmid, H, Bonazzi, V, Woods, S, Dutton-Regester, K, Stark, MS, Snowden, H, Van Doorn, R, Montgomery, GW, Martin, NG, Keane, TM, López-Otín, C, Gerdes, AM, Olsson, H, Ingvar, C, Borg, A, Gruis, NA, Trent, JM, Jönsson, G, Bishop, DT, Mann, GJ, Newton-Bishop, JA, Brown, KM, Adams, DJ & Hayward, NK 2015, 'Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma', Journal of the National Cancer Institute, vol. 107, no. 2, dju408. https://doi.org/10.1093/jnci/dju408
Aoude LG, Pritchard AL, Robles-Espinoza CD, Wadt K, Harland M, Choi J et al. Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma. Journal of the National Cancer Institute. 2015 Feb 1;107(2). dju408. https://doi.org/10.1093/jnci/dju408
Aoude, Lauren G. ; Pritchard, Antonia L. ; Robles-Espinoza, Carla Daniela ; Wadt, Karin ; Harland, Mark ; Choi, Jiyeon ; Gartside, Michael ; Quesada, Víctor ; 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 Doorn, Remco ; Montgomery, Grant W. ; Martin, Nicholas G. ; Keane, Thomas M. ; López-Otín, Carlos ; Gerdes, Anne Marie ; Olsson, Hakan ; Ingvar, Christian ; Borg, Ake ; Gruis, Nelleke A. ; Trent, Jeffrey M. ; Jönsson, Göran ; Bishop, D. Timothy ; Mann, Graham J. ; Newton-Bishop, Julia A. ; Brown, Kevin M. ; Adams, David J. ; Hayward, Nicholas K. / Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma. In: Journal of the National Cancer Institute. 2015 ; Vol. 107, No. 2.
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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.",
author = "Aoude, {Lauren G.} and Pritchard, {Antonia L.} and Robles-Espinoza, {Carla Daniela} and Karin Wadt and Mark Harland and Jiyeon Choi and Michael Gartside and V{\'i}ctor Quesada and Peter Johansson and Palmer, {Jane M.} and Ramsay, {Andrew J.} and Xijun Zhang and Kristine Jones and Judith Symmons and Holland, {Elizabeth A.} and Helen Schmid and Vanessa Bonazzi and Susan Woods and Ken Dutton-Regester and Stark, {Mitchell S.} and Helen Snowden and {Van Doorn}, Remco and Montgomery, {Grant W.} and Martin, {Nicholas G.} and Keane, {Thomas M.} and Carlos L{\'o}pez-Ot{\'i}n and Gerdes, {Anne Marie} and Hakan Olsson and Christian Ingvar and Ake Borg and Gruis, {Nelleke A.} and Trent, {Jeffrey M.} and G{\"o}ran J{\"o}nsson and Bishop, {D. Timothy} and Mann, {Graham J.} and Newton-Bishop, {Julia A.} and Brown, {Kevin M.} and Adams, {David J.} and Hayward, {Nicholas K.}",
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T1 - Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma

AU - Aoude, Lauren G.

AU - Pritchard, Antonia L.

AU - Robles-Espinoza, Carla Daniela

AU - Wadt, Karin

AU - Harland, Mark

AU - Choi, Jiyeon

AU - Gartside, Michael

AU - Quesada, Víctor

AU - Johansson, Peter

AU - Palmer, Jane M.

AU - Ramsay, Andrew J.

AU - Zhang, Xijun

AU - Jones, Kristine

AU - Symmons, Judith

AU - Holland, Elizabeth A.

AU - Schmid, Helen

AU - Bonazzi, Vanessa

AU - Woods, Susan

AU - Dutton-Regester, Ken

AU - Stark, Mitchell S.

AU - Snowden, Helen

AU - Van Doorn, Remco

AU - Montgomery, Grant W.

AU - Martin, Nicholas G.

AU - Keane, Thomas M.

AU - López-Otín, Carlos

AU - Gerdes, Anne Marie

AU - Olsson, Hakan

AU - Ingvar, Christian

AU - Borg, Ake

AU - Gruis, Nelleke A.

AU - Trent, Jeffrey M.

AU - Jönsson, Göran

AU - Bishop, D. Timothy

AU - Mann, Graham J.

AU - Newton-Bishop, Julia A.

AU - Brown, Kevin M.

AU - Adams, David J.

AU - Hayward, Nicholas K.

PY - 2015/2/1

Y1 - 2015/2/1

N2 - 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.

AB - 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.

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