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; 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

doi:10.1093/jnci/dju408

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 StarkHelen 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

Institut for Klinisk Medicin

92 Citationer (Scopus)

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 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.

Originalsprog	Engelsk
Artikelnummer	408
Tidsskrift	JNCI - Journal of the National Cancer Institute
Vol/bind	107
Udgave nummer	2
Sider (fra-til)	1-7
Antal sider	7
ISSN	0027-8874
DOI	https://doi.org/10.1093/jnci/dju408
Status	Udgivet - 1 feb. 2015

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10.1093/jnci/dju408

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Aoude, L. G., Pritchard, A. L., Robles-Espinoza, C. D., Wadt, K., Harland, M., Choi, J., Gartside, M., Quesada, V., Johansson, P., Palmer, J. M., Ramsay, A. J., Zhang, X., Jones, K., Symmons, J., Holland, E. A., Schmid, H., Bonazzi, V., Woods, S., Dutton-Regester, K., ... Hayward, N. K. (2015). Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma. JNCI - Journal of the National Cancer Institute, 107(2), 1-7. Artikel 408. https://doi.org/10.1093/jnci/dju408

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, A-M, 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', JNCI - Journal of the National Cancer Institute, bind 107, nr. 2, 408, s. 1-7. https://doi.org/10.1093/jnci/dju408

@article{33b7e91c15444393abf3a6d6022a0f63,

title = "Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma",

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 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.",

keywords = "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",

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 Anne-Marie Gerdes and H{\aa}kan 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}",

year = "2015",

month = feb,

day = "1",

doi = "10.1093/jnci/dju408",

language = "English",

volume = "107",

pages = "1--7",

journal = "JNCI - Journal of the National Cancer Institute",

issn = "0027-8874",

publisher = "Oxford University Press",

number = "2",

}

TY - JOUR

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, Håkan

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 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.

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 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.

KW - Adult

KW - Aged

KW - Codon, Nonsense

KW - DNA, Neoplasm

KW - Female

KW - Genetic Predisposition to Disease

KW - Germ-Line Mutation

KW - Humans

KW - Male

KW - Melanoma

KW - Middle Aged

KW - Pedigree

KW - Point Mutation

KW - Sequence Analysis, DNA

KW - Skin Neoplasms

KW - Telomere

KW - Telomere-Binding Proteins

KW - Telomeric Repeat Binding Protein 2

U2 - 10.1093/jnci/dju408

DO - 10.1093/jnci/dju408

M3 - Journal article

C2 - 25505254

SN - 0027-8874

VL - 107

SP - 1

EP - 7

JO - JNCI - Journal of the National Cancer Institute

JF - JNCI - Journal of the National Cancer Institute

IS - 2

M1 - 408

ER -

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

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