POT1 loss-of-function variants predispose to familial melanoma

Carla Daniela Robles-Espinoza; Mark Harland; Andrew J. Ramsay; Lauren G. Aoude; Victor Quesada; Zhihao Ding; Karen A. Pooley; Antonia L. Pritchard; Jessamy C. Tiffen; Mia Petljak; Jane M. Palmer; Judith Symmons; Peter A. Johansson; Mitchell S. Stark; Michael G. Gartside; Helen Snowden; Grant W. Montgomery; Nicholas G. Martin; Jimmy Z. Lite; Jiyeon Choi; Matthew Makowski; Kevin M. Brown; Alison M. Dunning; Thomas M. Keane; Carlos Lopez-Otin; Nelleke A. Gruis; Nicholas K. Hayward; D. Timothy Bishop; Julia A. Newton-Bishop; David J. Adams

doi:10.1038/ng.2947

POT1 loss-of-function variants predispose to familial melanoma

Carla Daniela Robles-Espinoza, Mark Harland, Andrew J. Ramsay, Lauren G. Aoude, Victor Quesada, Zhihao Ding, Karen A. Pooley, Antonia L. Pritchard, Jessamy C. Tiffen, Mia Petljak, Jane M. Palmer, Judith Symmons, Peter A. Johansson, Mitchell S. Stark, Michael G. Gartside, Helen Snowden, Grant W. Montgomery, Nicholas G. Martin, Jimmy Z. Lite, Jiyeon ChoiMatthew Makowski, Kevin M. Brown, Alison M. Dunning, Thomas M. Keane, Carlos Lopez-Otin, Nelleke A. Gruis, Nicholas K. Hayward, D. Timothy Bishop, Julia A. Newton-Bishop, David J. Adams

Division of Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

311 Citations (Scopus)

Abstract

Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases1, and rare variants in CDK4, BRCA2, BAP1 and the promoter of TERT have also been linked to the disease2,3,4,5. Here we set out to identify new high-penetrance susceptibility genes by sequencing 184 melanoma cases from 105 pedigrees recruited in the UK, The Netherlands and Australia that were negative for variants in known predisposition genes. We identified families where melanoma cosegregates with loss-of-function variants in the protection of telomeres 1 gene (POT1), with a proportion of family members presenting with an early age of onset and multiple primary tumors. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding and leading to increased telomere length. These findings suggest that POT1 variants predispose to melanoma formation via a direct effect on telomeres.

Original language	English
Pages (from-to)	478-481
Number of pages	4
Journal	Nature Genetics
Volume	46
Issue number	5
Early online date	30 Mar 2014
DOIs	https://doi.org/10.1038/ng.2947
Publication status	Published - May 2014

Keywords

3ref2021

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ng.2947

Antonia Pritchard
- antonia.pritcharduhi.acuk
- Division of Biomedical Sciences - Reader in Genetics and Immunology
- Melanoma Research Group
Person: Academic - Research and Teaching or Research only

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Robles-Espinoza, C. D., Harland, M., Ramsay, A. J., Aoude, L. G., Quesada, V., Ding, Z., Pooley, K. A., Pritchard, A. L., Tiffen, J. C., Petljak, M., Palmer, J. M., Symmons, J., Johansson, P. A., Stark, M. S., Gartside, M. G., Snowden, H., Montgomery, G. W., Martin, N. G., Lite, J. Z., ... Adams, D. J. (2014). POT1 loss-of-function variants predispose to familial melanoma. Nature Genetics, 46(5), 478-481. https://doi.org/10.1038/ng.2947

@article{e22cb78f72e34f67a755824adb0d8f8e,

title = "POT1 loss-of-function variants predispose to familial melanoma",

abstract = "Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases1, and rare variants in CDK4, BRCA2, BAP1 and the promoter of TERT have also been linked to the disease2,3,4,5. Here we set out to identify new high-penetrance susceptibility genes by sequencing 184 melanoma cases from 105 pedigrees recruited in the UK, The Netherlands and Australia that were negative for variants in known predisposition genes. We identified families where melanoma cosegregates with loss-of-function variants in the protection of telomeres 1 gene (POT1), with a proportion of family members presenting with an early age of onset and multiple primary tumors. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding and leading to increased telomere length. These findings suggest that POT1 variants predispose to melanoma formation via a direct effect on telomeres.",

keywords = "3ref2021",

author = "Robles-Espinoza, {Carla Daniela} and Mark Harland and Ramsay, {Andrew J.} and Aoude, {Lauren G.} and Victor Quesada and Zhihao Ding and Pooley, {Karen A.} and Pritchard, {Antonia L.} and Tiffen, {Jessamy C.} and Mia Petljak and Palmer, {Jane M.} and Judith Symmons and Johansson, {Peter A.} and Stark, {Mitchell S.} and Gartside, {Michael G.} and Helen Snowden and Montgomery, {Grant W.} and Martin, {Nicholas G.} and Lite, {Jimmy Z.} and Jiyeon Choi and Matthew Makowski and Brown, {Kevin M.} and Dunning, {Alison M.} and Keane, {Thomas M.} and Carlos Lopez-Otin and Gruis, {Nelleke A.} and Hayward, {Nicholas K.} and Bishop, {D. Timothy} and Newton-Bishop, {Julia A.} and Adams, {David J.}",

year = "2014",

month = may,

doi = "10.1038/ng.2947",

language = "English",

volume = "46",

pages = "478--481",

journal = "Nature Genetics",

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Robles-Espinoza, CD, Harland, M, Ramsay, AJ, Aoude, LG, Quesada, V, Ding, Z, Pooley, KA, Pritchard, AL, Tiffen, JC, Petljak, M, Palmer, JM, Symmons, J, Johansson, PA, Stark, MS, Gartside, MG, Snowden, H, Montgomery, GW, Martin, NG, Lite, JZ, Choi, J, Makowski, M, Brown, KM, Dunning, AM, Keane, TM, Lopez-Otin, C, Gruis, NA, Hayward, NK, Bishop, DT, Newton-Bishop, JA & Adams, DJ 2014, 'POT1 loss-of-function variants predispose to familial melanoma', Nature Genetics, vol. 46, no. 5, pp. 478-481. https://doi.org/10.1038/ng.2947

TY - JOUR

T1 - POT1 loss-of-function variants predispose to familial melanoma

AU - Robles-Espinoza, Carla Daniela

AU - Harland, Mark

AU - Ramsay, Andrew J.

AU - Aoude, Lauren G.

AU - Quesada, Victor

AU - Ding, Zhihao

AU - Pooley, Karen A.

AU - Pritchard, Antonia L.

AU - Tiffen, Jessamy C.

AU - Petljak, Mia

AU - Palmer, Jane M.

AU - Symmons, Judith

AU - Johansson, Peter A.

AU - Stark, Mitchell S.

AU - Gartside, Michael G.

AU - Snowden, Helen

AU - Montgomery, Grant W.

AU - Martin, Nicholas G.

AU - Lite, Jimmy Z.

AU - Choi, Jiyeon

AU - Makowski, Matthew

AU - Brown, Kevin M.

AU - Dunning, Alison M.

AU - Keane, Thomas M.

AU - Lopez-Otin, Carlos

AU - Gruis, Nelleke A.

AU - Hayward, Nicholas K.

AU - Bishop, D. Timothy

AU - Newton-Bishop, Julia A.

AU - Adams, David J.

PY - 2014/5

Y1 - 2014/5

N2 - Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases1, and rare variants in CDK4, BRCA2, BAP1 and the promoter of TERT have also been linked to the disease2,3,4,5. Here we set out to identify new high-penetrance susceptibility genes by sequencing 184 melanoma cases from 105 pedigrees recruited in the UK, The Netherlands and Australia that were negative for variants in known predisposition genes. We identified families where melanoma cosegregates with loss-of-function variants in the protection of telomeres 1 gene (POT1), with a proportion of family members presenting with an early age of onset and multiple primary tumors. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding and leading to increased telomere length. These findings suggest that POT1 variants predispose to melanoma formation via a direct effect on telomeres.

AB - Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases1, and rare variants in CDK4, BRCA2, BAP1 and the promoter of TERT have also been linked to the disease2,3,4,5. Here we set out to identify new high-penetrance susceptibility genes by sequencing 184 melanoma cases from 105 pedigrees recruited in the UK, The Netherlands and Australia that were negative for variants in known predisposition genes. We identified families where melanoma cosegregates with loss-of-function variants in the protection of telomeres 1 gene (POT1), with a proportion of family members presenting with an early age of onset and multiple primary tumors. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding and leading to increased telomere length. These findings suggest that POT1 variants predispose to melanoma formation via a direct effect on telomeres.

KW - 3ref2021

U2 - 10.1038/ng.2947

DO - 10.1038/ng.2947

M3 - Article

SN - 1061-4036

VL - 46

SP - 478

EP - 481

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -

POT1 loss-of-function variants predispose to familial melanoma

Abstract

Keywords

UN SDGs

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