Identification of a melanoma susceptibility locus and somatic mutation in TET2

Fengju Song; Christopher I. Amos; Jeffrey E. Lee; Christine G. Lian; Shenying Fang; Hongliang Liu; Stuart MacGregor; Mark M. Iles; Matthew H. Law; Neal I. Lindeman; Grant W. Montgomery; David L. Duffy; Anne E. Cust; Mark A. Jenkins; David C. Whiteman; Richard F. Kefford; Graham G. Giles; Bruce K. Armstrong; Joanne F. Aitken; John L. Hopper; Kevin M. Brown; Nicholas G. Martin; Graham J. Mann; D. Timothy Bishop; Julia A. Newton Bishop; Peter Kraft; Abrar A. Qureshi; Peter A. Kanetsky; Nicholas K. Hayward; David J. Hunter; Qingyi Wei; Jiali Han

doi:10.1093/carcin/bgu140

Identification of a melanoma susceptibility locus and somatic mutation in TET2

Fengju Song, Christopher I. Amos, Jeffrey E. Lee, Christine G. Lian, Shenying Fang, Hongliang Liu, Stuart MacGregor, Mark M. Iles, Matthew H. Law, Neal I. Lindeman, Grant W. Montgomery, David L. Duffy, Anne E. Cust, Mark A. Jenkins, David C. Whiteman, Richard F. Kefford, Graham G. Giles, Bruce K. Armstrong, Joanne F. Aitken, John L. HopperKevin M. Brown, Nicholas G. Martin, Graham J. Mann, D. Timothy Bishop, Julia A. Newton Bishop, Peter Kraft, Abrar A. Qureshi, Peter A. Kanetsky, Nicholas K. Hayward, David J. Hunter, Qingyi Wei, Jiali Han

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Abstract

Although genetic studies have reported a number of loci associated with melanoma risk, the complex genetic architecture of the disease is not yet fully understood. We sought to identify common genetic variants associated with melanoma risk in a genome-wide association study (GWAS) of 2298 cases and 6654 controls. Thirteen of 15 known loci were replicated with nominal significance. A total of 69 single-nucleotide polymorphisms (SNPs) were selected for in silico replication in two independent melanoma GWAS datasets (a total of 5149 cases and 12 795 controls). Seven novel loci were nominally significantly associated with melanoma risk. These seven SNPs were further genotyped in 234 melanoma cases and 238 controls. The SNP rs4698934 was nominally significantly associated with melanoma risk. The combined odds ratio per T allele = 1.18; 95% confidence interval (1.10-1.25); combined P = 7.70 × 10^-7. This SNP is located in the intron of the TET2 gene on chromosome 4q24. In addition, a novel somatic mutation of TET2 was identified by next-generation sequencing in 1 of 22 sporadic melanoma cases. TET2 encodes a member of TET family enzymes that oxidizes 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). It is a putative epigenetic biomarker of melanoma as we previously reported, with observation of reduced TET2 transcriptional expression. This study is the first to implicate TET2 genetic variation and mutation in melanoma.

Original language	English (US)
Article number	bgu140
Pages (from-to)	2097-2101
Number of pages	5
Journal	Carcinogenesis
Volume	35
Issue number	9
DOIs	https://doi.org/10.1093/carcin/bgu140
State	Published - Sep 2014

ASJC Scopus subject areas

Cancer Research

MD Anderson CCSG core facilities

Clinical Trials Office

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10.1093/carcin/bgu140

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Song, F., Amos, C. I., Lee, J. E., Lian, C. G., Fang, S., Liu, H., MacGregor, S., Iles, M. M., Law, M. H., Lindeman, N. I., Montgomery, G. W., Duffy, D. L., Cust, A. E., Jenkins, M. A., Whiteman, D. C., Kefford, R. F., Giles, G. G., Armstrong, B. K., Aitken, J. F., ... Han, J. (2014). Identification of a melanoma susceptibility locus and somatic mutation in TET2. Carcinogenesis, 35(9), 2097-2101. Article bgu140. https://doi.org/10.1093/carcin/bgu140

Song, F, Amos, CI, Lee, JE, Lian, CG, Fang, S, Liu, H, MacGregor, S, Iles, MM, Law, MH, Lindeman, NI, Montgomery, GW, Duffy, DL, Cust, AE, Jenkins, MA, Whiteman, DC, Kefford, RF, Giles, GG, Armstrong, BK, Aitken, JF, Hopper, JL, Brown, KM, Martin, NG, Mann, GJ, Bishop, DT, Newton Bishop, JA, Kraft, P, Qureshi, AA, Kanetsky, PA, Hayward, NK, Hunter, DJ, Wei, Q & Han, J 2014, 'Identification of a melanoma susceptibility locus and somatic mutation in TET2', Carcinogenesis, vol. 35, no. 9, bgu140, pp. 2097-2101. https://doi.org/10.1093/carcin/bgu140

@article{e2b0e7a01fce42faa0fae6c92a691238,

title = "Identification of a melanoma susceptibility locus and somatic mutation in TET2",

abstract = "Although genetic studies have reported a number of loci associated with melanoma risk, the complex genetic architecture of the disease is not yet fully understood. We sought to identify common genetic variants associated with melanoma risk in a genome-wide association study (GWAS) of 2298 cases and 6654 controls. Thirteen of 15 known loci were replicated with nominal significance. A total of 69 single-nucleotide polymorphisms (SNPs) were selected for in silico replication in two independent melanoma GWAS datasets (a total of 5149 cases and 12 795 controls). Seven novel loci were nominally significantly associated with melanoma risk. These seven SNPs were further genotyped in 234 melanoma cases and 238 controls. The SNP rs4698934 was nominally significantly associated with melanoma risk. The combined odds ratio per T allele = 1.18; 95% confidence interval (1.10-1.25); combined P = 7.70 × 10-7. This SNP is located in the intron of the TET2 gene on chromosome 4q24. In addition, a novel somatic mutation of TET2 was identified by next-generation sequencing in 1 of 22 sporadic melanoma cases. TET2 encodes a member of TET family enzymes that oxidizes 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). It is a putative epigenetic biomarker of melanoma as we previously reported, with observation of reduced TET2 transcriptional expression. This study is the first to implicate TET2 genetic variation and mutation in melanoma.",

author = "Fengju Song and Amos, {Christopher I.} and Lee, {Jeffrey E.} and Lian, {Christine G.} and Shenying Fang and Hongliang Liu and Stuart MacGregor and Iles, {Mark M.} and Law, {Matthew H.} and Lindeman, {Neal I.} and Montgomery, {Grant W.} and Duffy, {David L.} and Cust, {Anne E.} and Jenkins, {Mark A.} and Whiteman, {David C.} and Kefford, {Richard F.} and Giles, {Graham G.} and Armstrong, {Bruce K.} and Aitken, {Joanne F.} and Hopper, {John L.} and Brown, {Kevin M.} and Martin, {Nicholas G.} and Mann, {Graham J.} and Bishop, {D. Timothy} and {Newton Bishop}, {Julia A.} and Peter Kraft and Qureshi, {Abrar A.} and Kanetsky, {Peter A.} and Hayward, {Nicholas K.} and Hunter, {David J.} and Qingyi Wei and Jiali Han",

year = "2014",

month = sep,

doi = "10.1093/carcin/bgu140",

language = "English (US)",

volume = "35",

pages = "2097--2101",

journal = "Carcinogenesis",

issn = "0143-3334",

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T1 - Identification of a melanoma susceptibility locus and somatic mutation in TET2

AU - Song, Fengju

AU - Amos, Christopher I.

AU - Lee, Jeffrey E.

AU - Lian, Christine G.

AU - Fang, Shenying

AU - Liu, Hongliang

AU - MacGregor, Stuart

AU - Iles, Mark M.

AU - Law, Matthew H.

AU - Lindeman, Neal I.

AU - Montgomery, Grant W.

AU - Duffy, David L.

AU - Cust, Anne E.

AU - Jenkins, Mark A.

AU - Whiteman, David C.

AU - Kefford, Richard F.

AU - Giles, Graham G.

AU - Armstrong, Bruce K.

AU - Aitken, Joanne F.

AU - Hopper, John L.

AU - Brown, Kevin M.

AU - Martin, Nicholas G.

AU - Mann, Graham J.

AU - Bishop, D. Timothy

AU - Newton Bishop, Julia A.

AU - Kraft, Peter

AU - Qureshi, Abrar A.

AU - Kanetsky, Peter A.

AU - Hayward, Nicholas K.

AU - Hunter, David J.

AU - Wei, Qingyi

AU - Han, Jiali

PY - 2014/9

Y1 - 2014/9

N2 - Although genetic studies have reported a number of loci associated with melanoma risk, the complex genetic architecture of the disease is not yet fully understood. We sought to identify common genetic variants associated with melanoma risk in a genome-wide association study (GWAS) of 2298 cases and 6654 controls. Thirteen of 15 known loci were replicated with nominal significance. A total of 69 single-nucleotide polymorphisms (SNPs) were selected for in silico replication in two independent melanoma GWAS datasets (a total of 5149 cases and 12 795 controls). Seven novel loci were nominally significantly associated with melanoma risk. These seven SNPs were further genotyped in 234 melanoma cases and 238 controls. The SNP rs4698934 was nominally significantly associated with melanoma risk. The combined odds ratio per T allele = 1.18; 95% confidence interval (1.10-1.25); combined P = 7.70 × 10-7. This SNP is located in the intron of the TET2 gene on chromosome 4q24. In addition, a novel somatic mutation of TET2 was identified by next-generation sequencing in 1 of 22 sporadic melanoma cases. TET2 encodes a member of TET family enzymes that oxidizes 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). It is a putative epigenetic biomarker of melanoma as we previously reported, with observation of reduced TET2 transcriptional expression. This study is the first to implicate TET2 genetic variation and mutation in melanoma.

AB - Although genetic studies have reported a number of loci associated with melanoma risk, the complex genetic architecture of the disease is not yet fully understood. We sought to identify common genetic variants associated with melanoma risk in a genome-wide association study (GWAS) of 2298 cases and 6654 controls. Thirteen of 15 known loci were replicated with nominal significance. A total of 69 single-nucleotide polymorphisms (SNPs) were selected for in silico replication in two independent melanoma GWAS datasets (a total of 5149 cases and 12 795 controls). Seven novel loci were nominally significantly associated with melanoma risk. These seven SNPs were further genotyped in 234 melanoma cases and 238 controls. The SNP rs4698934 was nominally significantly associated with melanoma risk. The combined odds ratio per T allele = 1.18; 95% confidence interval (1.10-1.25); combined P = 7.70 × 10-7. This SNP is located in the intron of the TET2 gene on chromosome 4q24. In addition, a novel somatic mutation of TET2 was identified by next-generation sequencing in 1 of 22 sporadic melanoma cases. TET2 encodes a member of TET family enzymes that oxidizes 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). It is a putative epigenetic biomarker of melanoma as we previously reported, with observation of reduced TET2 transcriptional expression. This study is the first to implicate TET2 genetic variation and mutation in melanoma.

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Identification of a melanoma susceptibility locus and somatic mutation in TET2

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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