title: Transcriptome profiling identifies HMGA2 as a biomarker of melanoma progression and prognosis.
abstract: The genetic alterations contributing to melanoma pathogenesis are incompletely defined, and few independent prognostic features have been identified beyond the clinicopathological characteristics of the primary tumor. We used transcriptome profiling of 46 primary melanomas, 12 melanoma metastases, and 16 normal skin (N) samples to find genes associated with melanoma development and progression. Results were confirmed using immunohistochemistry and real-time PCR and replicated in an independent set of 330 melanomas using AQUA analysis of tissue microarray (TMA). Transcriptome profiling revealed that transcription factor HMGA2, previously unrecognized in melanoma pathogenesis, is significantly upregulated in primary melanoma and metastases (P-values=1.2 × 10(-7) and 9 × 10(-5)) compared with N. HMGA2 overexpression is associated with BRAF/NRAS mutations (P=0.0002). Cox proportional hazard regression model and log-rank test showed that HMGA2 is independently associated with disease-free survival (hazard ratio (HR)=6.3, 95% confidence interval (CI)=1.8-22.3, P=0.004), overall survival (OS) (stratified log-rank P=0.008), and distant metastases-free survival (HR=6.4, 95% CI=1.4-29.7, P=0.018) after adjusting for American Joint Committee on Cancer (AJCC) stage and age at diagnosis. Survival analysis in an independent replication TMA of 330 melanomas confirmed the association of HMGA2 expression with OS (P=0.0211). Our study implicates HMGA2 in melanoma progression and demonstrates that HMGA2 overexpression can serve as an independent predictor of survival in melanoma.
authors: Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University, Nashville, Tennessee, USA. Electronic address: leonid.raskin@vanderbilt.edu.
authors: Leon
authors: L
authors: Raskin
authors: Department of Dermatology, University of Michigan Medical School and School of Public Health, Ann Arbor, Michigan, USA; Department of Pathology, University of Michigan Medical School and School of Public Health, Ann Arbor, Michigan, USA.
authors: Douglas R
authors: DR
authors: Fullen
authors: Department of Pathology, University of Michigan Medical School and School of Public Health, Ann Arbor, Michigan, USA; Department of Internal Medicine, University of Michigan Medical School and School of Public Health, Ann Arbor, Michigan, USA.
authors: Thomas J
authors: TJ
authors: Giordano
authors: Department of Pathology, University of Michigan Medical School and School of Public Health, Ann Arbor, Michigan, USA.
authors: Dafydd G
authors: DG
authors: Thomas
authors: Department of Dermatology, University of Michigan Medical School and School of Public Health, Ann Arbor, Michigan, USA.
authors: Marcus L
authors: ML
authors: Frohm
authors: Department of Dermatology, University of Michigan Medical School and School of Public Health, Ann Arbor, Michigan, USA.
authors: Kelly B
authors: KB
authors: Cha
authors: Department of Biostatistics, University of Michigan Medical School and School of Public Health, Ann Arbor, Michigan, USA.
authors: Jaeil
authors: J
authors: Ahn
authors: Department of Biostatistics, University of Michigan Medical School and School of Public Health, Ann Arbor, Michigan, USA.
authors: Bhramar
authors: B
authors: Mukherjee
authors: Department of Dermatology, University of Michigan Medical School and School of Public Health, Ann Arbor, Michigan, USA.
authors: Timothy M
authors: TM
authors: Johnson
authors: Department of Internal Medicine, University of Michigan Medical School and School of Public Health, Ann Arbor, Michigan, USA; Department of Epidemiology, University of Michigan Medical School and School of Public Health, Ann Arbor, Michigan, USA; Department of Human Genetics, University of Michigan Medical School and School of Public Health, Ann Arbor, Michigan, USA; USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA.
authors: Stephen B
authors: SB
authors: Gruber
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D025743:HMGA2 Protein / Q000235:genetics*; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D059467:Transcriptome; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D025743:HMGA2 Protein; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
references: J Natl Cancer Inst. 2006 Apr 5;98(7):472-82
references: 16595783
references: Clin Cancer Res. 2005 Oct 15;11(20):7234-42
references: 16243793
references: N Engl J Med. 2006 Sep 7;355(10):1037-46
references: 16957149
references: BMC Med Genomics. 2008 Apr 28;1:13
references: 18442402
references: Nature. 2000 Aug 3;406(6795):536-40
references: 10952317
references: Pigment Cell Res. 2002 Aug;15(4):242-50
references: 12100489
references: Genome Biol. 2004;5(10):R80
references: 15461798
references: Biochemistry. 2003 Apr 22;42(15):4569-77
references: 12693954
references: Br J Cancer. 2005 Jun 20;92(12):2249-61
references: 15900300
references: Cancer Res. 2004 Aug 1;64(15):5270-82
references: 15289333
references: J Cell Biol. 2006 Jul 17;174(2):175-83
references: 16831886
references: Carcinogenesis. 2005 Jul;26(7):1224-32
references: 15760917
references: Curr Treat Options Oncol. 2012 Sep;13(3):327-39
references: 22743761
references: Cell Stem Cell. 2008 Nov 6;3(5):469-70
references: 18983959
references: Mol Cancer Res. 2008 Apr;6(4):663-73
references: 18403645
references: J Transl Med. 2006 Nov 27;4:50
references: 17129373
references: Genomics. 2007 Apr;89(4):451-9
references: 17229543
references: Clin Cancer Res. 2009 Nov 15;15(22):6939-46
references: 19887478
references: Pigment Cell Res. 2007 Dec;20(6):466-84
references: 17935490
references: Clin Cancer Res. 2007 Feb 1;13(3):806-15
references: 17289871
references: J Invest Dermatol. 2012 Feb;132(2):274-83
references: 21956122
references: Cancer Res. 2004 Mar 15;64(6):2024-9
references: 15026339
references: Cancer Res. 1998 May 15;58(10):2170-5
references: 9605762
references: Br J Cancer. 2006 Aug 21;95(4):496-505
references: 16880792
references: J Natl Cancer Inst. 2005 Aug 17;97(16):1180-4
references: 16106022
references: J Biol Chem. 2001 Mar 23;276(12):9366-74
references: 11112786
references: Cell Cycle. 2007 Nov 1;6(21):2585-90
references: 17957144
references: Oncogene. 2008 Nov 6;27(52):6623-34
references: 18679422
references: Cell Res. 2008 May;18(5):549-57
references: 18379589
references: CA Cancer J Clin. 2012 Jan-Feb;62(1):10-29
references: 22237781
references: Mol Cell Biol. 2000 Aug;20(15):5490-502
references: 10891489
references: Cell. 2005 Mar 11;120(5):635-47
references: 15766527
references: Gene. 2001 Oct 17;277(1-2):63-81
references: 11602345
references: Proc Natl Acad Sci U S A. 2005 Apr 26;102(17):6092-7
references: 15833814
references: Oncologist. 2007 Jan;12(1):20-37
references: 17227898
references: Nucleic Acids Res. 2003 Dec 1;31(23):6841-51
references: 14627817
references: Oncogene. 2008 Jan 24;27(5):565-73
references: 17891185
references: Genes Chromosomes Cancer. 2009 Jan;48(1):69-82
references: 18828159
references: EMBO J. 2009 Feb 18;28(4):347-58
references: 19153603
references: Cancer Cell. 2006 Jun;9(6):459-71
references: 16766265
references: J Natl Cancer Inst. 2009 Apr 1;101(7):452-74
references: 19318635
references: J Invest Dermatol. 2009 Jul;129(7):1740-51
references: 19212343
references: J Invest Dermatol. 2012 Mar;132(3 Pt 2):854-63
references: 22217739
references: Oncogene. 2004 May 20;23(23):4060-7
references: 15048078
references: Melanoma Res. 2006 Aug;16(4):267-73
references: 16845322
references: Oncogene. 2008 Nov 6;27(52):6698-706
references: 18679415
references: Mol Carcinog. 2007 Jul;46(7):503-11
references: 17477356
references: Int J Cancer. 2008 Jul 15;123(2):348-356
references: 18452175
references: Nat Rev Cancer. 2007 Dec;7(12):899-910
references: 18004397
references: J Clin Oncol. 2009 Dec 1;27(34):5772-80
references: 19884546
references: Nature. 2007 Feb 22;445(7130):851-7
references: 17314971
references: EMBO J. 1992 Mar;11(3):961-71
references: 1312467
references: Clin Cancer Res. 2012 Mar 1;18(5):1195-200
references: 22275506