|Grant Number:||5R01CA137365-04 Interpret this number|
|Primary Investigator:||Qureshi, Abrar|
|Organization:||Brigham And Women'S Hosp., Inc.|
|Project Title:||Molecular Signatures of Melanoma Histology and Progression: a Population Based a|
DESCRIPTION (provided by applicant): critical obstacle to molecular and genomic classification of primary melanoma has been the requirement to provide prognostic measures (i.e. Breslow thickness) and related histologic parameters in formalin-fixed, paraffin-embedded (FFPE) biospecimens, where unlike frozen material, unadulterated mRNA and DNA have been difficult or impossible to extract and study. With our collaborators, we have successfully applied a novel technology first developed by Fan et al in 2004 for global gene expression profiling of melanoma FFPE biospecimens. This platform, designated DASL for DNA-mediated Annealing, Selection, extension, and Ligation) renders formalin-fixed biospecimens embedded and archived in the form of paraffin blocks usable for gene expression analysis. We found two distinct subclasses characterized by two robust signatures: one broadly defined by a cluster of microphthalmia and melanocyte differentiation genes ("MITF" class) and a more heterogeneous group of inflammation, innate immune, and growth-related genes ("IIG" class). Our preliminary data indicate that DASL can successfully profile and recover the 2-class structure from FFPE primary melanomas in the Nurses Health Study 1. The Channing Laboratory at Brigham and Women's Hospital is home to large cohort studies, i.e. the Nurses' Health Study 1 (NHS1), Nurses' Health Study-2 (NHS2) and the Health Professionals Follow-up Study (HPFS). The further strength of these cohorts lies in disease follow-up with bi-annual updates on new cases and mortality and availability of tissue blocks from the primary tumor site for melanoma cases in the cohorts. We hypothesize that melanoma aggressiveness is determined by MITF/IIG classes and we propose to evaluate whether this 2-class structure is associated with known histological parameters (e.g. Breslow thickness), and melanoma recurrence/mortality. With access to unique population-based national cohorts and development of new technologies with our collaborators, the specific aims of this proposal are as follows: Specific Aim 1: Develop molecular signatures of NHS, NHS2 and HPFS melanoma FFPE samples using an Illumina expression array platform with over 6000 genes and a Sequonome platform to sequence MC1R and genotype specific loci for BRAF and NRAS to: a. Assign MITF or IIG class for each melanoma sample and evaluate their association with BRAF/NRAS/MC1R status and determinants of melanoma histology (e.g. Breslow thickness, Clark's level, vertical growth phase) b. Evaluate genome-wide (6,000 genes) class discovery for each melanoma sample and evaluate their association with BRAF/ NRAS/MC1R status and determinants of melanoma histology (e.g. Breslow, Clark's level, vertical growth phase) Specific Aim 2: Using the transcriptional and genomic signatures from Aim 1 to: a. Assign MITF or IIG class association with BRAF/NRAS/MC1R status and melanoma recurrence and mortality due to melanoma b. Evaluate genome-wide (6,000 genes) association with BRAF/NRAS/MC1R status and melanoma recurrence and mortality due to melanoma PUBLIC HEALTH RELEVANCE: Malignant melanoma of the skin is a lethal cancer with significant impact on morbidity and mortality. The clinical paradox is that melanoma is curable when diagnosed early and quite lethal with advanced disease. Since validation of the Clark's level for melanoma invasiveness in the 1960's, there has been little change in our understanding of the significant association between histologic grading of melanoma and melanoma recurrence and mortality. We hope to be able to identify biomarkers that point to pathways of metastatic potential and assist in earlier prognostication. Thus we aim to significantly improve the current paradigm for diagnosis and therapy for melanoma by eventually reducing mortality from this deadly skin cancer.
CXCR4 pathway associated with family history of melanoma.
Authors: Li WQ, Han J, Widlund HR, Correll M, Wang YE, Quackenbush J, Mihm MC, Canales AL, Wu S, Golub T, Hoshida Y, Hunter DJ, Murphy G, Kupper TS, Qureshi AA
Source: Cancer Causes Control, 2014 Jan;25(1), p. 125-32.
EPub date: 2013 Oct 25.
Obesity and the incidence of skin cancer in US Caucasians.
Authors: Pothiawala S, Qureshi AA, Li Y, Han J
Source: Cancer Causes Control, 2012 May;23(5), p. 717-26.
EPub date: 2012 Mar 27.
Use of tanning beds and incidence of skin cancer.
Authors: Zhang M, Qureshi AA, Geller AC, Frazier L, Hunter DJ, Han J
Source: J Clin Oncol, 2012 May 10;30(14), p. 1588-93.
EPub date: 2012 Feb 27.
Exonuclease 1 (EXO1) gene variation and melanoma risk.
Authors: Song F, Qureshi AA, Zhang J, Amos CI, Lee JE, Wei Q, Han J
Source: DNA Repair (Amst), 2012 Mar 1;11(3), p. 304-9.
EPub date: 2012 Jan 9.
Shorter telomeres associate with a reduced risk of melanoma development.
Authors: Nan H, Du M, De Vivo I, Manson JE, Liu S, McTiernan A, Curb JD, Lessin LS, Bonner MR, Guo Q, Qureshi AA, Hunter DJ, Han J
Source: Cancer Res, 2011 Nov 1;71(21), p. 6758-63.
EPub date: 2011 Oct 25.
Integrating pathway analysis and genetics of gene expression for genome-wide association study of basal cell carcinoma.
Authors: Zhang M, Liang L, Morar N, Dixon AL, Lathrop GM, Ding J, Moffatt MF, Cookson WO, Kraft P, Qureshi AA, Han J
Source: Hum Genet, 2012 Apr;131(4), p. 615-23.
EPub date: 2011 Oct 18.
Sunlight exposure, vitamin D, and risk of non-Hodgkin lymphoma in the Nurses' Health Study.
Authors: Bertrand KA, Chang ET, Abel GA, Zhang SM, Spiegelman D, Qureshi AA, Laden F
Source: Cancer Causes Control, 2011 Dec;22(12), p. 1731-41.
EPub date: 2011 Oct 11.
Genome-wide association study identifies novel loci predisposing to cutaneous melanoma.
Authors: Amos CI, Wang LE, Lee JE, Gershenwald JE, Chen WV, Fang S, Kosoy R, Zhang M, Qureshi AA, Vattathil S, Schacherer CW, Gardner JM, Wang Y, Bishop DT, Barrett JH, GenoMEL Investigators, MacGregor S, Hayward NK, Martin NG, Duffy DL, Q-Mega Investigators, Mann GJ, Cust A, Hopper J, AMFS Investigators, Brown KM, Grimm EA, Xu Y, Han Y, Jing K, McHugh C, Laurie CC, Doheny KF, Pugh EW, Seldin MF, Han J, Wei Q
Source: Hum Mol Genet, 2011 Dec 15;20(24), p. 5012-23.
EPub date: 2011 Sep 17.
Pathway analysis for genome-wide association study of basal cell carcinoma of the skin.
Authors: Zhang M, Liang L, Xu M, Qureshi AA, Han J
Source: PLoS One, 2011;6(7), p. e22760.
EPub date: 2011 Jul 28.
Heterogeneity in host risk factors for incident melanoma and non-melanoma skin cancer in a cohort of US women.
Authors: Qureshi AA, Zhang M, Han J
Source: J Epidemiol, 2011;21(3), p. 197-203.
EPub date: 2011 Apr 23.
No association between telomere length in peripheral blood leukocytes and the risk of nonmelanoma skin cancer.
Authors: Liang G, Qureshi AA, Guo Q, De Vivo I, Han J
Source: Cancer Epidemiol Biomarkers Prev, 2011 May;20(5), p. 1043-5.
EPub date: 2011 Feb 25.
Rotating night shifts and risk of skin cancer in the nurses' health study.
Authors: Schernhammer ES, Razavi P, Li TY, Qureshi AA, Han J
Source: J Natl Cancer Inst, 2011 Apr 6;103(7), p. 602-6.
EPub date: 2011 Feb 18.
A germline variant in the interferon regulatory factor 4 gene as a novel skin cancer risk locus.
Authors: Han J, Qureshi AA, Nan H, Zhang J, Song Y, Guo Q, Hunter DJ
Source: Cancer Res, 2011 Mar 1;71(5), p. 1533-9.
EPub date: 2011 Jan 26.
ASIP genetic variants and the number of non-melanoma skin cancers.
Authors: Lin W, Qureshi AA, Kraft P, Nan H, Guo Q, Hu FB, Jensen MK, Han J
Source: Cancer Causes Control, 2011 Mar;22(3), p. 495-501.
EPub date: 2011 Jan 9.