Grant Number:	4R01CA137365-03 Interpret this number
Primary Investigator:	Qureshi, Abrar
Organization:	Brigham And Women'S Hospital
Project Title:	Molecular Signatures of Melanoma Histology and Progression: a Population Based a
Fiscal Year:	2011

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.




Niacin intake and risk of skin cancer in US women and men.
Authors: Park S.M. , Li T. , Wu S. , Li W.Q. , Weinstock M. , Qureshi A.A. , Cho E. .
Source: International Journal Of Cancer, 2017-05-01 00:00:00.0; 140(9), p. 2023-2031.
EPub date: 2017-02-14 00:00:00.0.
PMID: 28152570
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Risk of second primary cancer associated with pre-diagnostic smoking, alcohol, and obesity in women with keratinocyte carcinoma.
Authors: Park S.M. , Li T. , Wu S. , Li W.Q. , Qureshi A.A. , Stampfer M. , Cho E. .
Source: Cancer Epidemiology, 2017 04; 47, p. 106-113.
EPub date: 2017-02-24 00:00:00.0.
PMID: 28242577
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Type 2 diabetes mellitus and risk of cutaneous squamous cell carcinoma.
Authors: Chen S.T. , Li T. , Han J. , Qureshi A.A. , Cho E. .
Source: Journal Of The American Academy Of Dermatology, 2016 Oct; 75(4), p. 831-4.
PMID: 27646740
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History of Severe Sunburn and Risk of Skin Cancer Among Women and Men in 2 Prospective Cohort Studies.
Authors: Wu S. , Cho E. , Li W.Q. , Weinstock M.A. , Han J. , Qureshi A.A. .
Source: American Journal Of Epidemiology, 2016-05-01 00:00:00.0; 183(9), p. 824-33.
EPub date: 2016-05-01 00:00:00.0.
PMID: 27045074
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Alcohol Intake is Associated with Increased Risk of Squamous Cell Carcinoma of the Skin: Three US Prospective Cohort Studies.
Authors: Siiskonen S. , Han J. , Li T. , Cho E. , Nijsten T. , Qureshi A. .
Source: Nutrition And Cancer, 2016 May-Jun; 68(4), p. 545-53.
PMID: 27145335
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Reply to S. Lehrer et al and J.C. Dowdy and R.M. Sayre.
Authors: Wu S. , Cho E. , Qureshi A.A. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2016-02-20 00:00:00.0; 34(6), p. 637-8.
EPub date: 2016-02-20 00:00:00.0.
PMID: 26729435
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Vitamin D Intake and Risk of Skin Cancer in US Women and Men.
Authors: Park S.M. , Li T. , Wu S. , Li W.Q. , Qureshi A.A. , Cho E. .
Source: Plos One, 2016; 11(8), p. e0160308.
EPub date: 2016-08-24 00:00:00.0.
PMID: 27557122
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Caffeine Intake, Coffee Consumption, and Risk of Cutaneous Malignant Melanoma.
Authors: Wu S. , Han J. , Song F. , Cho E. , Gao X. , Hunter D.J. , Qureshi A.A. .
Source: Epidemiology (cambridge, Mass.), 2015 Nov; 26(6), p. 898-908.
PMID: 26172864
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Use of permanent hair dyes and risk of vitiligo in women.
Authors: Wu S. , Li W.Q. , Cho E. , Harris J.E. , Speizer F. , Qureshi A.A. .
Source: Pigment Cell & Melanoma Research, 2015 Nov; 28(6), p. 744-6.
PMID: 26212072
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Alcohol consumption and risk of cutaneous basal cell carcinoma in women and men: 3 prospective cohort studies.
Authors: Wu S. , Li W.Q. , Qureshi A.A. , Cho E. .
Source: The American Journal Of Clinical Nutrition, 2015 Nov; 102(5), p. 1158-66.
PMID: 26423390
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Citrus Consumption and Risk of Cutaneous Malignant Melanoma.
Authors: Wu S. , Han J. , Feskanich D. , Cho E. , Stampfer M.J. , Willett W.C. , Qureshi A.A. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2015-08-10 00:00:00.0; 33(23), p. 2500-8.
EPub date: 2015-08-10 00:00:00.0.
PMID: 26124488
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Alcohol Intake And Risk Of Incident Psoriatic Arthritis In Women
Authors: Wu S. , Cho E. , Li W.Q. , Han J. , Qureshi A.A. .
Source: The Journal Of Rheumatology, 2015 May; 42(5), p. 835-40.
PMID: 25834201
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Association Between Brafv600e And Nrasq61r Mutations And Clinicopathologic Characteristics, Risk Factors And Clinical Outcome Of Primary Invasive Cutaneous Melanoma
Authors: Wu S. , Kuo H. , Li W.Q. , Canales A.L. , Han J. , Qureshi A.A. .
Source: Cancer Causes & Control : Ccc, 2014 Oct; 25(10), p. 1379-86.
PMID: 25048604
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Long-term Ultraviolet Flux, Other Potential Risk Factors, And Skin Cancer Risk: A Cohort Study
Authors: Wu S. , Han J. , Laden F. , Qureshi A.A. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2014 Jun; 23(6), p. 1080-9.
PMID: 24876226
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Cumulative Ultraviolet Radiation Flux In Adulthood And Risk Of Incident Skin Cancers In Women
Authors: Wu S. , Han J. , Vleugels R.A. , Puett R. , Laden F. , Hunter D.J. , Qureshi A.A. .
Source: British Journal Of Cancer, 2014-04-02 00:00:00.0; 110(7), p. 1855-61.
PMID: 24595003
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Cxcr4 Pathway Associated With Family History Of Melanoma
Authors: Li W.Q. , Han J. , Widlund H.R. , Correll M. , Wang Y.E. , Quackenbush J. , Mihm M.C. , Canales A.L. , Wu S. , Golub T. , et al. .
Source: Cancer Causes & Control : Ccc, 2014 Jan; 25(1), p. 125-32.
PMID: 24158781
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Use Of Tanning Beds And Incidence Of Skin Cancer
Authors: Zhang M. , Qureshi A.A. , Geller A.C. , Frazier L. , Hunter D.J. , Han J. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2012-05-10 00:00:00.0; 30(14), p. 1588-93.
PMID: 22370316
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Obesity And The Incidence Of Skin Cancer In Us Caucasians
Authors: Pothiawala S. , Qureshi A.A. , Li Y. , Han J. .
Source: Cancer Causes & Control : Ccc, 2012 May; 23(5), p. 717-26.
PMID: 22450736
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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 A.L. , Lathrop G.M. , Ding J. , Moffatt M.F. , Cookson W.O. , Kraft P. , Qureshi A.A. , et al. .
Source: Human Genetics, 2012 Apr; 131(4), p. 615-23.
PMID: 22006220
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Exonuclease 1 (exo1) Gene Variation And Melanoma Risk
Authors: Song F. , Qureshi A.A. , Zhang J. , Zhan J. , Amos C.I. , Lee J.E. , Wei Q. , Han J. .
Source: Dna Repair, 2012-03-01 00:00:00.0; 11(3), p. 304-9.
PMID: 22230721
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Genome-wide association study identifies novel loci predisposing to cutaneous melanoma.
Authors: Amos C.I. , Wang L.E. , Lee J.E. , Gershenwald J.E. , Chen W.V. , Fang S. , Kosoy R. , Zhang M. , Qureshi A.A. , Vattathil S. , et al. .
Source: Human Molecular Genetics, 2011-12-15 00:00:00.0; 20(24), p. 5012-23.
EPub date: 2011-12-15 00:00:00.0.
PMID: 21926416
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Sunlight Exposure, Vitamin D, And Risk Of Non-hodgkin Lymphoma In The Nurses' Health Study
Authors: Bertrand K.A. , Chang E.T. , Abel G.A. , Zhang S.M. , Spiegelman D. , Qureshi A.A. , Laden F. .
Source: Cancer Causes & Control : Ccc, 2011 Dec; 22(12), p. 1731-41.
PMID: 21987081
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Shorter Telomeres Associate With A Reduced Risk Of Melanoma Development
Authors: Nan H. , Du M. , De Vivo I. , Manson J.E. , Liu S. , McTiernan A. , Curb J.D. , Lessin L.S. , Bonner M.R. , Guo Q. , et al. .
Source: Cancer Research, 2011-11-01 00:00:00.0; 71(21), p. 6758-63.
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No Association Between Telomere Length In Peripheral Blood Leukocytes And The Risk Of Nonmelanoma Skin Cancer
Authors: Liang G. , Qureshi A.A. , Guo Q. , De Vivo I. , Han J. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2011 May; 20(5), p. 1043-5.
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Rotating Night Shifts And Risk Of Skin Cancer In The Nurses' Health Study
Authors: Schernhammer E.S. , Razavi P. , Li T.Y. , Qureshi A.A. , Han J. .
Source: Journal Of The National Cancer Institute, 2011-04-06 00:00:00.0; 103(7), p. 602-6.
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Asip Genetic Variants And The Number Of Non-melanoma Skin Cancers
Authors: Lin W. , Qureshi A.A. , Kraft P. , Nan H. , Guo Q. , Hu F.B. , Jensen M.K. , Han J. .
Source: Cancer Causes & Control : Ccc, 2011 Mar; 22(3), p. 495-501.
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A Germline Variant In The Interferon Regulatory Factor 4 Gene As A Novel Skin Cancer Risk Locus
Authors: Han J. , Qureshi A.A. , Nan H. , Zhang J. , Song Y. , Guo Q. , Hunter D.J. .
Source: Cancer Research, 2011-03-01 00:00:00.0; 71(5), p. 1533-9.
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Heterogeneity In Host Risk Factors For Incident Melanoma And Non-melanoma Skin Cancer In A Cohort Of Us Women
Authors: Qureshi A.A. , Zhang M. , Han J. .
Source: Journal Of Epidemiology / Japan Epidemiological Association, 2011; 21(3), p. 197-203.
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Pathway Analysis For Genome-wide Association Study Of Basal Cell Carcinoma Of The Skin
Authors: Zhang M. , Liang L. , Xu M. , Qureshi A.A. , Han J. .
Source: Plos One, 2011; 6(7), p. e22760.
PMID: 21829505
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