Skip to main content
Grant Details

Grant Number: 5R01CA233524-03 Interpret this number
Primary Investigator: Thomas, Nancy
Organization: Univ Of North Carolina Chapel Hill
Project Title: Identification of Lethal Melanomas at the Time of Diagnosis
Fiscal Year: 2022


PROJECT SUMMARY/ABSTRACT Melanoma incidence rates continue to increase, whereas rates for most other cancers have declined. Emerging systemic therapies for patients who have progressed to metastatic melanoma are extending survival, but can be toxic, immensely costly and have variable efficacy. There are efforts to extend the use of new agents to earlier disease stages as adjuvant therapies. Better prediction of lethal melanoma at time of diagnosis is important to determine those who would benefit from adjuvant therapies and, conversely, avoid toxicity in those whose melanomas are unlikely to recur. Our central hypothesis is that it is possible to determine the combinations of genetic alterations and immune responses in tumor samples that define a melanoma likely to be ultimately lethal if not treated early. Conversely, we hypothesize that it will be possible to identify somatic profiles of the tumors that indicate a very low risk of recurrence and ultimate death of the patient, obviating the need for expensive, toxic treatments in such patients. We also hypothesize that host characteristics, including germline variants in multiple genes, will be associated with lethal melanoma. In Aim 1, we will test whether common somatic mutations in 104 genes/gene regions in tumors are associated with death from melanoma. These genes include known oncogenic drivers (BRAF, NRAS and TERT) and tumor suppressors (NF1, CDKN2A/CDKN2B, PTEN and TP53). We will also test the hypothesis that measuring the immune cell milieu will add information to survival prediction beyond conventional grading of tumor-infiltrating lymphocytes. We will then explore how best to combine the genetic alterations, immune measures and 2018 American Joint Committee on Cancer (AJCC) tumor stage to identify those melanomas highly likely to be ultimately lethal. In Aim 2, we will determine the extent to which the host characteristics of germline variants, phenotypic characteristics, sun exposure, age and gender differ among melanoma cases characterized as potentially lethal vs. nonlethal, leading to the identification of a subset of the population at high risk for lethal melanoma. This research will be undertaken using a resource that is uniquely suited to addressing these issues, the international, population-based Genes, Environment and Melanoma (GEM) Study, which collected epidemiologic data, pathology and tumor sections for a large cohort of incident primary cutaneous melanoma cases diagnosed in the year 2000. We have available a minimum of 10 years of follow-up of vital status and cause of death for all cases. GEM is an ideal resource because the end of the follow-up period precedes the targeted and immune therapy era, allowing us to study factors affecting the natural history of the disease. The vast majority of GEM cases (more than 85%) presented with local disease, and we project that at least 80% of the deaths will occur in cases initially presenting with local or regional disease. The results should enhance our ability to identify lethal melanomas at an early stage when treatments may be more effective and, conversely, to identify melanomas with a very low risk of recurrence for which unnecessary and potentially toxic treatments can be confidently avoided.


Association of functional, inherited vitamin D-binding protein variants with melanoma-specific death.
Authors: Gibbs D.C. , Thomas N.E. , Kanetsky P.A. , Luo L. , Busam K.J. , Cust A.E. , Anton-Culver H. , Gallagher R.P. , Zanetti R. , Rosso S. , et al. .
Source: JNCI cancer spectrum, 2023-08-31; 7(5), .
PMID: 37494457
Related Citations

Methylation of nonessential genes in cutaneous melanoma - Rule Out hypothesis.
Authors: Gorlov I.P. , Conway K. , Edmiston S.N. , Parrish E.A. , Hao H. , Amos C.I. , Tsavachidis S. , Gorlova O.Y. , Begg C. , Hernando E. , et al. .
Source: Melanoma research, 2023-06-01; 33(3), p. 163-172.
EPub date: 2023-02-20.
PMID: 36805567
Related Citations

Sex-Specific Associations of MDM2 and MDM4 Variants with Risk of Multiple Primary Melanomas and Melanoma Survival in Non-Hispanic Whites.
Authors: Ward S.V. , Autuori I. , Luo L. , LaPilla E. , Yoo S. , Sharma A. , Busam K.J. , Olilla D.W. , Dwyer T. , Anton-Culver H. , et al. .
Source: Cancers, 2023-05-11; 15(10), .
EPub date: 2023-05-11.
PMID: 37345045
Related Citations

Pathway Alterations in Stage II/III Primary Melanoma.
Authors: Kostrzewa C.E. , Luo L. , Arora A. , Seshan V.E. , Ernstoff M.S. , Edmiston S.N. , Conway K. , Gorlov I. , Busam K. , Orlow I. , et al. .
Source: JCO precision oncology, 2023 Mar; 7, p. e2200439.
PMID: 36926987
Related Citations

Landscape of mutations in early stage primary cutaneous melanoma: An InterMEL study.
Authors: Luo L. , Shen R. , Arora A. , Orlow I. , Busam K.J. , Lezcano C. , Lee T.K. , Hernando E. , Gorlov I. , Amos C. , et al. .
Source: Pigment cell & melanoma research, 2022 Nov; 35(6), p. 605-612.
EPub date: 2022-08-12.
PMID: 35876628
Related Citations

Minimally invasive microbiopsy for genetic profiling of melanocytic lesions: A case series.
Authors: Jain M. , Autuori I. , Everett N. , Harris U. , Yamada M. , Prow T. , Busam K. , Marchetti M.A. , Halpern A.C. , Orlow I. .
Source: Journal of the American Academy of Dermatology, 2022 Oct; 87(4), p. 903-904.
EPub date: 2021-12-16.
PMID: 34922919
Related Citations

Characterization of the CpG Island Hypermethylated Phenotype Subclass in Primary Melanomas.
Authors: Conway K. , Tsai Y.S. , Edmiston S.N. , Parker J.S. , Parrish E.A. , Hao H. , Kuan P.F. , Scott G.A. , Frank J.S. , Googe P. , et al. .
Source: The Journal of investigative dermatology, 2022 Jul; 142(7), p. 1869-1881.e10.
EPub date: 2021-11-27.
PMID: 34843679
Related Citations

Disease-Associated Risk Variants in ANRIL Are Associated with Tumor-Infiltrating Lymphocyte Presence in Primary Melanomas in the Population-Based GEM Study.
Authors: Davari D.R. , Orlow I. , Kanetsky P.A. , Luo L. , Edmiston S.N. , Conway K. , Parrish E.A. , Hao H. , Busam K.J. , Sharma A. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2021 Dec; 30(12), p. 2309-2316.
EPub date: 2021-10-04.
PMID: 34607836
Related Citations

Association of Melanoma-Risk Variants with Primary Melanoma Tumor Prognostic Characteristics and Melanoma-Specific Survival in the GEM Study.
Authors: Davari D.R. , Orlow I. , Kanetsky P.A. , Luo L. , Busam K.J. , Sharma A. , Kricker A. , Cust A.E. , Anton-Culver H. , Gruber S.B. , et al. .
Source: Current oncology (Toronto, Ont.), 2021-11-16; 28(6), p. 4756-4771.
EPub date: 2021-11-16.
PMID: 34898573
Related Citations

Comparison of community pathologists with expert dermatopathologists evaluating Breslow thickness and histopathologic subtype in a large international population-based study of melanoma.
Authors: Yardman-Frank J.M. , Bronner B. , Rosso S. , From L. , Busam K. , Groben P. , Tucker P. , Cust A. , Armstrong B. , Kricker A. , et al. .
Source: JAAD international, 2021 Sep; 4, p. 25-27.
EPub date: 2021-06-01.
PMID: 34409386
Related Citations

Differences in Melanoma Between Canada and New South Wales, Australia: A Population-Based Genes, Environment, and Melanoma (GEM) Study.
Authors: Yardman-Frank J.M. , Glassheim E. , Kricker A. , Armstrong B.K. , Marrett L.D. , Luo L. , Cust A.E. , Busam K.J. , Orlow I. , Gallagher R.P. , et al. .
Source: JID innovations : skin science from molecules to population health, 2021 Mar; 1(1), .
EPub date: 2021-01-25.
PMID: 33768212
Related Citations

Non-Cell-Autonomous Activity of the Hemidesmosomal Protein BP180/Collagen XVII in Granulopoiesis in Humanized NC16A Mice.
Authors: Lin L. , Hwang B.J. , Li N. , Googe P. , Diaz L.A. , Miao E. , Vilen B. , Thomas N.E. , Ting J. , Liu Z. .
Source: Journal of immunology (Baltimore, Md. : 1950), 2020-11-15; 205(10), p. 2786-2794.
EPub date: 2020-09-30.
PMID: 32998984
Related Citations

Association of Known Melanoma Risk Factors with Primary Melanoma of the Scalp and Neck.
Authors: Wood R.P. , Heyworth J.S. , McCarthy N.S. , Mauguen A. , Berwick M. , Thomas N.E. , Millward M.J. , Anton-Culver H. , Cust A.E. , Dwyer T. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2020 Nov; 29(11), p. 2203-2210.
EPub date: 2020-08-20.
PMID: 32856602
Related Citations

Human genes differ by their UV sensitivity estimated through analysis of UV-induced silent mutations in melanoma.
Authors: Gorlov I.P. , Amos C.I. , Tsavachidis S. , Begg C. , Hernando E. , Cheng C. , Shen R. , Orlow I. , Luo L. , Ernstoff M.S. , et al. .
Source: Human mutation, 2020 Oct; 41(10), p. 1751-1760.
EPub date: 2020-07-15.
PMID: 32643855
Related Citations

Association of IRF4 single-nucleotide polymorphism rs12203592 with melanoma-specific survival.
Authors: Ward S.V. , Gibbs D.C. , Orlow I. , Thomas N.E. , Kanetsky P.A. , Luo L. , Cust A.E. , Anton-Culver H. , Gruber S.B. , Gallagher R.P. , et al. .
Source: The British journal of dermatology, 2020 Jul; 183(1), p. 163-165.
EPub date: 2020-02-19.
PMID: 31958143
Related Citations

Inherited Melanoma Risk Variants Associated with Histopathologically Amelanotic Melanoma.
Authors: Gibbs D.C. , Orlow I. , Vernali S. , Powell H.B. , Kanetsky P.A. , Luo L. , Busam K.J. , Sharma A. , Kricker A. , Armstrong B.K. , et al. .
Source: The Journal of investigative dermatology, 2020 Apr; 140(4), p. 918-922.e7.
EPub date: 2019-09-27.
PMID: 31568773
Related Citations

Back to Top