Progression of Mutations From Moles To Melanoma Identified

Boris C. Bastian, MD, PhD Professor of Dermatology and Pathology Gerson and Barbara Bass Bakar Distinguished Professor in Cancer Research University of California, San Francisco

Dr. Bastian Interview with:
Boris C. Bastian, MD, PhD
Professor of Dermatology and Pathology
Gerson and Barbara Bass Bakar Distinguished Professor in Cancer Research
University of California, San Francisco

Medical Research: What is the background for this study? What are the main findings?

Dr. Bastian:  The cost of DNA sequencing has dropped substantially since the initial sequencing of the human genome in 2001. As a result, the most common cancer subtypes have now been sequenced, revealing the pathogenic mutations that drive them. A typical cancer is driven by 5-10 mutations, but we still do not understand the order in which these mutations occur for most cancers.

Determining the order in which mutations occur is challenging for cancers that are detected at a late stage. Melanomas, however, lend themselves to this type of analysis because they are pigmented and found on the surface of the skin, allowing them to be identified early. Sometimes, melanomas are even found adjacent to their remnant precursor neoplasms, such as benign nevi (also known as common moles). We performed detailed genetic analyses of 37 cases of melanomas that were adjacent to their intact precursor neoplasms. We microdissected and sequenced the surrounding uninvolved normal tissue, the precursor neoplasm, and the descendent neoplasm. By comparing the genetic abnormalities in each of the microdissected areas, we were able to decipher the order of genetic alterations for each case.

Our work reveals the stereotypic pattern of mutations as they occur in melanoma. Mutations in the MAPK pathway, usually affecting BRAF or NRAS, occur earliest, followed by TERT promoter mutations, then CDKN2Aalterations, and finally TP53 and PTEN alterations. Benign nevi typically harbor a single pathogenic alteration, whereas fully evolved melanomas harbor three or more pathogenic alterations. We also identified an intermediate stage of neoplasia with some but not all of the pathogenic mutations required for fully evolved melanoma. There has been a longstanding debate whether morphologically intermediate lesions, such as dysplastic nevi, truly constitute biological intermediates or whether they simply represent a gray zone of histopathological assessment. Our data indicates that these neoplasms are genuine biological entities. Finally, we observe evidence of UV-radiation-induced DNA damage at all stages of pathogenesis, implicating UV radiation in both the initiation and progression of melanoma.

Medical Research: What should clinicians and patients take away from your report?

Dr. Bastian:  The malignant potential of melanocytic neoplasms has traditionally been estimated by morphological assessment. This form of evaluation has limitations, as it is inherently subjective. We report objective genetic criteria that could assist in the diagnosis and staging of melanocytic neoplasms. In particular, genetic criteria may facilitate the assessment of intermediate neoplasms for which inter-observer morphological agreement is particularly low.

It is clear from epidemiologic studies that UV radiation is a pathogenic factor promoting the development of melanoma. Our study clarifies this role, implicating UV radiation in both the formation of precursor lesions and the progression from precursor lesions to melanoma. Therefore, clinicians should continue to advise their patients to avoid the sun, and in particular, patients with numerous nevi should avoid the sun

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Bastian:  Our finding that morphologically intermediate lesions are distinct biological entities resolves many questions regarding this controversial category of neoplasms. Future studies are necessary to delineate the relationship of the number and types of genetic alterations and the clinical and histopathological presentation. It will be important to precisely quantify the malignant potential of dysplastic nevi and other morphologically intermediate lesions in order to guide the clinical management of these neoplasms. It will also be important to utilize genetic criteria to identify and subgroup these neoplasms, as we anticipate that intermediate neoplasms will be genetically diverse and the malignant potential of a given neoplasm will be influenced significantly by its underlying genetic abnormalities.


A. Hunter Shain, Ph.D., Iwei Yeh, M.D., Ph.D., Ivanka Kovalyshyn, D.O., Aravindhan Sriharan, M.D., Eric Talevich, Ph.D., Alexander Gagnon, B.A., Reinhard Dummer, M.D., Jeffrey North, M.D., Laura Pincus, M.D., Beth Ruben, M.D., William Rickaby, M.B., Ch.B., Corrado D’Arrigo, M.B., Ch.B., Ph.D., Alistair Robson, F.R.C.Path., and Boris C. Bastian, M.D.

N Engl J Med 2015; 373:1926-1936
November 12, 2015

DOI: 10.1056/NEJMoa1502583

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Boris C. Bastian, MD, PhD (2015). Progression of Mutations From Moles To Melanoma Identified