Gruber lecturer discusses role of UV radiation in mole mutations

Boris C. Bastian, MD, PhD

As treating melanoma is difficult, so is developing melanoma. It requires a complex series of genetic mutations — often driven by exposing moles to sunlight — occurring in the right order to overwhelm the system set up to stop the mutated cells.

Research into this mutational process was explained in Sunday’s Lila and Murray Gruber Memorial Cancer Research Award and Lectureship, “How Moles Become Cancer.” In an interview before the presentation, lecturer Boris C. Bastian, MD, PhD, explored the potential to use this research data to identify problematic lesions and improve the prevention of melanoma.

“Ultraviolet radiation is a major driver in the equation of what comes down to a probability game needed to get the right number of mutations into one and the same cell. The most likely way to do that is to create a bunch of precursor lesions that consist of progeny of an initial cell from which they all have inherited a mutant oncogene, all of which are now at risk to acquire the next mutation. That is why moles are a risk factor and precursor for melanoma,” he said.

Dr. Bastian is part of a team that recently published research on that mutational process. He is the Gerson and Barbara Bass Bakar Distinguished Professor of Cancer Biology and executive director of the Clinical Cancer Genomics Laboratory at the University of California in San Francisco. He also is a professor in the UCSF departments of dermatology and pathology.

Researchers started by methodically sequencing 293 cancer-relevant genes in 150 areas of 37 primary melanomas and their immediately adjacent precursor lesions. They defined a series of genetic alterations during melanoma progression. They also identified distinct evolutionary trajectories for different melanoma subtypes, according to an abstract based on the research.

“We found in all of these combined lesions in which a melanoma arose from an adjacent precursor that there were shared mutations between the precursor and melanoma areas. The shared mutations were the mutations that were acquired early during the evolution. In the melanoma portions, there were invariably more mutations than in the respective nevus portions, including mutations that led to the transformation of the nevus to become malignant,” Dr. Bastian said. “That allowed us to establish a sequential order in which mutations accumulate during the evolution of melanoma from these precursor lesions.”

Nevi, which pathologists unanimously graded as benign, only showed a single mutation, whereas melanomas had multiple mutations and chromosomal aberrations. The study identified a set of lesions that showed an intermediate number of mutations, which pathologists graded as borderline lesions. The finding supports the existence of a biologic intermediate state and is likely to advance the decade-long debate over the existence of dysplastic nevi, he said.

These intermediate lesions had a high frequency of telomerase promoter mutations. These mutations are thought to give cancer cells an advantage to overcome the limited replicative lifespan of normal cells. Finding these mutations in these pre-neoplastic lesions was unexpected as they were considered senescent long before their cells reached their replicative limit. This indicates that a lot more cell divisions have taken place in these small lesions than their number of cells would suggest, Dr. Bastian said, showing that these lesions are turning over many times during their life span, painting a more dynamic picture than current models of nevi.

“The pattern in which these mutations arise teaches us about the various barriers that constrain moles from becoming malignant and how these barriers get overrun during the transformation to melanoma,” Dr. Bastian said. “That also led to a dramatic insight. The carcinogenic mechanism that led to the overrunning of these barriers was clearly UV radiation.

“To generate a melanoma, you have to get the right combination of putting the gas pedal down with BRAF and BRAS mutations, disabling the brakes, and changing some of the cellular differentiation programs by inactivating epigenetic regulators to fully transform those cells.”

That insight also should be used to develop a game plan to prevent the development of melanomas, Dr. Bastian said.

“The prevention message should be expanded to include the statement, ‘Keep your moles out of the sun,’ and that will significantly reduce the probability of having your mole cells turn cancerous,” he said.

The insights gained from the research could also be used to develop algorithms to better prevent melanomas by identifying high-risk lesions and removing them before they become cancerous.

“If we were able to clinically and histopathologically identify lesions that have more than one mutation on board, and if we were to remove all of those, I think we could significantly reduce the incidence of new melanomas. That is perhaps the most important finding in terms of what it does for impacting melanoma morbidity and mortality,” Dr. Bastian said.

The next step in the study of mutations should be to align the genetic alterations with the known clinical and histologic descriptors of dysplasia, he said.

“My intuition is that we will find some reproducible histopathologic features that will help us better identify high-risk lesions,” Dr. Bastian said. “Then, we can work on establishing clinical guidelines on how to treat those.”

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