Genetic mutations that result in melanoma have been cataloged over the years. The missing piece has been an understanding of the order of their occurrence and how they move from a benign lesion to one that is cancerous. An article by Boris C. Bastian, MD, PhD, Gerson and Barbara Bass Bakar Distinguished Professor of Cancer Research at the University of California, San Francisco; Hunter Shane, PhD, a postdoctoral fellow at the university; and others hopes to help answer some of those questions.
“Over last 20 years, we have shown that there are distinct types of melanoma,” Bastian said. “These differ in cell of origin, mutational processes that alter the cells, and types of mutations that occur.”
Researchers have made substantial advances in finding the genetic alterations that lead to advanced disease. However, the order in which the lesions evolve these mutations wasn’t clear.
“There are a series of pathogenic or driver mutations in fully involved lesions,” Bastian said. “We set out in this study to look at changes in melanomas where at least some of the noncancerous precursor lesion was still identifiable.”
A total of 37 formalin-fixed, paraffin-embedded melanocytic neoplasms were retrieved from the archives of hospitals in San Francisco, London, and Zurich. Overall, 150 distinct areas were prepared for genetic sequencing.
Each area was assessed microscopically by eight dermatopathologists and categorized as benign, intermediate but probably benign, intermediate but probably malignant, or malignant according to how far the pathologists judged the areas had progressed toward malignancy.
Closer to Malignant, More Mutations Seen
All those lesions unanimously deemed benign had only a single mutation, BRAF V600E, a common, well-established mutation in melanoma. This single genetic alteration appears to be all that is needed to form a common mole.
Pathologists also agreed at the malignant end of the spectrum where melanomas tended to show multiple mutations such as mutation of TERT and loss of CDK2NA. They also saw mutations of PTEN or TP53 in more advanced primary melanomas.
“One of the unexpected findings was there clearly were lesions that are genetically intermediate between clearly benign and clearly malignant,” Bastian said. “These genetically intermediate lesions happened to also be those in which there was significant disagreement among the pathologists and which were placed between the benign and malignant categories by the consensus vote of the pathologists. Those were the lesions that without exception had multiple mutations.”
He further noted that controversy has persisted for decades about whether an intermediate stage lies between clearly benign and clearly malignant as a melanoma forms from a precursor lesion.
Distinct Genetic/Biologic Stages
“What we show for the first time is that there is a genetically and biologically distinct intermediate phase,” Bastian continued. “This is the first wave of new investigation looking at these intermediate lesions that may allow us to refine our clinical and histopathological criteria into a much more detailed risk assessment.”
Multiple evolutionary trajectories exist that start differently and lead to several types of melanoma. Those results confirm earlier observations suggesting melanoma has subtypes.
Strong UV Signature
The findings also point to a very strong UV signature in the genetic mutations. It is the first time that UV radiation has been shown to be the major pathogenic mechanism transforming benign lesions into melanomas by creating the mutations required for full transformation.
“The intermediate lesions tended to have significantly more mutations [than] the precursors,” Bastian said. “The increased numbers had a very strong UV signature telling us that this is what was transforming precursor in full-blown melanoma. We were stunned by the five- to sevenfold increase in the number of these mutations when compared to the precursor lesions.”
These results give people another reason to stay away from sources of UV radiation. He thinks that avoiding UV radiation could prevent existing moles from progressing to malignancy. Avoiding UV essentially gives the person another chance to stop the progression.
“We haven’t told anybody to keep their moles out of the sun,” Bastian said. “We can infer clearly that the pathogenic variable in turning lesions into cancer is UV radiation. By reducing exposure of your moles, you are likely to also be decreasing the possibility of transformation into melanoma.”
Changes in Diagnosis/Treatment
Some early indicators might exist of possible changes in how we diagnose and possibly even treatment melanoma.
“We can take this information, after other studies have confirmed it, and possibly look for specific mutations in a suspicious lesion,” Bastian said. “Current diagnosis is done through a microscope and doesn’t produce highly repeatable verdicts for a subset of lesions. It is likely that an assay could be developed based on genetic alterations that could place individual lesions on that trajectory from clearly benign to clearly malignant based on objective criteria.”
What is not yet clear is whether this is a stepwise movement or if it is possible to skip the intermediate level. He points to families prone to develop melanoma over multiple generations.
“They inherit a nonfunctional copy of one of the genes that usually gets mutated later and then random mutation leads to BRAF mutation as the second change,” Bastian said. “Whether this reversal of order could allow them to ‘skip’ one of these intermediate stages and form a melanoma without an apparent precursor is an intriguing proposition. We really don’t address the possibility in our research, and any ability to do so still needs to be determined.”
Lawrence Mark, MD, PhD, associate professor of dermatology at the Indiana University School of Medicine in Indianapolis, said he thinks that the article is interesting and important because it gives an early scientific indication validating what both clinical experience and intuition have been telling physicians about the development and progression of melanomas.
“We have hypothesized that melanoma arises through a chain of mutations leading to more and more deranged cellular activity to the point it could no longer control itself,” Mark said. “This study provides support for something we thought was true. When you start thinking about things in the right manner, you can start looking for things that might stop the pathway toward melanoma.”
Asad Umar, DVM, PhD, chief of the Gastrointestinal and Other Cancers Research Group at the National Cancer Institute, said that the importance of this study is that it is similar to other recent articles that examined the genomic landscape of cancers from other organs also showing a similar pattern. The article “does give us an early indication of a possible sequence for turning benign lesions into melanoma,” Umar said. “Right now the major takeaway, if these results can be replicated, is establishing genomic risk factors that can be added to other risk factors in deciding who should be [monitored] more closely.”
Direct Effects a Long Way Off
Although he does acknowledge the value of the additional information, he said he thinks that direct effects on either diagnosis or treatment are not likely soon. For example, translating this into a screening test is probably a long way off, if it is even feasible.
“The problem is quite difficult if you think about it,” Umar said. “If only 5% of lesions go on to progress to cancer, you have to sequence 100 lesions to just find five to follow and which ones are the meaningful ones? Even if you could find the 5% that might become cancerous you would have to follow them for a long time as benign moles don’t progress to cancer overnight.”
Some BRAF-inhibitor medications have shown some promise, but they are still early in development. However, nothing in this particular study offers guidance for a treatment anytime soon.
Concerns About Design
Umar has some concerns about the design of the study and how that might affect its influence.
“It is a strange design in my opinion and that is a limitation to be considered,” he said. “They looked at slides for both cancers and pre-cancers that they already knew had cancer, which limited their sets to just those regions that they targeted. It is a problem in that it doesn’t give you an unbiased opinion.”
That issue limits the sample size and it won’t apply to everyone. He said a larger sample set with unbiased samples could yield a better picture of other possible cancer-driving mutations.
“If you move outside the area of the lesion itself, you start to see mutations indicating a path but [that] doesn’t mean that is the only path,” Umar said. “We can’t be sure until we look at other possible pathways to the same point. There are usually multiple genomics paths in cancer.”
Adding a Piece of the Puzzle
But in the end, the results do help in understanding, at the very least, a piece of the genomic puzzle in melanoma.
“Our study sheds light on some long-existing murky areas and provides additional clarity in others,” Bastian said. “Hopefully this will motivate others to revisit the problem to identify and develop better criteria for diagnosis and recognition of intermediate lesions and a better understanding of what actually constitutes a melanoma.”
A version of this article originally appeared in the Journal of the Nation Cancer Institute.
Featured image credit: 28 F w/ in-transit met (melanoma) by Niels Olson. CC BY-SA 2.0 via Flickr.
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