New Form of Melanoma Yields Overwhelming Number of Mutations

Desmoplasmic melanoma possesses a mutation that protects tumors from destruction by the immune system.

A newly discovered form of skin cancer that is extremely rare and deadly may possess the highest burden of gene mutations of any cancer to-date. The cancer, referred to as desmoplasmic melanoma (DM), possesses a mutation that may shield nascent tumors from destruction by the immune system and allow further mutations to develop.

“The focus of our lab has been to show that there’s not just one ‘melanoma’ but many different types,” said senior author Boris Bastian, MD, PhD, the Gerson and Barbara Bass Bakar Distinguished Professor in Cancer Research at UCSF. “We’ve already discovered genetic profiles that let us begin to separate them into groups and study them individually. But this is one type that has so far been left behind.”

Most melanomas grow rapidly and appear as dark brown blemishes on the skin, but DM is almost completely the opposite, developing more slowly and appearing as unpigmented scar-like bumps. As the cancer grows deeper into the nerves, a tingling sensation accompanies the bumps. Its unusual appearance leads to delayed or incorrect diagnoses, which can be deadly, as the cancer tends to metastasize directly to the lung.

“Because these tumors are not pigmented, people often don’t notice them until they’re quite large,” said lead author A. Hunter Shain, PhD, a postdoctoral fellow in Bastian’s lab. “And then it might be too late.”

Because DM accounts for a very small percentage of melanomas, scientists have found it difficult to gather enough specimens to study in order to gain more information about its genetic basis until now. Previous research that studied a smaller number of samples looked for the mutations associated with more common forms of melanoma but found no leads. This means that while DM is very deadly, virtually nothing is known about the disease.

The new study evaluated 62 samples of DM acquired from UCSF, the Memorial Sloan Kettering Cancer Center in New York and the Melanoma Institute Australia in Sydney. Researchers performed next-generation, whole genome and exome sequencing to identify common mutations between the samples.

Much like its atypical physical appearance, DM’s genetic basis is a medical anomaly. The researchers detected few of the mutations commonly seen in other melanoma types, but instead identified mutations of pathways frequently implicated in other cancers for which some targeted therapies already exist.

The researchers also found two other important discoveries as a result of the study.

The first deals with the high number of mutations observed in DM samples. Most solid tumors carry about 2 mutations per million base pairs, the genetic “letters” that make up genomes.

Melanomas will typically have a greater number of mutations, approximately 15 per million base pairs. But the number of mutations observed in DM samples was through the roof, with an estimation of 62 mutations per million base pairs, a number previously unheard of.

“This is the highest number of mutations we’ve ever seen in an untreated tumor without any apparent defect in DNA repair,” Bastian said.

The second important finding involved the discovery of a common mutation in DM that was not previously observed in other cancer cells, which occurred in a promoter region that regulates expression of the NFKBIE gene. This gene plays a key role in turning down immune responses.

“This is the first time this gene has popped up in any cancer,” Bastian said. “What’s more, it’s rare among known cancer mutations in that it resides in the regulatory ‘dark matter’ of the genome, and not within the part of a gene that codes for a protein. Regulatory mutations like this routinely escape all but the most comprehensive genomic analysis.”

Many scientists believe that cancers with high numbers of mutations will be detected and killed quickly from circulating immune cells before they spiral out of control. In the case of the NFKBIE mutation, however, the promoter may allow affected cells to go undetected by the body’s immune surveillance long enough to accumulate the numerous other mutations that eventually drive the cells to a cancerous state, Bastian suggested.

“It may be like a cloak of invisibility for the cancer cells,” he said.

While this exact mechanism of cancer growth in DM is still unproven, it does suggest that immune checkpoint blockade therapy, a proven successful therapy in treating more common forms of melanoma, could be a particularly effective first line of attack against DM.

“Other melanomas with high mutation burden tend to have increased sensitivity to immune checkpoint blockade,” Bastian said. “We think successful tumors somehow quench the immune response, but through this technique, by adding an antibody that interferes with the quenching, you unleash the immune system and the tumors shrink away almost completely.”