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Unprecedented Number of Mutations Identified in Rare Melanoma

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Key Points

  • Desmoplasmic melanoma accounts for 4% of melanomas.
  • Most solid tumors carry about two mutations per million base pairs, whereas more common melanomas carry about 15 per million base pairs. Desmoplasmic melanoma tumors carried about 62 mutations per million base pairs.
  • One of the most common desmoplasmic melanoma mutations, never before seen in cancer cells, occurred in a promoter region that regulates expression of the NFKBIE gene, which plays an important role in "turning down" immune responses.

A rare form of skin cancer known as desmoplasmic melanoma may possess the highest burden of gene mutations of any cancer, suggesting that immunotherapy may be a promising approach for treatment, according to an international team led by University of California San Francisco (UCSF) scientists. One of these mutations, never before observed in any cancer, may shield nascent desmoplasmic melanoma tumors from destruction by the immune system and allow further mutations to develop. These findings were published by Shain et al in Nature Genetics.

“The focus of our laboratory 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.”

Rare, Difficult-to-Detect Cancer

Unlike many melanomas, which grow rapidly and appear as dark-brown discolorations of the skin, desmoplasmic melanoma is unusual in that it develops slowly and forms unpigmented, scar-like bumps, occasionally accompanied by tingling sensations as the cancer grows into nerves. Its unusual appearance leads to delayed or incorrect diagnoses, which can be deadly, as the cancer tends to metastasize directly to the lungs.

“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 Dr. Bastian’s laboratory. “And then it might be too late.”

Desmoplasmic melanoma accounts for 4% of melanomas, but until now, its genetic basis was unknown, partly because it has been difficult for researchers to assemble a sufficient number of biopsy specimens to study. In previous research based on small numbers of specimens, scientists had looked for the mutations associated with more common forms of melanoma but had found no leads, said Dr. Bastian, who is a member of the UCSF Helen Diller Family Comprehensive Cancer Center.

As a result, Dr. Shain said, “though desmoplasmic melanoma is a very deadly form of melanoma, virtually nothing is known about it.”

In this study, researchers obtained 62 desmoplasmic melanoma samples from UCSF, Memorial Sloan Kettering Cancer Center, and Melanoma Institute Australia. They then performed next-generation, whole genome, and exome sequencing, parsing the coding regions of the tumors’ genetic code “letter by letter” to identify common mutations between the samples.

In line with its atypical clinical presentation, desmoplasmic melanoma appears to be a genetic oddball among melanomas. 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.

Mutation Specifics

Two other findings suggested an intriguing portrait of how desmoplasmic melanoma develops and how it might be treated.

First was the discovery that desmoplasmic melanoma tumors carry a surprisingly high number of mutations. Most solid tumors carry about two mutations per million base pairs. More common melanomas, which often are caused by exposure to the ultraviolet component of sunlight, have more mutations—about 15 per million base pairs. In the current study, however, desmoplasmic melanoma tumors carried about 62 mutations per million base pairs. “This is the highest number of mutations we’ve ever seen in an untreated tumor without any apparent defect in DNA repair,” Dr. Bastian said.

A second key finding was that one of the most common desmoplasmic melanoma mutations, never before seen in cancer cells, occurred in a promoter region that regulates expression of the NFKBIE gene, which plays an important role in "turning down" immune responses. “This is the first time this gene has popped up in any cancer,” Dr. 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.”

Evading the Immune System

Many researchers believe that cancers with high numbers of mutations are quickly detected and destroyed by circulating immune cells before they spiral out of control. However, the mutated NFKBIE promoter may allow affected cells to fly under the radar of the body’s immune surveillance long enough to accumulate the numerous other mutations that eventually drive the cells to a cancerous state, Dr. Bastian speculated.

Though this mechanism of cancer growth in desmoplasmic melanoma is still unproven, it suggests that immune checkpoint blockade therapy, which has proven successful in treating more common forms of melanoma, could be a particularly effective first line of attack against desmoplasmic melanoma.

“Other melanomas with high mutation burden tend to have increased sensitivity to immune checkpoint blockade,” Dr. 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.”

This study was supported by the National Institutes of Health, the American Skin Association, the Well Aging Research Center at the Samsung Advanced Institute of Technology, the Dermatology Foundation, and the Oregon Health and Sciences University Knight Cancer Institute. The authors declared no potential conflicts of interest in this research.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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