Desmoplastic Melanoma Carries High Mutation Burden

The first thorough genomic sequencing of desmoplastic melanoma shows that these tumors carry an unusually high number of mutations—among the highest known for all cancers. The results suggest that patients may respond well to immunotherapy, which relies on detecting differences between normal and cancerous cells.

Prior to this study, “almost nothing” was known about the mutations involved in desmoplastic melanoma, says coauthor A. Hunter Shain, PhD, a postdoctoral fellow in dermatology and pathology at the University of California, San Francisco (UCSF). Although researchers have sequenced other cancers such as breast cancer, pancreatic cancer, and commonly diagnosed melanomas, “this one got kind of left behind.”

Desmoplastic melanoma accounts for only 4% of melanomas, and it tends to elude early diagnosis because it lacks pigmentation. Researchers have studied desmoplastic melanomas, but they have been unable to identify common pathogenic mutations.

The team, led by Boris Bastian, MD, PhD, professor of dermatology and pathology at UCSF, performed whole-genome and exome sequencing on tumors from 20 patients and matched normal DNA samples. Based on those results, they chose 293 candidate genes to sequence in 42 additional tumors. Overall, the samples carried a median of 62 mutations per megabase, the researchers report in Nature Genetics. In contrast, mutation rates are about 15 per megabase in common melanomas and 2 per megabase in many other solid cancers. The patterns of DNA alterations suggest that ultraviolet radiation caused the mutations.

The high mutation burden could help the immune system identify cancerous cells, making patients strong candidates for immune checkpoint blockade therapy. “More mutations might actually be good,” says Antoni Ribas, MD, PhD, a professor of hematology and oncology at the David Geffen School of Medicine at the University of California, Los Angeles, who was not involved in the study. In an analysis of clinical trials, Ribas's team found that patients with desmoplastic melanoma seemed to respond better to anti-PD1 and anti–PD-L1 therapy than those with more common melanomas.

Shain's study also points to other possible treatments. About a quarter of the samples contained mutations in well-studied oncogenes, such as EGFR and MET, the products of which are already targeted by FDA-approved drugs. If first-line therapy fails, those drugs “could be a second line of therapy,” says Shain. First-line treatments typically include surgery, radiation, or immunotherapy.

In addition, the team identified recurrent promoter mutations of NFKBIE, a gene that had not previously been linked to any cancer. The protein encoded by NFKBIE inhibits activity of proinflammatory NF-κB transcription factors. By upregulating NFKBIE, the mutations may help disguise the tumor from the immune system, says Shain.

It's not clear whether existing drugs, such as EGFR and MET inhibitors, will effectively treat patients, says Ribas. More research is needed to determine whether the mutant proteins play the same role in desmoplastic melanoma as they do in other cancers. Shain's team is working to better understand these mutations, including the NFKBIE mutation, in model organisms.