Rare Melanoma carries unprecedented burden of mutations

A rare, deadly form of skin cancer known as desmoplasmic melanoma (DM) 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 UC San Francisco scientists. One of these mutations, never before observed in any cancer, may shield nascent DM 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."Two findings suggested an intriguing portrait of how DM develops, and how it might be treated.
First was the discovery that DM tumors carry a surprisingly high number of mutations. Most solid tumors carry about two mutations per million base pairs, the genetic "letters" that make up genomes. 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, DM 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," Bastian said.
A second key finding was that one of the most common DM 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," 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."