Rare melanoma may have highest burden of mutation among cancers

A new study has found that desmoplasmic melanoma (DM), a rare but deadly form of skin cancer, appears to carry the highest burden of genetic mutation of any cancer, which suggests it is a good target for immunotherapy, according to a press release from the University of California: San Francisco (UCSF) (Sept. 4, 2015).

One of the mutations observed in DM tumours had never previously been observed in cancer cells, and may shield DM cells from destruction by the immune system, according to the release. This shielding may in turn allow for further mutations to develop.

“The focus of our lab has been to show that there's not just one ‘melanoma’ but many different types,” senior author Boris Bastian, MD, PhD, the Gerson and Barbara Bass Bakar Distinguished Professor in Cancer Research at UCSF was quoted saying in the release. “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.”

DM develops slowly into unpigmented scar-like areas on the skin, with occasional tingling sensations as the tumour grows into nearby nerves, according to the release, which notes these differences from the more common fast-developing, pigmented lesions associated with melanoma can lead to dangerously delayed or wrong diagnosis. This is particularly worrisome in DM as it can metastasize directly into the lungs.

Very little has been known about DM, which makes up approximately 4% of melanomas, in part because researchers have had difficulty gathering sufficient biopsy specimens, according to Dr. Bastian.

The new study included 62 DM samples which were examined through whole genome and exome sequencing, with the samples compared to identify common mutations between them. Interestingly, DM cells had few of the mutations normally associated with other forms of melanoma, but instead had pathway mutations often associated with other cancers for which targeted therapies already exist, according to the release.

Most solid tumours have roughly two mutations per million base pairs in the genome, according to the release, and more common melanomas have up to about 15 per million base pairs. The DM tumours examined in this study had approximately 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 in the release.

One of the most common mutations observed in DM cells was found in a region of the genome which regulates the expression of the NFKBIE gene, known to play a significant role in down regulating immune responses – a mutation that had never previously been observed in cancer cells.

This mutation “may be like a cloak of invisibility for the cancer cells,” Dr. Bastian said in the release, noting that it may allow the affected cells to go undetected by the immune mechanisms that are believed to identify and destroy cells with large numbers of mutations, thereby allowing the DM cells to accumulate more such mutations.

The study authors suggest that immune checkpoint blockade therapy may be valuable in DM. “Other melanomas with high mutation burden tend to have increased sensitivity to immune checkpoint blockade,” Dr. Bastian said in the release. “We think successful tumours 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 tumours shrink away almost completely.”

More information available at: http://www.newswise.com/articles/view/639533/


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