Cancer cells can avoid detection by the immune system.
Moreover, it seems likely that one of these mutations may be specifically involved in shielding new DM tumors from destruction by the immune system.
DM is different in formation and appearance from other melanomas. It develops slowly and is unpigmented and scar-like in appearance. A tingling sensation may occur as it grows into nerves.
Being less recognizable than other forms of melanoma, it may be some time before DM is noticed or correctly diagnosed. By then, it is often too late for treatment, especially as it metastatizes directly to the lungs. It accounts for 4% of melanomas.
The team focused on showing that there are different types of melanoma with different genetic profiles, which enables them to be categorized in groups and as individual types, according to Dr. Boris Bastian, PhD, the Gerson and Barbara Bass Bakar Distinguished Professor in cancer research at the University of California-San Francisco (UCSF).
Due to the difficulty in collecting specimens of DM and its lack of similarity with more common types of melanoma, its genetic basis has only now started to become clear.
As lead author, A Hunter Shain, PhD, a postdoctorlal Fellow in Dr. Bastian's lab, says:
"Because these tumors are not pigmented, people often don't notice them until they're quite large [...] and then it might be too late [...]. Though DM is a very deadly melanoma, virtually nothing's known about it."
The study involved obtaining 62 DM samples from the US and Australia, on which the researchers carried out next-generation, whole-genome and exome sequencing. The coding regions of the tumor's genetic code were parsed "letter by letter" in order to find common mutations between the samples.
While the samples seemed to share few mutations with other melanoma types, mutation pathways were found that were common to other cancer types, for which treatments already exist.
Scientists generally believe that if a high number of mutations occur, these will be detected quickly by immune cells and destroyed before they spiral out of control. However, DM seems to buck the trend.
Sequencing reveals unusual genetic mutations
The research made two key discoveries about DM: the first relating to the number of gene mutations and the second to the type of mutation that occurs.
DM has the highest number of mutations the researchers had ever seen in an untreated tumor, without apparent defect in DNA repair.
One of the most common DM mutations, not previously seen in cancer cells, was discovered in a promoter region that regulates expression of the NFKBIE gene. This gene plays an important role in rebuffing immune responses. The unusual location of this gene means that it is very difficult for scientists to detect it in routine gene analysis, and it is also very effective in "cloaking" malignant cells during the development of cancer.
The implication is that the action of the mutated NFKBIE promoter may help "quench" the immune system, which then enables the affected cells to escape detection by the immune system long enough to accumulate other mutations, thus allowing the cancer to develop.
The findings support a growing emphasis on immune checkpoint blockade therapy, which aims to disarm or remove the secretions that prevent the immune system from recognizing cancer cells as harmful.
Dr. Bastian speculates that "by adding an antibody which interferes with the quenching, you unleash the immune system, and the tumors shrink away almost completely."
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