A new study shows different mutation classes associated with distinct melanoma sub-types
Skin cancer remains one of the most common forms of the disease in the U.S. Though melanomas account for less than 5% of all skin cancers, they cause the large majority of deaths from the disease. Some parts of the skin (like the palms and soles) develop cancers much less frequently, and the rare ‘acral melanomas’ that originate from these types of skin have less in common with other skin cancers.
Understanding the genomic differences in these sub-types of melanoma can help to identify drugs that target cancer-specific genetic changes in patients. As part of this larger goal, an open-access paper in Nature earlier this month describes the exome sequences of twenty-five metastatic melanoma samples. Michael Berger and his colleagues compared the sequences from these tumors to matched blood samples from the same patients to identify differences between the cancer sample and normal tissue. Two of these twenty-five samples were acral melanomas, and one of the cutaneous tumors studied originated from a patient with a long history of chronic sun exposure.
Their analysis identified distinct similarities and differences in the genomic changes in each of these tumor types. The tumor with long-term UV exposure had the highest frequency of point mutations, or single base changes like transversions and substitutions, the most common type of DNA damage associated with UV irradiation, whereas the acral melanomas had the lowest frequency of such changes.
On the other hand, genomic re-arrangements, or mutations where chunks of chromosomes are randomly broken off and spliced, were common in both acral and cutaneous melanomas. Many of these re-arranged chromosomal regions contained large genes implicated in cancer-related processes, such as the tumor suppressors CSMD1 and PTEN and MAGI2, which binds and stabilizes PTEN. Other genes included FHIT, MACROD2 and A2BP1. The well-studied BRAFV600E mutation was found in 16 of the 25 tumors, the rest had mutations in the NRAS gene. BRAF and NRAS mutations occurred in a mutually exclusive fashion in all tumors except the hyper-mutated sample. The researchers also identified PREX2 mutations in many of the tumor samples sequenced; one acral melanoma sample had nine different mutations in the gene. To see whether this novel gene could be a significant biomarker for melanoma, the researchers screened an additional set of 107 samples for PREX2 mutations, and found them in a significant fraction (14%) of these tumors.
The mutational signatures of sub-types of melanoma identified in these samples are similar to those described in previous studies. In particular, this research confirms the prevalence of genomic re-arrangements in acral melanomas, and the increased mutation frequency seen with greater exposure to UV-rays and sunlight. (It even validates a song a little further.)
These results are important both for choosing the best treatments for patients, and for researchers working on more precise ways to treat melanoma. For example, the recently approved drug vemurafenib specifically targets the BRAFV600E mutation found in many of these tumors. Could the PREX2 mutations identified in this study be used to develop similar drugs? Given the diverse PREX2 mutations even in this small cohort, it seems unlikely that a single mutation in the gene plays a critical role in driving melanoma development. The different mutations of PREX2 seem to converge on a single property, where cells with the mutant gene grow into tumors faster and make more of the PREX2 protein. Rather than targeting specific SNPs, researchers may be able to use such data to identify metabolic pathways or regulatory mechanisms that are good therapeutic targets to develop drugs.
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