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Precision Oncology: Creating a Genomic Guide for Melanoma Therapy

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Melanoma cell

Caption: Human malignant melanoma cell viewed through a fluorescent, laser-scanning confocal microscope. Invasive structures involved in metastasis appear as greenish-yellow dots, while actin (green) and vinculin (red) are components of the cell’s cytoskeleton.
Credit: Vira V. Artym, National Institute of Dental and Craniofacial Research, NIH

It’s still the case in most medical care systems that cancers are classified mainly by the type of tissue or part of the body in which they arose—lung, brain, breast, colon, pancreas, and so on. But a radical change is underway. Thanks to advances in scientific knowledge and DNA sequencing technology, researchers are identifying the molecular fingerprints of various cancers and using them to divide cancer’s once-broad categories into far more precise types and subtypes. They are also discovering that cancers that arise in totally different parts of the body can sometimes have a lot in common. Not only can molecular analysis refine diagnosis and provide new insights into what’s driving the growth of a specific tumor, it may also point to the treatment strategy with the greatest chance of helping a particular patient.

The latest cancer to undergo such rigorous, comprehensive molecular analysis is malignant melanoma. While melanoma can rarely arise in the eye and a few other parts of the body, this report focused on the more familiar “cutaneous melanoma,” a deadly and increasingly common form of skin cancer [1].  Reporting in the journal Cell [2], The Cancer Genome Atlas (TCGA) Network says it has identified four distinct molecular subtypes of melanoma. In addition, the NIH-funded network identified an immune signature that spans all four subtypes. Together, these achievements establish a much-needed framework that may guide decisions about which targeted drug, immunotherapy, or combination of therapies to try in an individual with melanoma.

In the groundbreaking study, an international team of 300 researchers sequenced and analyzed the complete sets of DNA, or genomes, of primary and metastatic tumor samples, as well as blood samples, from more than 330 people with melanoma. By comparing the genomes of each patient’s cancer cells with that of his or her healthy blood cells, the researchers were able to catalog the full range of genomic changes that distinguished each patient’s cancer.

Those comparisons turned up more than 220,000 mutations in all—many of which were of a sort known to occur commonly with exposure to the sun’s ultraviolet (UV) radiation. This mutation rate was the highest of any type of cancer analyzed by the TCGA network to date. Using sophisticated analytics, the researchers then worked to zero in on a much smaller set of mutations—13 to be exact—that play a pivotal role in driving melanoma. The short list includes some genes that have previously been implicated in melanoma, along with several new culprits.

Based on these findings, the TCGA team proposed a genomic classification system that divides melanoma into four distinct subtypes. Three of the subtypes are defined by the presence of a specific genetic mutation linked to melanoma: BRAF, RAS, and NF1. [I was particularly intrigued by the findings related to the NF1 gene, as my lab identified this gene way back in 1990 and had no idea at the time it would turn out to be important in this form of cancer.] The fourth represents a more variable group, dubbed “triple-wild-type,” which is distinguished by the absence of BRAF, NRAS, or NF1 mutations. According to the researchers, all four subtypes share common signaling pathways, but differ in how those pathways are activated. By themselves, the subtypes don’t appear to predict any particular patient outcome. However, this detailed survey of melanoma’s genomic landscape will provide valuable information for the development and more precise use of targeted drugs.

Likewise, another discovery arising from the TCGA analysis may have major implications for immunotherapy strategies. The team, led by researchers at the University of Texas M.D. Anderson Cancer Center, Houston, found that approximately one-third to one-half of the tumors from all four melanoma subtypes showed increased activity of immunity-related genes, presumably because of the presence of immune cells in the tumor samples. Individuals whose cancers displayed this “immune infiltration” signature had better odds of survival than those who did not. In addition, the study uncovered a potential new biomarker called LCK, a protein found in white blood cells. The findings suggest that the presence of LCK, when coupled with the immune infiltration signature, may predict a favorable outcome for cutaneous melanoma patients whose cancer has spread to surrounding tissue or nearby lymph nodes.

These findings provide yet another example of how cancer research has been leading the way in precision medicine, thanks in large part to TCGA and other science supported by NIH. Still, much more remains to be done. As part of the new Precision Medicine Initiative, researchers will explore fundamental aspects of cancer biology, seek to understand the mechanisms of drug resistance, and accelerate the design and testing of more precisely targeted cancer treatments, including combination therapies.

Prevention of cancer and other diseases will also be a major focus of the Precision Medicine Initiative. For melanoma, we already know that protecting your skin from too much sun exposure is crucial—more than 90 percent of cases are linked to UV radiation. Still, questions remain about exactly how an individual’s genetic makeup and UV exposures interact to influence melanoma risk. By collecting genomic information and tracking environmental exposures through mobile health devices, the Precision Medicine Initiative’s national research cohort of 1 million or more Americans will offer an opportunity to get answers to those questions.

References:

[1] Rates of new melanomas – deadly skin cancers – have doubled over last three decades. Centers for Disease Control and Prevention. June 2, 2015.

[2] Genomic classification of cutaneous melanoma. The Cancer Genome Atlas Network. Cell. 2015 Jun 18;161(7):1681-96.

Links:

The Cancer Genome Atlas (National Cancer Institute, National Human Genome Research Institute/NIH)

Cutaneous melanoma (The Cancer Genome Atlas/NIH)

A Snapshot of Melanoma (National Cancer Institute/NIH)

Precision Medicine Initiative (NIH)

NIH Support: National Cancer Institute; National Human Genome Research Institute

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