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Peering at brain and skin cancers through a genomic lens, scientists begin to rewrite rules for identifying tumor types

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A pair of studies from investigators with The Cancer Genome Atlas (TCGA) Research Network has provided new insights into the genomic workings of deadly types of brain and skin cancers. The findings point to new ways of classifying the cancers based on genomics, which should lead to smarter ways to predict disease behavior and better decisions about treatment.

Therapies for melanoma, the most serious and potentially lethal form of skin cancer, have seen a renaissance in recent years. Novel immunotherapies - treatments that kick-start the body's immune system - have joined a raft of new drugs aimed at specific genetic targets. One of the more common targets, a mutation in the BRAF gene, plays a role in as many as half of all melanomas.

In one study, TCGA researchers from over 50 institutions and more than five countries analyzed the genomes of 333 melanoma skin tumors, identifying molecular subtypes that may help clinicians determine which tumors are more aggressive and which are more likely to respond to certain treatments. The researchers, led by Lynda Chin, M.D., Jeffrey Gershenwald, M.D., and Ian Watson, Ph.D., at The University of Texas MD Anderson Comprehensive Cancer Center in Houston, reported their results online June 18 in Cell.

In the paper, researchers report that cutaneous, or skin, melanomas can be grouped into one of four subtypes, which are based on genetic mutations: BRAF mutant, RAS mutant, NF1 mutant and Triple-WT (wild-type). Such genomic classification should help better personalize treatment for patients. For example, Triple-WT tumor subtype is characterized by mutations in growth-promoting enzymes called receptor tyrosine kinases, which could potentially be treated with drugs that inhibit their activity.

The TCGA investigators also found something they didn't necessarily expect: a group of patients - who had higher than normal immune cell gene activity in their melanoma tumors that had spread elsewhere -- lived longer. The findings suggest that the likely outcome and treatment of some patients with melanoma may be affected by the type and activity level of immune cells found in the tumor.

"This likely has implications for immune therapy, which has been a game changer in melanoma, among the fastest growing cancers in incidence," said Dr. Watson. "We see this immune system gene activity equally distributed across the melanoma subtypes. Along with targeted therapies, this will inform personalized treatment decisions."

"The observation of the immune activity is a highlight of the paper with potential clinical applications," said Dr. Chin, who is now with the University of Texas System in Austin. "We saw dramatic clinical responses to immune checkpoint inhibitors in a subset of melanoma patients whose disease had spread elsewhere. This result leads one to wonder if patients with high immune activity are those who will respond to this class of therapy." Checkpoint inhibitors are drugs that free the immune system to attack tumors. She noted, however, that that the study does not offer evidence proving that the presence of such immune activity predicts response to checkpoint therapy.   

New insights into a secretive brain tumor

In the brain tumor report, which appeared online June 10 in the New England Journal of Medicine (NEJM), a team of more than 300 TCGA investigators revealed new ways of viewing rare and often deadly brain cancers called lower grade gliomas (LGG).

The researchers determined that brain tumors are better defined based on their genetic make-up, thereby painting a clearer picture of the cancer, than when pathologists simply look under the microscope. They devised a promising new approach to help predict how the disease may progress and what treatments might be most effective. The findings could quickly change the way these cancers are diagnosed and treated, and unexpectedly, could help combat the worst kind of glioma.

Every year, approximately 23,000 Americans develop brain cancer, resulting in about 14,000 deaths. Gliomas account for roughly a third of brain cancers. Lower grade gliomas are among the most difficult brain cancers to treat, in part, because they're difficult to diagnose.

Scientists have traditionally classified LGG into three groups of tumors - astrocytomas, oligodendrogliomas and oligoastrocytomas - though pathologists studying tumor tissue under the microscope frequently get ambiguous results.

The scientists identified three new molecular classifications of tumors, each with a distinct clinical picture. The tumor categories include those with mutations in the IDH gene, the TP53 gene, or a chromosomal abnormality called 1p/19q co-deletion.  

Using the genomic make-up of a tumor to guide treatment isn't new, but this is the first time scientists have expanded this approach to brain tumors. The investigators know that LGG that carry mutations in the IDH1 or IDH2 gene - which make up most of the adult LGG cases - and those with 1p/19q co-deletions tend to do well with treatment. But they were surprised to find that one of the molecular groups called IDH wild type (wt), which lacks mutations, is aggressive, and has molecular alterations typical of glioblastoma multiforme (GBM), a more dangerous and higher grade cancer type. The researchers suggest that IDHwt may be a precursor to GBM, which could have implications for treatments and new clinical trials.

The new classifications may enable clinicians to combine both genomic data with evidence from tissue pathology to predict the disease course and provide more complete diagnoses and risk assessments, as well as better treatment choices and improved trial designs.

"Now an oligodendroglioma will not just be classified by what it looks like under the microscope, but will also have a molecular basis for the diagnosis," said lead author Daniel Brat, M.D., Ph.D., at Emory University School of Medicine in Atlanta. "That's a big step to start defining tumors by their molecular alterations. It's potentially practice-changing."

Both teams realize their research efforts are part of a long, arduous process toward understanding how cancer behaves, and developing ways to combat it, at times on a person by person basis. The power of TCGA lies in its ability to discern patterns and to try to make sense of the molecular madness of cancer.

Launched in 2008, TCGA and the research teams funded through this program have revealed the genomic details of a number of different tumor types, such as colon, breast, ovarian and kidney. TCGA is a collaboration jointly supported and managed by the National Cancer Institute and the National Human Genome Research Institute, both parts of the National Institutes of Health.

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Posted: June 24, 2015