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Molecular Classification May Improve Method Physicians Use to Diagnose, Treat Gliomas

Molecular Classification May Improve Method Physicians Use to Diagnose, Treat Gliomas

Junho 10, 2015

ROCHESTER, Minn -- June 10, 2015 -- The molecular makeup of brain tumours can be used to sort patients with gliomas into 5 categories, each with different clinical features and outcomes, according to research published online today in the New England Journal of Medicine.

The finding could change the methods that physicians rely on to determine prognosis and treatment options.

“Our findings are going to weigh heavily on the future classification of brain tumours,” said Daniel H. Lachance, MD, Mayo Clinic, Rochester, Minnesota. “The time of classifying these tumours solely according to histology as astrocytoma, oligodendroglioma or mixed oligoastrocytoma could be a thing of the past. This molecular data helps us better classify glioma patients, so we can begin to understand who needs to be treated more aggressively and who might be able to avoid unnecessary therapies.”

The new approach categorises gliomas according to the presence of 3 genetic alterations -- 1p/19q co-deletion, IDH mutation, and TERT mutation. The first 2 are already checked routinely in clinical practice, so a test that incorporates all 3 tumour markers could be available as early as this summer.

Gliomas are typically managed with a combination of surgery, radiation therapy, and chemotherapy, but even with aggressive treatment the majority of patients succumb to the disease.

For a significant number of cases, the standard methods -- which use histology to classify gliomas according to their visible characteristics -- are not effective enough to accurately predict the tumour’s subsequent behaviour, potential for response to therapy, and long-term prognosis.

Over the last 25 years, scientists have found hundreds of genetic defects that could form the basis of a more improved classification system. Three of these alterations stand out because they occur early during glioma formation, are more prevalent in gliomas, and are sometimes associated with desirable clinical outcomes.

The first one -- 1p/19q co-deletion -- has been associated with increased tumour sensitivity to chemotherapy. The second is a mutation in IDH1 or IDH2, which is generally associated with improved prognosis. The third is a mutation in TERT, which enhances the activity of the enzyme telomerase to lengthen the telomeres that protect the ends of chromosomes. These mutations can be seen in the most aggressive and least aggressive forms of human glioma.

The researchers explored whether these 3 tumour markers could be used to define molecular groups that better inform glioma treatment. First, they scored tumours as negative or positive for 1p/19q co-deletion, IDH mutation, and TERT mutation in 317 gliomas from the Mayo Clinic Case-Control Study. The researchers then compared patient characteristics among the top 5 molecular groups (triple-positive, TERT- and IDH-mutated, IDH-mutated-only, TERT-mutated-only, and triple-negative) and found that the patients within each group had similar age of onset and overall survival. They replicated and validated their results in 351 gliomas from the UCSF Adult Glioma Study, and 419 gliomas from the Cancer Genome Atlas (TCGA) Study.

The results will enable clinicians to make better predictions about which specific treatment course is necessary for each individual patient. For example, the researchers found that the molecular classification can identify patients with histologically defined lower-grade tumours who have less favourable outcomes and deserve more aggressive therapy.

Though the researchers focused on three main mutations to define their molecular groups, they recognised that gliomas likely contain other genetic alterations, such as variants that might predispose to cancer and mutations that might be acquired as tumours grow and progress. They looked for associations between the 5 molecular groups and variants they had previously shown were linked to glioma risk, as well as other mutations known to accumulate in cancer. The researchers found that these other genetic changes recurred in specific patterns within the molecular groups, further validating their biologic significance.

“These molecular groups could represent distinct types of gliomas, with different origins and paths to progression,” said Robert B. Jenkins, MD, Mayo Clinic. “Now that we know more about the germline alterations that predispose to these tumours and the ensemble of mutations that are associated with each type of glioma, we can start thinking about building models of the disease that can help us find new therapies to precisely target specific types of glioma.”

SOURCE: Mayo Clinic

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Junho 2015