Institut Curie and Inserm research scientists and physicians have just shown that precise knowledge of alterations in chromosome 1 can be used to improve the treatment of gliomas, the most frequent brain tumors in adults. Diagnosis and treatment of these tumors are difficult because of their heterogeneity and variable malignancy. Using DNA chips, the authors of this report were able to distinguish the tumors with the best prognosis, whose chromosome 1 has undergone a specific deletion. Screening for these deletions should be incorporated into standard diagnostic tests by the end of 2005.

These results are published in the September 2005 issue of Annals of Neurology.

Gliomas are the most frequent brain tumors in adults, and account for over 50% of primary tumors. They are classified into three groups: astrocytomas - 70% of all these tumors - derive from astrocytes, cells close to the neurones; oligodendrogliomas derive from cells that produce the sheaths of nerve fibers; and oligoastrocytomas which are mixed tumors combining the characteristics of the first two types. Gliomas are graded I to IV according to their malignancy. Grade 1 tumors are clinically benign and can be treated surgically. Grade II, III and IV tumors are increasingly malignant and require additional treatments (chemotherapy and/or radiotherapy).

Classification and grading of gliomas are essentially based on subtle microscopic characteristics and are therefore problematical. There is no specific marker or genetic signature, and the present classification seems inadequate in predicting the outcome of each type of glioma.

Chromosome 1 and the prognosis of gliomas

By studying the specific genetic alterations of a subgroup of more chemosensitive gliomas, their classification can be refined: the loss of the short arm(1) of chromosome 1 has thus been associated with a better prognosis and improved response to chemotherapy. Jean-Yves Delattre(2) and his team at the Pitié-Salpêtrière Hospital and Olivier Delattre(3) and his team at the Institut Curie have identified several types of deletions of chromosome 1, only one of which is associated with gliomas with a good prognosis. These findings were recorded using array CGH analysis (see "Further information"), a technique that can establish high-resolution maps revealing genome anomalies (amplifications, deletions). Only the complete loss of the short arm of chromosome 1 combined with complete loss of the long arm of chromosome 19 signifies a good prognosis. Partial loss of the short arm of chromosome 1, on the other hand, characterizes more aggressive tumors. This retrospective study was done with samples from the tumor library of the Pitié-Salpêtrière Hospital using a technology developed at the Institut Curie.

In terms of fundamental research, these findings suggest that the genes involved in these two deletions, and hence associated with gliomas of good and poor prognosis, are different.

In clinical terms, the array CGH technique should improve the diagnosis of gliomas and hence their treatment. Screening for these chromosome 1 deletions should be incorporated into standard diagnostic tests by the end of 2005.

Genomics and notably DNA chips generate new information on the alterations underlying cancers. Using these tools, physicians can revamp and refine tumor classification to enable more individualized treatments. MORE

Researchers at Johns Hopkins have identified three new genetic mutations in brain tumors, a discovery that could pave the way for more effective cancer treatments.

The Johns Hopkins team, in conjunction with researchers at the J. Craig Venter Institute in Rockville, Md., discovered DNA abnormalities in two tyrosine kinase proteins already known to disrupt normal cell activity and contribute to tumor formation.

The discovery of these mutations is especially significant, the researchers say, because tyrosine kinases can be targeted using pharmaceuticals.

"We picked these proteins to sequence because receptor tyrosine kinases sit on the cell surface where anticancer drugs can get at them," said Gregory J. Riggins, M.D., co-lead author of the study and an associate professor in the Department of Neurosurgery at The Johns Hopkins University School of Medicine.

In the study, the researchers identified two of the previously unknown mutations in fibroblast growth receptor 1 (FGFR1) and one in platelet derived growth factor receptor alpha (PDGFRA).

FGFR1 and PDGFRA, said Riggins, have been implicated in several other cancers such as colorectal, breast and ovarian cancer, as well as chronic myelogenous leukemia, gastrointestinal stromal tumors and lymphoma.

Riggins and colleagues analyzed a catalog of 518 protein kinase sequences taken from the Human Genome Project. Using high-throughput gene sequencing equipment based at the Venter Institute's Joint Technology Center, they resequenced 20 targeted proteins from tissue samples of brain tumor cells from Johns Hopkins. The cells came from 19 glioblastoma tumors from eight females and 11 males ranging in age from 7 to 77 years. Glioblastomas are malignant tumors of the central nervous system usually found in the cortex of the brain.

Researchers discovered the mutations after comparing the resequenced genes with corresponding genes from the human genome sequence.

A previous study by Johns Hopkins researchers, led by Victor Velculescu, M.D., Ph.D., used high-throughput gene sequencing to identify 14 mutated genes that have potential links to the growth of colon cancer cells, according to Riggins. These discoveries suggest potential future therapies that might use small molecules and antibodies to regulate the function of the mutated genes.

The success of that study prompted researchers to take the same approach to search for new drug targets for glioblastoma, a brain tumor for which current therapies are weak.

According the Riggins, the recent advances in genomic information and technology have set the stage for the assembling of a complete catalog of molecular alterations that contribute to cancers. Genes involved in the tyrosine kinase family will be important in these future studies because they play a significant role in signaling between cancer cells and what's around them. Combined with the remarkable clinical success doctors have had with the molecular targeting of this family of genes, Riggins said, these new findings could result in effective new treatments for cancer.

"The next step," he added, "is to find inhibitors of these mutations and find out how we can reverse the effects of these mutations in the cancer cell. Our hope is that we can target enough of these mutations to treat the cancer."