Microarray Chip

(Best Syndication News) Although there are several causes of cancer, researchers today announced major breakthroughs in determining the genetic relationship of the disease. The Cancer Genome Atlas (TCGA) Research Network sponsored by the National Institute of Health (NIH) is playing a central role in finding the genetic pathways associated with all sorts of cancers.

Research conducted by the Johns Hopkins Kimmel Cancer Center was published today in the Sept. 5, 2008, issue of Science Express. Research conducted by the Dana-Farber Cancer Institute was published in the Journal Nature. Both articles describe their work involved in finding an array of broken, missing, underactive and overactive genes that can lead to cancer.

Microarrasy and Statistical Analysis

The researchers used high-density microarrays to analyze copy number alterations (amplifications and deletions) and next-generation sequencing technologies to evaluate gene expression. A microarray is an electronic chip first developed in the 1980s but fined tuned in the 1990s for identifying gene expression. They also developed statistical algorithms to integrate the complementary genetic analyses.

Pancreatic and Glioblastoma Multiforme (GBM) Brain Cancer

Although the research can provide an insight into other cancers, the two teams focused on pancreatic and brain cancer. Both of these cancers are very aggressive. They investigated the “universe” of genomic changes involved in all types of human cancer and demonstrated the value of such efforts in advancing cancer research and improving patient care.

Not only is Glioblastoma Multiforme (GBM) the most common form of brain cancer, accounting for 52 percent of all brain cancer, it is also the most virulent. It occurs in 2 or 3 people out of every 100,000 people in Europe and North America. The Dana Farber study focused on GBM.

The John Hopkins scientists focused on mutations in virtually all known human protein-encoding genes (more than 20,000 of them) in 24 pancreatic cancers and 22 brain cancers. The most common pancreatic tumor, which accounts for 95 percent of all cases, is adenocarcinomas (M8140/3). The prognosis of this with this cancer is poor, with only 5 percent still alive five years after diagnosis.

Dana Farber Cancer Institute Study

Research scientists at the Dana-Farber Cancer Institute analyzed 206 specimens of glioblastoma tissue donated by patients at four medical centers. They evaluated an array of flaws simultaneously, looking for "typos" in the DNA code of a gene that alters its function; too many or too few copies of a given gene; damage to chromosomes causing loss or dislocation of pieces; gene activity that is higher or lower than normal.

"The findings of significant mutations in genes that have implications for therapeutic development illustrate precisely how unbiased and systematic cancer genome analyses can lead to paradigm-shifting discoveries," says Lynda Chin, MD, at Dana-Farber and Harvard Medical School (HMS).

The Dana-Farber team also found a link between DNA methylation of specific genes and DNA repair defects. This could help explain the resistance effects of a common chemotherapy drug used for brain cancer. DNA methylation is the process of turning genes on or off without affecting their structure.

Out of the 20,000 protein-coding genes in the GBM tumor cells, the scientists narrowed their efforts to just 601 genes. Previous research has discovered five major gene mutations. The new research has discovered three more.

The three gene mutations include:

1. The NF1 gene, which causes neurofibromatosis.
2. The ERBB2 gene which was known to be involved in breast cancer.
3. The PIK3 signaling pathway that is abnormally activated in a number of cancers, but this particular gene, PIK3R1, had been only rarely implicated in any cancer.

"Each of these mutated genes defines a new target for glioblastoma treatment," said Matthew Meyerson, MD, PhD, at Dana-Farber, Harvard Medical School (HMS).

The Dana Farber scientists found three signaling pathways were disrupted in more than three-quarters of the GBM tumors. Pathways are networks of genes and proteins that act together to carry out a cellular function.

The pathways are:

1. The cyclin-dependent kinase/retinoblastoma pathway that regulates cell division.
2. The p53 tumor suppressor pathway, which is involved in response to DNA damage and cell death.
3. The receptor tyrosine kinase pathway that carries signals that control cell growth.

Methylation Change In GBM

The researchers have already begun to look at new gene lists for mutational analyses. Chin says the “most exciting” finding was the important connection between a methylation change in the glioblastoma cells and which drugs should be used for treatment.

Brain tumors that contain a methylated, or silenced form of a gene known as MGMT, are known to be more susceptible to the cancer drug temozolomide (Temodar). Therefore, Temodar is routinely given along with radiation to patients with MGMT methylation.

"This could have immediate clinical applications," said Chin, but she cautions that if doctors use Temodar and the tumor comes back, it was very likely to become resistant to treatment because of "hypermutation".

The Johns Hopkins Kimmel Cancer Center Study

The same Johns Hopkins scientists who conducted this new research also completed a map of breast cancer and colorectal cancer genomes in 2007. Now they believe they have completed the most comprehensive mapping of “virtually all” the mutations of human protein-encoding genes, comprised of more than 20,000 genes, in 24 pancreatic cancers and 22 brain cancers.

Pathways

The researchers from the Johns Hopkins Center found that a core set of regulatory gene processes and pathways were altered in the majority of tumors studied. In pancreatic cancer, the 12 pathways -- including those linked to DNA damage control, cell maturation, and tumor invasion -- were altered in 67 percent to 100 percent of tumors.

The pathways will likely be used for therapies. "This perspective changes the way we think about solid tumors and their management, because drugs or other agents that target the physiologic effects of these pathways, rather than individual gene components, are likely to be the most useful approach for developing new therapies," says Bert Vogelstein, M.D., co-director of the Ludwig Center at Johns Hopkins and a Howard Hughes Medical Institute investigator.

IDH1 Gene Mutation and GBM

They also found numerous gene mutations including 83 cancer genes in pancreatic cancer and 42 in the most lethal form of GBM brain cancer. There was another 70 genes that were overexpressed. This will lead to potential diagnostic and screening targets to help determine the best treatment.

The isocitrate dehydrogenase 1 (IDH1) gene mutation was found frequently in one type of GBM brain cancer which mostly occurs in younger patients. It was also associated with an improved survival rate. It was also identified in the lower grade tumors that could develop into life threatening GBMs.

"Patients with IDH1 mutations seem to be different from other patients with GBM, both clinically and biologically," says Victor Velculescu, M.D., Ph.D., associate professor of oncology. "It is conceivable that these patients will ultimately benefit from different treatments, potentially by targeting IDH1."

Conclusion

Although this research has improved our understanding of cancer, it has also showed how complex the disease is. The genetic tests may offer a way to detect the cancers early and determine the best treatment. The treatments may involve pathway blockers and other genetic manipulating drugs.

"The landscape of human cancers is clearly more complex than has been previously appreciated. Fighting it is going to be more of a guerilla war than a conventional one because there are dozens of mutated genes in each tumor," says Kenneth W. Kinzler, Ph.D., co-director of the Ludwig Center at Johns Hopkins and professor of oncology. "Individually, these mutations don't seem formidable. But working together, they form an enemy that will require us to develop novel strategies to combat them, and the best long-term strategy may be early detection of tumors, when the number of guerilla warriors is still small and more easily handled."

By Dan Wilson
Best Syndication News Writer