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Genome Studies Uncover New Genes, Pathways Involved in Deadly Cancers

NEW YORK (GenomeWeb News) – A trio of new papers is providing unprecedented insights into the genetics of two of the deadliest forms of cancer — pancreatic cancer and glioblastoma mutiforme, the most common form of brain cancer.
 
Using a combination of copy number analysis, sequencing, methylation, and gene expression studies, two teams of researchers have discovered a slew of new mutations, amplifications, and deletions behind the cancers. In two papers published online today in Science Express, an international team of researchers examined more than 20,000 genes from 24 pancreatic and 22 brain cancer patients.
 
Meanwhile, a team of researchers collaborating under the auspices of the National Institute of Health’s Cancer Genome Atlas Research Network assessed hundreds of glioblastoma multiforme tumor samples, focusing on about 600 genes of interest. Their work, which uncovered three new brain cancer risk genes and several new pathways of interest, was published online today in Nature. It marked the first time results from the Cancer Genome Atlas were published.
 
“We can see the mutations in all the genes of each pathway that control growth, replication, and death in the cancer cell,” Baylor College of Medicine Human Genome Sequencing Center researcher David Wheeler, co-author on the Nature paper, said in a statement. “Researchers have never seen the whole landscape like this before, and it’s providing many new insights into strategies to diagnose and treat cancer.”
 
Nearly 40,000 individuals are diagnosed with pancreatic cancer each year in the US and only about five percent survive. Glioblastoma, the most common type of primary brain tumor, is similarly devastating. Most of the roughly 20,000 Americans diagnosed with GBM annually survive just over a year.
 
Last year, a group of researchers led by investigators at Johns Hopkins University characterized the genetic mutations behind 11 breast and 11 colorectal cancer samples. For the latest papers, the team looked at gene sequence, copy number variation, and gene expression in order in 24 advanced pancreatic adenocarcinomas and 22 GBM samples.
 
After assessing 20,661 genes in pancreatic and brain cancer samples, the researchers pinpointed individual genes and pathways affected in each type of cancer.
 
On average, the pancreatic cancer samples contained 63 somatic alterations. Overall though, the researchers detected 1,562 somatic mutations, along with 198 additional homozygous deletions, and 144 high copy amplifications in the pancreatic cancer samples.
 
“At first glance, these tumors seem very complex,” co-senior author Kenneth Kinzler, an oncology researcher at Johns Hopkins University, said in a teleconference with reporters. But by looking at pathways, he said, “a simpler picture emerges.” Indeed, many of the mutated genes were involved in just a dozen signaling pathways that were altered in between 67 percent and 100 percent of the pancreatic cancer samples.
 
Similarly in their GBM analysis, the researchers identified a bounty of new and previously identified mutations, including alterations in the TP53, RB1, and PI3K pathways.
 
In particular, the team was intrigued by one individual mutation: an amino acid substitution in the active site of isocitrate dehydrogenase 1 protein, coded by a gene called IDH1. Some 12 percent of samples contained the IDH1 mutation, which was especially common in younger brain cancer patients, turning up almost half of GBM patients under 35 years old.
 
Based on these results, Victor Velculescu, an oncology researcher at Johns Hopkins University, told reporters that GBM appears to actually be two diseases, one that involves IDH1 mutations and one that doesn’t. That finding may have prognostic implications, the researchers added, since patients with the IDH1 mutation tended to have longer survival times.
 
Whereas the authors of the Science papers focused on many genes in a few dozen tumors, the Cancer Genome Atlas group — researchers from 18 institutions and organizations led by investigators at BCM, Washington University in St. Louis, and the Broad Institute — presented data on fewer genes in hundreds of samples. They analyzed mutations, CNVs, gene expression, and DNA methylation in 206 GBM multiforme samples and did detailed sequence analysis on 601 genes in 91 GBMs and matched control tissues.
 
Using this approach, they identified three new genes that were frequently mutated in GBM: ERBB2, a gene that’s often altered in breast cancer, the neurofibromatosis gene 1 (NF1), and PIK3R1, a gene involved in a PI3 kinase signaling pathway.
 
They also identified disruptions that affected three distinct pathways — mediating cell division, tumor suppression and apoptosis, and cell growth — in three quarters of the tumors.
 
These findings represent preliminary results for the $100 million Cancer Genome Atlas project, researchers noted. The TCGA team intends to sequence 500 brain cancer samples, eventually covering the entire tumor exome. The project is currently sequencing a second set of genes and this TCGA data will be released onto the group’s website as it is generated.
 
Taken together, the three papers have implications for not only understanding, but also treating and diagnosing cancer. For instance, the Nature study points to methylation changes and “hyper-mutations” that may explain the resistance of some brain tumors to certain chemotherapy drugs.
 
The pathways identified in each study also provide new targets for drug discovery. Rather than trying to identify individual molecular targets, future efforts will likely rely on screening drugs against these commonly affected pathways, Bert Vogelstein, co-lead author on the Science papers and a pharmacology researcher at Johns Hopkins, told reporters.
 
TCGA’s Wheeler also emphasized the importance of looking at pathways rather than genes alone. “If we know what pathways are key to the formation of a tumor, we can design drugs to block those pathways,” he said. “In cancer, key pathways are co-opted to make the cell grow and divide in an uncontrolled way.”
 
In addition, tracking the genes and pathways identified in studies such as these could aid early detection and cancer prevention efforts, Vogelstein emphasized.
 
“This answers the big question about whether the cancer genome project is worthwhile,” BCM Human Genome Sequencing Center Director Richard Gibbs, a co-author on the Cancer Genome Atlas paper, said in a statement. “The results show that it is — definitely.”
 
In a statement issued today, NIH Director Elias Zerhouni echoed that, saying, “Clearly it is time to move ahead and apply the power of large-scale, genomic research to many other types of cancer.”
 

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