Like many areas of research, the biomedical sciences have seen numerous recent advances that will no doubt have an impact on human health. For many researchers, however, 2008 may most be remembered as the year of the cancer genome. Several key studies this year have offered an unprecedented view of the genetic profiles of tumors, and demonstrate the power of genomic analysis to study the molecular mechanisms that play a role in carcinogenesis.
Two Landmark Studies on Brain Cancer
In September, two groups reported large-scale resequencing efforts in glioblastoma, the most common form of brain cancer. The first study – published online in the journal Nature – was the pilot project of the Cancer Genome Atlas (TCGA) research network, a coordinated effort involving more than a dozen U.S. research institutions with funding from the NCI/NHGRI divisions of NIH. TCGA researchers sequenced several hundred known or suspected cancer genes in tumor samples and matched controls from 91 patients. This work expanded upon and complemented a second study – published in the journal Science – in which a consortium led by Johns Hopkins studied sequence aberrations from 21 GBM tumors. The Hopkins study implicated a new gene, IDH1, in which mutations were associated with longer survival among GBM patients. The TCGA report identified three genes with significant roles in GBM:
- NF1, a gene previously identified as the cause of neurofibromatosis 1, a rare, inherited disorder characterized by uncontrolled tissue growth along nerves
- ERBB2, a gene that is well-known for its involvement in breast cancer
- PIK3R1, a gene that affects activity of an enzyme called PI3 kinase that is deregulated in many cancers.
Insight into Chemotherapy Resistance
TCGA researchers also made another very exciting finding: a possible mechanism for chemotherapy resistance. It was already known that patients with methylation (inactivation) of the MGMT gene respond better to temozolomide, an alkylating chemotherapy drug commonly used to treat brain cancer. Some patients who receive this treatment later relapse with GBM that doesn’t respond to temozolomide. By integrating methylation and sequence-mutation data, TCGA researchers found that this may be due to mutations in DNA mismatch-repair genes that are induced by the alkylating therapy. It may be that a combined treatment could mitigate cancer’s ability to persist in these patients.
Next Up: Lung Adenocarcinoma
Another important study, this one of lung adenocarcinoma, appeared in the print edition of Nature in October. This was the report of the tumor sequencing project (TSP), another consortium that sequenced 623 genes in 188 patients with the most common form of lung cancer. The TSP study identified over 1,000 somatic mutations across the samples, and implicated 26 genes that were frequently altered in lung adenocarcinoma. Another interesting finding was that patients who smoked had 4 times the number of mutations and less chance of survival than non-smokers. Just a friendly reminder that yes, smoking can kill you.
AML: The First Complete Cancer Genome
FInally, in November, the masterpiece – in a study published in the journal Nature, scientists at Washington University in St. Louis reported whole genome sequencing of a patient with acute myelogenous leukemia (AML). It was two accomplishments, really: the first cancer genome, and the first whole-genome sequence from a woman. Over a period of nine months and at a cost of around $1 million, we sequenced DNA from tumor cells (to ~33x) and normal skin cells (to ~14x) using Illumina/Solexa technology. I can’t begin to tell you the sheer amount of data this represents. We’re talking around 98 billion bases in short (36 bp) reads from around 100 runs on the Solexa platform. And the number of validated, somatic coding mutations? Ten. It seems like a lot of effort for just 10 mutations, but the AML study demonstrated that second-generation sequencing platforms are a powerful approach to study cancer genomics. Next year, we’ll probably see 50 complete cancer genomes sequenced. But as the peanut butter jar principle tells us, first is best!