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While some investigators are mapping the structural alterations
in the cancer genome, others are searching for new oncogenes that
The most comprehensive of the efforts to map structural
alterations is The Cancer Genome Atlas (TCGA), a nationwide
research network of more than a dozen institutions, including
Dana-Farber and the Broad Institute. Its goal is to fully
characterize the architecture of the cancer genome. The first
published paper of the TCGA pilot project, led by Lynda Chin, MD, of the Department of Medical Oncology, and Matthew Meyerson, MD, PhD, focused on an integrative analysis
of DNA copy number variations, gene expression, and DNA methylation
aberrations in 206 glioblastoma tumor samples, as well as
nucleotide sequence aberrations in 91 samples.
Interim analysis revealed alterations in three core pathways
(RB, p53, and RTK/RAS/PI3K) and somatic mutations in three genes
(ERBB2, NF1, and PIK3R1) not previously associated with
glioblastoma. "No one had looked at this cancer in enough specimens
and in high enough resolution before to derive that information,"
says Meyerson. Moreover, because PI3K inhibitors are already in
development, adds Chin, "the PIK3R1 discovery may soon lead to new
clinical trials in glioblastoma and enable stratification of
patients based on their PIK3R1 status."
One of the most exciting insights from the interim analysis came
from integrating the sequencing and DNA methylation data with
treatment information. Combining these data sparked a new
hypothesis for the mechanism of resistance to temozolomide
(Temodar, a standard treatment for glioblastoma): the tumor cell
bypasses the drug by inactivating DNA repair machinery.
Their ultimate goal is to sequence and map every base pair of
the cancer genome across a large collection of samples from
ovarian, lung, and other tumors and disseminate the data to the
Not all genetic mutations play an essential role in
carcinogenesis. The goal of Project Achilles, led by William Hahn,
MD, PhD, in collaboration with Meyerson, Levi Garraway, MD, PhD, Kornelia Polyak, MD, PhD, of the Department of Medical
Oncology, and Todd Golub, MD, of Pediatric Oncology, is to find and exploit
cancer's vulnerabilities using integrative genomic approaches.
"Each genomic approach is powerful, but gives you only one
dimension of information," explains Hahn. "By combining different
approaches, you quickly find a small set of genes – and in some
cases, just one gene – that satisfy all criteria" for the
development of cancer.
In one study, Hahn and colleagues, including postdoctoral fellow
Ron Firestein, MD, PhD, in Hahn's lab and clinical fellow Adam
Bass, MD, in Meyerson's, set out to find the genes required for
full transformation to colon cancer. At Dana-Farber's RNAi facility
and at the Broad, investigators used RNA interference to conduct
two loss-of-function screens: one for genes essential for
proliferation, the other for those that regulate the
Wnt/beta-catenin pathway (implicated in virtually all colon
cancers), resulting in a subset of genes at the intersection of the
two screens. Next, they determined which genes of this subset were
also amplified in colon cancer specimens. Using high-density SNP
arrays - originally designed for genome-wide detection of single
nucleotide polymorphisms (SNPs) associated with disease, but
modified by Meyerson to assess copy number variations – a single
gene emerged from the SNP arrays, CDK8, a new oncogene mutated in
up to 50 percent of colon cancers.
The investigators applied a similar rationale to hunt for breast
cancer oncogenes. They added another tool from the genomic arsenal,
thanks to Marc Vidal, PhD, of the Department of Cancer Biology
and director of Dana-Farber's Center for Cancer Systems Biology.
Vidal had compiled a library of open reading frames (ORFs), the
coding sequences of genes. While short interfering RNAs allow
investigators to knock down genes of interest, ORFs allow them to
over-express genes to screen for gain-of-function mutations, a
common occurrence in breast cancer. Integrating RNAi, the ORF
library, and high-density SNP arrays, they discovered the oncogene
IKBKE, which is mutated in 30 percent of breast cancers. Since the
products of CDK8 and IKBKE are kinases, which lend themselves to
small-molecule inhibition, these two discoveries alone could have
an impact on patients.
"We're able to do this research because we have resources at
Dana-Farber and the Broad that do not exist anywhere else," notes
Hahn. "It feels almost effortless, because we're all
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