One year after completing the first large-scale report
sequencing breast and colon cancer
genes,
Johns Hopkins Kimmel Cancer Center scientists have
studied the vast majority of protein-
coding genes, which now suggest a landscape dominated by
genes that each are mutated in relatively
few cancers.
Their report, published online in the Oct. 11 issue of
Science Express, indicates that while little
is known about these less commonly mutated genes, they can
be grouped into clusters according to
their pathways.
"There are gene 'mountains' represented by those that
are frequently altered and have been
the focus of cancer research for years, in part because
they were the only genes known to contribute
to cancer," said Bert Vogelstein, an investigator at the
Howard Hughes Medical Institute and co-
director of the Ludwig Center at Johns Hopkins. "Now, we
can see the whole picture, and it is clear
that lower peaks, or gene 'hills,' are the predominant
feature."
In a systematic search of 18,191 genes representing
more than 90 percent of the protein-
coding genes in the human genome — about 5,000 more
than in the first screen — the Johns Hopkins
scientists discovered that most cancer-causing gene
mutations are quite diverse and can vary from
person to person. They found that an average 77 genes are
mutated in an individual colon cancer and
81 in breast cancer. Of these, about 15 are likely to
contribute to a cancer's key characteristics, and
most of these genes may be different for each patient.
Kenneth W. Kinzler, professor of oncology at the
Kimmel Cancer Center, said, "Fifteen years
ago, we said the p53 gene was the most commonly mutated
gene in cancer. It's amazing that this is
still true."
With no more higher-frequency mutations on the
horizon, the investigators say that
"personalized medicines" may now focus on the more
complicated pathways that link these less
commonly mutated genes.
As an example, the Johns Hopkins team charted the path
of nine genes less frequently mutated
in breast or colon cancers. Each of the genes' protein
products interacted with an average of 25 other
proteins, encoded by separate genes also found to be
mutated in the cancers. The finding suggests
that these genes converge in similar pathways. "The hard
part used to be finding these mutant genes,"
said Victor Velculescu, associate professor of oncology at
the Kimmel Cancer Center. "Now the
challenge will be to link them to specific pathways and
understand their function."
The scientists say that directing therapies at common
pathways that are linked by both
prevalent and rare gene mutations is a better approach than
aiming treatments at specific genes. They
also note that personalized cancer genomics paves the way
for tailored therapies and diagnostics
focusing on the alterations identified in a particular
patient's cancer. Many of the mutations identified
by scientists could be important in developing
individualized cancer vaccines and monitoring patients
for early recurrence of their disease.
For the study, the scientists screened the same set of
tissue samples used for their first
genome draft — 11 each of breast and colorectal
cancers, removed from patients after surgery. Then,
they evaluated all mutated genes in a second group of 24
samples from each cancer, and a subset of
the most promising mutations were studied in a further 96
colorectal cancers. They compared the
genetic sequence of these tumors with that of normal tissue
samples from the same patients using
computer software that matches up gene codes in cancer and
normal cells.
Within each cell, chemicals called nucleotides pair up
to form the rungs of a DNA ladder that
carry genetic instructions guiding everything from
cell-to-cell contact to eye color. Changes in the
nucleotide arrangement can create errors in the proteins
made from the DNA. Buildup of damaged
proteins can turn a normal cell into a cancerous one.
Laura Wood, a postdoctoral fellow at the Kimmel Cancer
Center, said that these results can help
direct the global race to map additional cancer genomes.
For other cancers, she said that scientists
should expect to find a similar genetic landscape —
"few mountains surrounded by many hills."
Other research participants from Johns Hopkins are D.
William Parsons, Sian Jones, Jimmy Lin,
Tobias Sjoblom, Rebecca Leary, Dong Shen, Simina M. Boca,
Thomas Barber, Janine Ptak, Natalie
Silliman, Steve Szabo, Saraswati Sukumar, Ben Ho Park,
Nickolas Papadopoulos and Giovanni Parmigiani.
Funding for this study was provided by the Virginia
and D.K. Ludwig Fund for Cancer Research,
Department of Defense, Pew Charitable Trusts, Palmetto
Health Foundation, Maryland Cigarette
Restitution Fund, State of Ohio Biomedical Research and
Technology Transfer Commission, Clayton
Fund, Blaustein Foundation, National Colorectal Cancer
Research Alliance, Strang Cancer Prevention
Center, Division of Cancer Prevention of the National
Cancer Institute, Avon Foundation, Flight
Attendant Medical Research Institute, V Foundation for
Cancer Research and Summer Running Fund.