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Represents next major step in cancer genome sequencing
Release Date: October 11, 2007

October 11, 2007

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 October 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," says Bert Vogelstein, M.D., 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 found 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.

"Fifteen years ago, we said the p53 gene was the most commonly mutated gene in cancer.  It's amazing that this is still true," says Kenneth W. Kinzler, Ph.D., professor of oncology at the Johns Hopkins Kimmel Cancer Center.

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.  It suggests that these genes converge in similar pathways.  "The hard part used to be finding these mutant genes, now the challenge will be to link them to specific pathways and understand their function," says Victor Velculescu, M.D., Ph.D., associate professor of oncology at the Johns Hopkins Kimmel Cancer Center.

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 that were 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 Johns Hopkins' Kimmel Cancer Center says that these results can help to direct the global race to map additional cancer genomes. For other cancers, she says scientists should expect to find a similar genetic landscape - "few mountains surrounded by many hills."

Funding for this study was provided by The Virginia and D.K. Ludwig Fund for Cancer Research, the Department of Defense, Pew Charitable Trusts, The Palmetto Health Foundation, The Maryland Cigarette Restitution Fund, the State of Ohio Biomedical Research and Technology Transfer Commission, the Clayton Fund, the Blaustein Foundation, the National Colorectal Cancer Research Alliance, the Strang Cancer Prevention Center, the Division of Cancer Prevention of the National Cancer Institute, the Avon Foundation, the Flight Attendant Medical Research Institute, the V Foundation for Cancer Research, and the Summer Running Fund.

Additional research participants include 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 from Johns Hopkins; Zoltan Dezso, Vadim Ustyanksky, Tatiana Nikolskaha, and Yuri Nicolsky from GeneGo Inc. and the
Vavilov Institute of General Genetics, Moscow, Russia; Rachel Karchin and Paul Wilson from the Department of Biomedical Engineering at The Johns Hopkins University; Joshua S. Kaminker and Zemin Zhang from Genentech; Randal Croshaw and Phillip Buckhaults from the University of South Carolina; Joseph Willis and Dawn Dawson and Sanford Markowitz from Case Western Reserve University; Michail Shipitsin and Kornelia Polyak from the Dana Farber Cancer Institute, James K.V. Willson from the University of Texas Southwestern Medical Center; Charit L. Pathiyagoda, P.V. Krishna Pant, and Dennis G. Ballinger from Perlegen Sciences; Andrew B. Sparks from Complete Genomics Inc.; James Hartigan, Douglas R. Smith, and Erick Suh from Agencourt Bioscience Corporation.

* Illustration caption: Landscape of a typical colorectal cancer.  Large peaks indicate the gene mountains, small peaks indicate the hills. The dots correspond to genes that were mutated in the particular cancer (called Mx38) illustrated.

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