Scientists at Hopkins crack the genetic code of bc...

[RobinP]

Just saw this news flash below on FOX news and thought I would pass it on. Yes, there is a genetic basis for cancer...

Cancer's Genetic Code Cracked Thursday, September 07, 2006
By Daniel J. DeNoon


Scientists say they have cracked the genetic code of breast and colon cancers, letting them "study the enemy's game plan.”

The breakthrough comes from a huge effort led by researchers at Johns Hopkins Kimmel Cancer Center. It's not the first-ever look at cancer genes. But it's the first time scientists have used 21st-century technology to scan the entire genome of breast and colon cancers, says Will Parsons, MD, PhD.

Parsons, a Johns Hopkins and National Cancer Institute researcher, is a member of the research team, which includes Victor E. Velculescu, MD, PhD; Bert Vogelstein, MD; and Kenneth W. Kinzler, PhD, of Johns Hopkins.

"We already know that cancer is the result of a series of mutations in normal cells," Parsons tells WebMD. "Now we have a blueprint for how that works."

How important is this finding?

It's not going to help people now suffering from cancer. But for researchers trying to find future cancer treatments, this is very big news. That's why Elias A. Zerhouni, MD, director of the National Institutes of Health, calls the findings "truly remarkable" and "groundbreaking."

(Story continues below)

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The findings appear in the Sept. 7 online issue of Sciencexpress.

The Cancer Fight: 50 Years of Milestones

Fewer American Women Dying of Breast Cancer



Complex Cancer Game Plan

The Johns Hopkins team painstakingly analyzed more than 13,000 genes in 11 breast cancers and 11 colon cancers.

They hoped to find that just a handful of genes cause cancer. Instead, they found some 200 cancer-related genes.

The researchers also hoped they'd find some gene mutations common to all cancers -- or at least genes common to all breast or colon cancers. That didn't happen, either. Each tumor had about a dozen cancer-related mutations that differed from tumor to tumor.

"The genetic basis of colon cancer and breast cancer are quite different; if we look at the most important genes, only two mutations occur on both lists," Parsons says. "I wasn't expecting it to be quite that diverse.

“And even if we look at two tumors of the same kind -- two colon cancers -- they would be very different. None had more than six genes mutated in common", says Parsons.

The complexity is intimidating but not totally unexpected. It simply means there won't be a magic bullet. Researchers will have to look at each kind of cancer to tease out treatment targets.

This isn't bad news -- it's biology, says Harold J. Burstein, MD, PhD, of Harvard Medical School and the Dana Farber Cancer Institute in Boston.

"If you are the Army Corps of Engineers rebuilding New Orleans, you need to know how many weak links you have in the levees," Burstein tells WebMD. "If you guess four or five, and it's 20, you have not fixed the problem. So if in cancer, you look only at four or five genes and there really are a dozen, you have a problem."

Burstein notes that the study wasn't able to say which mutations happen in which order. He says it's possible many of the mutations occur only after the tumor is growing wildly, and it may yet be possible to pinpoint a smaller number of truly significant mutations.

"The transformation from normal cells to cancer cells is still a complicated problem," Burstein says. "What we hope we have here is a roadmap to help us go after them."

Where that roadmap eventually will lead is to a new generation of targeted cancer therapies, says Parsons.

"New cancer treatments like Gleevec for leukemia, and Herceptin for breast cancer, are based on knowing the genetic basis of these cancers," Parson's says. "We will be able to come up with more of these treatments based on the huge amount of information that will become available from studies like this.”

Cancer Prevention: What Really Works?



By Daniel J. DeNoon, reviewed by Louise Chang, MD

SOURCES: Sjöblom, T. Sciencexpress, Sept. 7, 2006; online edition. Will Parsons, MD, PhD, pediatric oncology fellow, Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Md. Harold J. Burstein, MD, PhD, Harvard Medical School and Dana Farber Cancer Institute, Boston. News release, National Institutes of Health/National Human Genome Research Institute. News release, Johns Hopkins Kimmel Cancer Center.

[RobinP]

Public release date: 7-Sep-2006
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Contact: Vanessa Wasta
wastava@jhmi.edu
410-955-1287
Johns Hopkins Medical Institutions
Genome code cracked for breast and colon cancers

Johns Hopkins Kimmel Cancer Center scientists have completed the first draft of the genetic code for breast and colon cancers. Their report, published online in the September 7 issue of Science Express, identifies close to 200 mutated genes, now linked to these cancers, most of which were not previously recognized as associated with tumor initiation, growth, spread or control.

"Just as sequencing the human genome laid the groundwork for subsequent research in genetics, these data lay the foundation for decades of research on colon and breast cancers," says Victor Velculescu, M.D., Ph.D., assistant professor of oncology at the Johns Hopkins Kimmel Cancer Center.

Although gene discoveries by independent scientists scattered around the world have provided clues, Velculescu says relatively few genes have been shown to be altered in cancers. The Hopkins gene hunters say the number of genes that were altered in breast and colorectal cancer genomes surprised them. "We expected to find a handful of genes, not 200," says Tobias Sjöblom, a lead author and postdoctoral fellow at Hopkins' Kimmel Cancer Center.

Despite the potential rewards envisioned by cancer biologists, efforts to map cancer genes have drawn criticism from others who say that funding dollars should be spent on projects yielding more immediate benefits for detection and treatment.

"These are good debates to have," says Kenneth Kinzler, Ph.D., professor of oncology and co-director of the Ludwig Center at Johns Hopkins, but "we are convinced that this kind of study will provide one of the best road maps possible for beating cancer. Who would pass up the opportunity to read the enemy's game plan?"

Some gene alterations already have led to successful detection and treatment strategies. These include the breast cancer drug Herceptin – which targets a breast cancer cell receptor made by the Her2-neu gene -- and blood tests for hereditary colon cancer, based on the APC gene and others identified by the Hopkins group.

"Cancer scientists recognize that merely identifying pieces of DNA that have a role in the disease is a beginning, not an end to our work," says Bert Vogelstein, M.D., an investigator at the Howard Hughes Medical Institute and co-director of the Ludwig Center at Johns Hopkins, "but by using a more systematic method to identify genes that play an essential role in cancer, we will be able to guide that work."

The Hopkins team began their project with 11 samples each from breast and colon cancers, removed from patients after surgery. Within each tumor cell, billions of individual chemicals called nucleotides pair together in a preprogrammed fashion to build the rungs of a DNA ladder that compose genetic instructions. Changes called mutations in the nucleotides can create coding errors that transform a normal cell into a cancerous one.

To locate the altered nucleotides, the scientists compared the genetic code of their tumor samples with normal ones. First, they used the Human Genome Project (HGP) to identify the sequences of best-known genes – more than 13,000 in all – roughly two-thirds of the total number of genes identified by the HGP. The actual number of human genes is still in dispute, but is estimated to be about 20,000.

Then, in each tumor, the scientists examined the DNA code of these 13,000 genes by dividing each gene into overlapping sections – about 10 per gene – to get 130,000 sections for analysis. Each segment was amplified through a process called polymerase chain reaction, purified, and its sequence determined using more than three million biochemical reactions. The sequences were fed through computer software that matches up normal sequences with those from tumor samples. The software highlighted more than 800,000 suspicious regions that were visually inspected, one by one, to verify that they were true mutations that altered protein code rather than normal variations or minor changes with no effect on the gene product.

In total, the Hopkins team combed through 465 million nucleotides – several encyclopedias' worth of letters – to find approximately 1,500 DNA nucleotides that differed from the normal code in important ways. Virtually all these mistakes were mere single-nucleotide "typos." Some 200 genes were significantly mutated; the mutated genes in breast and colon cancers were almost completely distinct, suggesting very different pathways for the development of each of these cancer types. Says Kinzler, "This gives us some understanding of why breast and colon cancers, and most likely other cancers as well, are very different diseases and develop through different processes. When we say this will drive cancer research for the next couple of decades, this is one of the reasons. Now researchers will study how these mutations occur in breast and colon cancers, perhaps searching for environmental agents or cellular processes that drive these changes."

The Hopkins team also found that the average number of mutant genes in each cancer is about 100, and at least 20 are likely to be crucial for tumor formation. "Each cancer has a different blueprint," says Velculescu. "No two patients are identical." Other cancers also can be evaluated using the Hopkins approach, which they say has been developed over the past two decades and made possible through recent advances in DNA sequencing and bioinformatics.

"These findings will guide and provide support for future comprehensive genetic studies including those envisioned by The Cancer Genome Atlas Project," says Vogelstein. Future research will include performing similar analyses on other tumors types, charting the pathways through which each mutant gene acts, and looking for common mutations that can be targeted with cancer drugs or used to detect the disease earlier.

###

This research was supported by the Virginia and D.K. Ludwig Fund for Cancer Research, the National Institutes of Health, 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, Avon Foundation, Flight Attendant Medical Research Institute and the V Foundation for Cancer Research.

The Johns Hopkins research team also includes Siân Jones, Laura D. Wood, D. Williams Parsons, Jimmy Lin, Thomas Barber, Diana Mandelker, Rebecca J. Leary, Janine Ptak, Natalie Silliman, Steve Szabo, Giovanni Parmigiani, Ben Ho Park and Nickolas Papadopoulos. Other authors include Phillip Buckhaults, Christopher Farrell, and Paul Meeh from the University of South Carolina; Sanford D. Markowitz from Case Western Reserve University, University Hospitals of Cleveland and Howard Hughes Medical Institute; Joseph Willis and Dawn Dawson from Case Western Reserve University and University Hospitals of Cleveland; James K. V. Willson and Adi F. Gazdar from the University of Texas Southwestern Medical Center; James Hartigan from Agencourt Bioscience Corporation; Leo Wu and Changsheng Liu from SoftGenetics LLC; and Kurtis E. Bachman from the University of Maryland Greenebaum Cancer Cancer.

[pattyz]

This is priceless, Robin!! I love it. There is now some hard 'proof' of what we always say: we are all different, we all respond differently, we progress differently...etc.


Thank you very much for posting this.

(I see a need for clones, now, to keep at this 24/7, in a back room somewhere!)

best to you,
pattyz

[Cathya]

Robin;

Fasinating....and powerful. It is amazing to think that we really are all different!! Thanks so much for posting.

Cathy

[Cathya]

Robin;

Along a somewhat similar vein to your article I thought this one would be of interest to you....the method is interesting and can be used with many cancers.....like breast for instance. Cathy



First-Ever Genomic Test Predicts Which Lung Cancer Patients Need Chemotherapy To Live8/11/2006

Durham, NC - Duke University Medical Center scientists have developed the first-ever genomic test to predict which patients with early-stage lung cancer will need chemotherapy to live and which patients can avoid the toxic regimen of drugs.

The test has the potential to save tens of thousands of lives each year by recommending chemotherapy for patients who are currently advised against it, said the test's developers at Duke's Institute for Genome Sciences & Policy.

The test's promising results have initiated a landmark multi-center clinical trial, to be led by Duke investigators next year. Patients with early-stage non-small cell lung cancer, the most common and fatal form of cancer, will receive the genomic test and its results will determine their treatment.

The new test, called the Lung Metagene Predictor, scans thousands of genes to identify patterns of gene activity in individual tumors that indicate a patient is likely to suffer a recurrence of disease. Recurrent tumors are typically fatal, so identifying at-risk patients is critical to properly treating them, said the Duke researchers.

"Using the unique genomic signatures from each tumor, our new test predicted with up to 90 percent accuracy which early-stage lung cancer patients would suffer a recurrence of their cancer and which patients would not," said Anil Potti, M.D., an assistant professor of medicine and lead author of the study. "We now have a tool that can be used to move these high-risk patients from the 'no chemotherapy' group into the aggressive treatment group."

The researchers will publish their findings in the Aug. 10, 2006, issue of the New England Journal of Medicine. The research was funded by the National Institutes of Health.

The genomic test can theoretically apply to any cancer, but the Duke team focused its effort on lung cancer because the survival rate is just 15 percent. Lung cancer now kills more Americans each year than breast, prostate and colorectal cancers combined. But toxic chemotherapy drugs are prescribed only to patients with relatively large and aggressive tumors.

Early-stage patients - those with small, stationary tumors - are considered at low risk of recurrence. Hence, they only receive surgery but not chemotherapy. The dilemma, said Potti, is that a third or more of early-stage patients who appear to be at low risk will experience a recurrent tumor.

"Until now, there simply has been no way to identify the 30 percent to 40 percent of early-stage lung cancer patients who would experience a recurrence," Potti said. "Now, with our test, we can say with confidence that we can identify this group of patients so they can be treated accordingly."

The upcoming trial is the first to use a genomic test to select treatment options for individual lung cancer patients, said David Harpole, M.D., a professor of thoracic surgery at Duke and principal investigator of the upcoming clinical trial. The trial, to begin within six months, will enroll more than 1,000 patients at multiple centers in the United States and Canada.

"If we can use the test to increase patient survival by even 5 percent, we would save 10,000 lives a year," Harpole said.

The Duke researchers developed the test by analyzing the activity of genes from early-stage lung cancer patients whose disease outcomes were known. The Duke scientists then validated the genomic test in 129 patients by comparing the test's predictions with the patient's actual outcomes. The test predicted their risk of recurrence with 90 percent accuracy, the study showed.

If proven to be effective in the clinical trial, the test will replace the current method of assessing risk, which is imprecise and provides only a broad estimate of a patient's risk, said Joseph Nevins, Ph.D., a professor of molecular genetics at Duke and senior author of the study being reported.

Physicians now assign each patient to a clinical "stage" based on the size of the patient's tumor, whether it has invaded lymph nodes and whether it has spread to other organs. They use this staging method to prescribe the best treatment options. But staging parameters are general, at best, and do not accurately define who should receive chemotherapy, Nevins said.

"Instead of placing all patients with small tumors in the same early-stage category, as physicians currently would do, we can now assess their risk based on the tumor's genomic profile," Nevins said. "The current system of 'staging' lung cancer tumors will eventually become obsolete."

To employ the test, physicians take a sample of the tumor as it is removed during surgery. They extract its "messenger RNA," which represents the activity of thousands of genes in the tumor. Messenger RNA translates a gene's DNA code into proteins that run the cell's activities. Hence, it is a barometer of a gene's activity level inside the cell.

Scientists label the messenger RNA with fluorescent tags. The fluorescent RNA is then placed on a tiny glass slide, called a gene chip. There, it binds to its complementary DNA sequence on the gene chip.

When scanned with special light, the fluorescent RNA emits a telltale luminescence that demonstrates how much RNA is present on the chip - and thus which genes are most active in a given tumor. The physicians then use a rigorous statistical analysis to assess the relative risk of large grouping of genes, called metagenes, which have similar characteristics.

The test generates a risk "number" for each patient. If their risk exceeds 50 percent, the patient is advised to get chemotherapy.

"This new genomic test is a clear example of personalized medicine, where we use the unique molecular characteristics of each patient's tumor to guide treatment decisions," said Geoffrey Ginsburg, M.D., Ph.D., a professor of medicine and co-author of the study.

Eventually, physicians will use genomic tests not only to predict patient outcomes, but also to select the individual drugs that will best match a tumor's molecular makeup, Ginsburg said. Other collaborators on the study being reported include, from Duke, Sayan Mukherjee, Holly Dressman, Andrea Bild, Rebecca Petersen, Jason Koontz, Michael Kelley and Mike West; Robert Kratzke of the University of Minnesota; and Mark Watson of Washington University in St. Louis. SOURCE: Duke University Medical Center

[heblaj01]

While the discovered genetic make up of breast & colon cancers is important in many ways as a first step toward more accurate diagnostics & targeted treatments it appears to make the genetic search for a cure very difficult if not impossible in the forseable future because of the large number of genes involved & their changing groups for various cancers.

If on one hand one is to try inhibit the activity of all involved genes the probability is high that normal processes will be affected meaning a high rate of unbearable side effects.
If on the other hand only a selected group of genes (the most agressive) are selected for inhibition, then the treatment is not likely to avoid in the long term the other genes from causing recurrence. And the successfull treatment
will be selective (as in the case of Herceptin) not applicable to all cancers.
This also means a lot of distinct research tasks.

This is why I think other research approaches dealing with simpler (everything is relative!) more common features to the majority of cancers are more promissing in the medium term.
Among these approaches I hope that control of angiogenesis (which is common to nearly all cancers) will eventually provide safe long term stabilization if not cure to a lot of cancers. Even with antiangiogenesis there are potential side effects since new blood vessels are necessary in pregnancy & wound healing. But some of the endogenous antiangiogenesis molecules when administered externally did not appear to affect wound healing.