Readers of genome decipher signatures of cancer patient outcomes


Anaheim, Calif. -- Since 2003, the human genome has stood before cancer researchers as an open book laden with vital but encrypted information that one day could lead to the prevention, treatment, and control of the family of diseases known as cancer.

By perusing the contents from the Human Genome Project for clues into the molecular origins and risks for cancer, scientists are now defining sets of genes or "signature portfolios" that best describe a patient's chances for developing cancers, fending off malignancies, and responding to treatment.

Scientists here at the 96th Annual Meeting of the American Association for Cancer Research tendered "mini-book reports" on research findings made possible by the information encoded in the Human Genome Project.

"Death from Cancer Signature:" Abstract 1644

One such portfolio, dubbed the "Death from Cancer Signature," identifies a set of eleven genes associated with cell proliferation and renewal in both human stem cells and by ten different types of human cancer diagnosed in a wide range of organs.

Despite the ominous sound of its name, information gleaned from these eleven genes unveils opportunities for clinical advances unavailable prior to the full disclosure of the Human Genome Project, according to Gennadi V. Glinsky, M.D., Ph.D., associate professor at the Sidney Kimmel Cancer Center, San Diego, Calif.

"The genes in 'the Death from Cancer Signature' will alert physicians and patients to those who are at much higher risk for metastatic complications and more severe cancer illness as the disease progresses," said Glinsky.

"Those people are genetically less likely to respond to the conventional therapies that work for many other patients."

Early identification of patients who carry in their chromosomes 'the Death from Cancer Signature' will allow clinicians and patients to consider therapeutic strategies beyond the conventional at the time of diagnosis.

"Those patients can be directed toward options that include more aggressive, often customized therapeutic strategies," Glinsky said. "Many of those patients can consider clinical trial options that they may otherwise have overlooked or not feel justified.

"If you identify the ones who are at a high likelihood of therapy failure, and therefore are candidates for more aggressive and often individually designed therapies, required treatment can be initiated closer to the time of diagnosis rather than much later when the disease has spread and become incurable."

Those with this genetic portfolio also would be further encouraged to enroll in clinical trials with new therapies targeted to earlier stages of cancer progression, when the opportunity for success remains high.

"If these patients knew that they carried the poor prognosis profile of genes in 'the Death from Cancer Signature,' they may elect to become involved in studies that would improve their likelihood of reaching that five-year survival landmark, and beyond," Glinsky said.

Knowledge of the genetic and molecular markers associated with highly aggressive clinical course of cancer might ultimately lead to identification of crucial genetic pathways that can lead to lethal progression of disease and associated with therapy resistance phenotype. The components of these pathways would become attractive targets for development of novel, target-tailored individualized anti-cancer drugs.

Monitoring the Effectiveness of Anti-Cancer Therapies: Abstract 9243

A specific set or polymorphism of 40 genes comprises a "signature" that may predict patient response to chemoradiotherapy among esophageal cancer patients, according to research by Xifeng Wu, M.D., Ph.D., epidemiology professor at the University of Texas M. D. Anderson Cancer Center, Houston, Texas.

"The ability to forecast patient response to therapies enables clinicians to develop custom chemotherapeutic strategies to improve survival within esophageal cancer patients," Wu said.

Wu's studies included a genetic analysis of tumor samples from 210 human patients, focusing on cellular pathways relevant to 5-FU and platinum analogue activity and disposition within the tumor. 5-FU is a widely used chemotherapy drug that is a nucleotide analogue. It works to inhibit thymidylate synthase (TS) and therefore DNA synthesis. Platinum is a heavy metal component included among traditional cancer chemotherapies, including cisplatin.

Wu and colleagues noted that among single nucleotide polymorphisms (SNPs) found in the signature gene, methylenetetrahydrofolate reductase (MTHFR), the AC or CC variants were associated with a hazard ratio of 0.56, almost half the risk observed in MTHFR AA patients. The MTHFR AC or CC individuals lived longer, with a median survival length of 51.3 months, compared to 25.37 months for the AA variant patients.

"Perhaps the most significant finding from our study of MTHFR was that the combination of the two variant alleles was associated with significantly reduced risks of recurrence and death," Wu said. "This joint effect exceeded the effect of either polymorphism by itself."

MTHFR includes the genetic information necessary for cells to generate an enzyme essential in the folic acid, or vitamin B9, metabolic pathway. The variant alleles of both SNPs result in reduced MTHFR enzymatic activity. Reduced MTHFR activity increases the amount of folate in tumor cells.

The prediction power of the signature set analysis was enhanced when a combination of genes in the set were considered together, Wu noted.

Wu's data also indicated that certain genetic polymorphisms, such as XRCC1(R399Q), was associated with almost three-fold the risk, with reduced complete pathological response to radiation treatment.

Information gleaned from the newly isolated signature set may allow clinicians to predict which esophageal cancer patients will respond optimally to certain anti-cancer drugs.

"With the information from Human Genome project in hand, cancer researchers have accelerated the pace of finding genetic polymorphisms," Wu said. "This information may help determine who has a predisposition to what disease and how an individual will react to a certain drug."

Nine-Gene Signature Predicts Survival in Colon Cancer patients: Abstract 3574

A Danish study of genetic samples from 101 colon cancer tumors revealed a small set of nine genes that indicate good prognosis and more lengthy survival among colon cancer patients.

This small set of genes is characterized by short, repetitive DNA sequences known as tumor microsatellite regions. Some of these microsatellites are unstable (MSI); others are stable (MSS).

Mogens Kruh°ffer, Ph.D., associate professor, Aarhus University Hospital, Aarhus, Denmark, and colleagues from Denmark and Finland, discovered that each of these regions, the unstable and stable, display distinct genetic signatures. What's more, the unstable microsatellite version of genes was associated with longer survival.

"It was previously shown that patients with stage II MSI tumors had a better prognosis than stage II MSS tumors, and that all stage III patients have similar prognoses independent of MS-status," Kruh°ffer said.

"Our findings confirm that data, but we also found a gene expression signature consistent in MSI tumors that identifies those stage II patients with better prognosis."

MSI tumors make up approximately 15 percent of all colon cancer cases, Kruh°ffer said.

Melanoma-derived Signature Set Predicts Treatment Outcome: Abstract 121

An array analysis of more than 42,000 genes disclosed a cluster of 60 genes that predicted positive treatment outcome among patients with melanoma tumors, said Alain Spatz, M.D., pathologist and cancer researcher from the Gustave-Roussy Institute, Villejuif, France.

From a battery of 108 primary melanoma tumors, Spatz and colleagues isolated 361 genes that differed in expression between patients who remained tumor-free for four or more years, compared to those with recurrent metastatic tumor development.

The Spatz group further distilled the results to a group of 60 genes that provided the best candidate "signature" for disease prognosis. Criteria included gene activity with tumor thickening, and the presence of gene-associated antibodies among tumor-free patients.

"This gene classifier set included sub-clusters associated with important prognostic variables, predicting poor or better outcome," Spatz said.

Such information may be used to suggest new treatment targets specific to this form of skin cancer.

"In cutaneous melanomas, no active adjuvant therapy has been fully demonstrated so far," Spatz said. "The identification of new potential therapeutic targets is crucial and overcomes the importance of prognostication methods.

"Some of the genes in our signature belong to the same cellular pathways and have been previously associated with tumor progression in vivo in other tumors but not in melanomas. We have now inhibitors that work in other tumor types to consider in melanoma cancer for targeting some of the related proteins."

Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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