Gene Studies Reveal Cancer's Secrets

TUESDAY April 21, 2009 -- A close look at a tumor's or patient's genetics can provide important, potentially lifesaving clues to preventing and treating cancer.

So say scientists who outlined their research Tuesday in five presentations at the American Association for Cancer Research's annual meeting, in Denver.

"This is an interesting set of presentations," John S. Witte, a professor in the Institute for Human Genetics at the University of California, San Francisco, said during a midday press conference. "All the studies have an impact on the potential to predict risk or recurrence or response to treatment," he said.

In the first study, researchers led by Dr. Charles Mullighan, an assistant member at St. Jude Children's Research Hospital, Memphis, found that children with acute lymphoblastic leukemia (ALL) who have mutations in the JAK tyrosine kinase gene generally have poor outcomes, including a higher risk of recurrence of their cancer. The finding suggests the gene could be a potential diagnostic tool and a new therapeutic target.

Despite improvements in treatment, some children with ALL will relapse, Mullighan told reporters.

For the study, the Memphis team analyzed the genes of 221 children with the disease.

Although JAK mutations were not previously known to occur in children with ALL, they were discovered in 10 percent of these patients. The mutations were associated with a deletion of the genes IKZF1 and CDKN2A/B and poor outcome. And, over four years, 71 percent of the children with JAK and IKZF1 alterations had a relapse of their disease, compared with only 23 percent for patients without these genetic alterations, the researchers found.

But there was good news, too. "When we treated the cancer cells with a JAK inhibitor, the cells died," Mullighan said. "This suggests that these JAC mutations are a new therapeutic target in this subtype of leukemia."

Another study on leukemia found that a set of genetic variants increases the risk for chronic lymphocytic leukemia (CLL). The findings of this study add more pieces to the puzzle and could lead to better prevention and prognosis of the disease, according to lead researcher Susan Slager, associate professor of biostatistics at the Mayo Clinic in Rochester, Minn.

About 15,000 Americans will develop CLL each year, and 4,000 will die, so it is one of the rarer cancers, Slager said during the teleconference. However, "if you have a family member with chronic lymphocytic leukemia, your chances of getting the disease are eight times higher than that of the general population," she noted.

An earlier analysis identified seven DNA sequencing aberrations called "single nucleotide polymorphisms" (SNPs) that might lead to chronic lymphocytic leukemia. In the current study, researchers confirmed these findings in a separate sample of patients. They found the strongest genetic association for the disease was for a SNP on the 11q24 gene, where the risk was 50 percent higher. This was followed by a 39 percent increased risk with a separate SNP on the 6p25 gene.

"Our findings will hopefully understand the biology of the disease, which may help us predict the disease, and it may help us develop better treatments and prognostic markers," Slager said.

Results of another study presented at the meeting showed that genetic variants in what's known as the microRNA processing pathway may predict a woman's risk for ovarian cancer.

"Ovarian cancer is the fifth leading cause of cancer in women in the United States, and one of the major risk factors is a family history of ovarian cancer, indicating that a genetic component contributes to ovarian cancer risk," Dr. Xifeng Wu, a professor in the department of epidemiology at the University of Texas M. D. Anderson Cancer Center in Houston, said during the teleconference.

For the study, Wu's and team evaluated 70 SNPs in eight microRNA pathway genes. These were taken from 380 ovarian cancer cases, as well as from 146 healthy women.

The researchers found 16 SNPs that were predictive of ovarian cancer risk. Patients who carried five or fewer of these SNPs were at low risk for ovarian cancer. However, patients with six and seven SNPs had more than a twofold increased risk, and those with eight or more had over a fivefold increased risk.

In addition, as the number of these SNPs increases, so does resistance to treatment and poorer survival, Wu said.

This information, along with other genetic and lifestyle risk factors, could be used to develop an ovarian cancer risk-prediction model, Wu said.

In a fourth study, researchers led by Dr. Gangning Liang, an associate professor of research in the department of urology at the University of Southern California, reported finding a DNA modification called a "methylation pattern," that may diagnosis bladder cancer and detect patients at risk for recurrence of the disease.

"Bladder cancer is the fifth most common cancer in men and the sixth most common in women," Liang said during the teleconference. "It is mainly found in smokers."

DNA methylation is a process in which genes can be either silenced or activated in cancer. For the study, researchers measured DNA methylation in 12 patients who did not have bladder cancer, 52 patients with non-invasive bladder tumors and 39 patients with invasive bladder tumors.

Comparing cancerous tissue with normal bladder tissue, they found 158 "hypermethylated" loci and 366 "hypomethylated" locations. In addition, they found 21 places that were hypermethylated in the normal-appearing bladder tissue in patients with bladder cancer.

These loci may be markers for identifying people at risk for bladder cancer, the researchers said.

In addition, the scientists found that non-invasive tumors had a distinct pattern of hypomethylation compared with invasive tumors. This finding supports the idea that two forms of bladder cancer develop along different paths.

Bladder cancer can easily recur, Liang noted. "It requires frequent and invasive monitoring. We think these results are clinically useful and have benefits for the patient, because we can detect these methylation changes in the patient's urine," he explained. "So, we can use a noninvasive method to monitor the patient and may also be able to screen for bladder cancer in high-risk populations, like smokers," he said.

In a final report, researchers led by Sunita Setlur, an instructor in pathology at Brigham and Women's Hospital and Harvard Medical School, found no association between the gene variant UGT2B17 and the risk of prostate cancer. Although this gene had been linked to the risk for prostate cancer in two earlier studies, this new study found no such association.

For the study, researchers looked at 269 men of whom 156 had prostate cancer. The researchers looked at the number of copies of the UGT2B7 gene and found that although deletion patterns for UGT2B17 and UGT2B28 genes were between 3.4 percent and 19.9, this did not increase the risk for prostate cancer.

"We did not see any association between polymorphism of UGT2B17 and UGT2B28 with cancer," Setlur said during Tuesday's teleconference.

More information

For more about cancer, visit the American Cancer Society.

Posted: April 2009


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