National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
August 11, 2009 • Volume 6 / Number 16

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Cancer Research Highlights


Blood Type Influences Pancreatic Cancer Risk

A variation in the gene that determines ABO blood type influences the risk of pancreatic cancer, according to the results of the first genome-wide association study (GWAS) for this highly lethal disease. The genetic variation, a single nucleotide polymorphism (SNP), was discovered in a region of chromosome 9 that harbors the gene that determines blood type, the researchers reported August 2 online in Nature Genetics. The ABO gene produces proteins that direct certain carbohydrates onto the surface of red blood cells, the result of which determines the blood type. Compared with people who have type O blood, a SNP that produces the blood types A, B, or AB was associated with higher pancreatic cancer risk.

“Although it will take much more work, this finding may lead to improved diagnostic and therapeutic interventions that are so desperately needed,” stated study co-author Dr. Patricia Hartge from NCI’s Division of Cancer Epidemiology and Genetics (DCEG).

The study had two stages. In the first, the researchers analyzed genomes of 1,896 patients with pancreatic cancer and 1,939 control subjects who were part of 12 prospective cohort studies, including the Nurses’ Health Study and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening trial, and one hospital-based case-control study, to identify SNPs associated with increased pancreatic cancer risk. In the second stage, they attempted to validate any risk-associated SNPs via a “fast-track replication” study of more than 5,000 pancreatic cancer cases and control subjects drawn from 8 pancreatic cancer case-control studies. The SNP in the ABO gene emerged from this process.

Another SNP associated with pancreatic cancer risk was identified in the first stage—one in the SHH gene which other research has suggested is related to pancreatic cancer development—but the finding was not duplicated in the validation stage. Further research into SHH’s potential role in pancreatic cancer is needed, the research team concluded.

Another GWAS study to find SNPs associated with pancreatic cancer risk is already under way, involving pancreatic cancer cases and controls from the eight studies included in the replication phase of this current Nature Genetics study.

“Pancreatic cancer is the newest beneficiary of high-throughput genotyping that, over the past 2 years, has yielded scores of genetic hot-spots linked to risk for cancer and other diseases,” said co-author Dr. Stephen Chanock, chief of DCEG’s Laboratory of Translational Genomics. “As more variants are discovered and follow-up studies are conducted to examine the biological effects of these variants, a better understanding will emerge of the inherited risk factors and mechanisms that lead to the development of pancreatic cancer.”

Second Cancer Patient has Genome Sequenced

Researchers from the Washington University School of Medicine in St. Louis have sequenced the genomes of cancer cells and normal skin cells taken from a 38-year-old man with acute myeloid leukemia (AML). By comparing the results with other patients with AML, the researchers identified recurring mutations that may play a role in the disease, according to findings in the August 5 New England Journal of Medicine. Last year, these researchers sequenced the genome of a woman who died from the disease.

In the current study, the researchers found 10 non-inherited (somatic) mutations and 2 DNA insertions or deletions in parts of the genome that code for proteins or small functional RNAs. In addition, they found 52 somatic mutations in parts without a known gene but with potential regulatory functions. The investigators then probed samples from 187 other patients with AML to search for these 64 mutations; 4 of them appeared in at least one other patient. These included a mutation in the gene IDH1, which has been shown to be mutated in some malignant gliomas, and two mutations (in the genes NPM1 and NRAS), which were previously linked to AML. The fourth was found in a regulatory segment.

The fact that these four mutations were found in the genome of more than one AML patient suggests “that these mutations are not random and are probably important for the pathogenesis of this tumor,” explained the authors. However, they cautioned that to understand the full range of mutations that can drive cancer, thousands of additional cancer genomes will likely need to be sequenced.

The researchers noted that rapid advances in sequencing technology since they published the first AML genome 10 months ago allowed them to sequence more of the genome while simultaneously reducing the technical work and time it required.

“This study opens a clear window into the rapid advancements that are being made in cancer-genome sequencing,” said Dr. James Downing from St. Jude Children’s Research Hospital in an accompanying editorial. As the technology in the field continues to improve, “the cost of obtaining the complete DNA sequence of a cancer cell will rapidly decrease, thus making it possible to acquire data from a larger number of cancers.”


Many Prostatectomy Patients Face Low Risk of Prostate Cancer Death

The first large-scale, multi-institution study of prostate cancer mortality since prostate-specific-antigen (PSA) screening has become widely used found that men who undergo prostatectomy have a very high chance of surviving at least 15 years. Among nearly 13,000 patients with a median age of 61, prostate cancer mortality was 12 percent, compared with 38 percent from all causes, according to a July 27 report in the Journal of Clinical Oncology.

Researchers developed a risk assessment tool to determine each patient’s risk of death from prostate cancer according to various clinical factors (such as PSA score) and analysis of the tumor characteristics at biopsy (Gleason score). When patients were stratified into 4 groups according to their calculated risk, 73 percent were in the lowest quartile with only a 5 percent risk of death, and only 2 percent were in the highest quartile with a 38 percent risk.

So many men faced such a low risk, wrote lead author Dr. Andrew J. Stephenson of the Cleveland Clinic, that “potentially many of these patients may have had a similarly low risk of prostate cancer-specific mortality had they received no treatment.” The authors observed that “in the United States, only 2 percent of patients younger than 65 years choose active surveillance,” with most opting for radiation and/or surgery. The study did not compare radical prostatectomy with other forms of treatment.

Cases diagnosed more recently had a better outcome, perhaps reflecting more effective prostate screening and treatment methods in recent years, the authors noted. Other factors, such as PSA velocity and body-mass index, had no statistically significant relationship with risk.

As for the most aggressive cancers, the authors acknowledged “the difficulty in identifying patients at substantially increased risk based on clinical factors alone,” and called for the development of “novel markers specifically associated with the biology of lethal prostate cancer.”


Low Glucose around Tumors Can Cause Cancer-fueling Mutations

Low levels of glucose around tumors may fuel the development of genetic mutations that help colorectal cancer cells thrive, researchers from Johns Hopkins University reported online August 6 in Science Express. Colorectal tumors with cells harboring these same genetic mutations, however, may be susceptible to treatments that target cancer cells’ ability to turn glucose into energy.

The researchers showed that in colorectal cancer cell lines with mutations in the KRAS or BRAF genes, expression levels of the GLUT1 gene, which produces proteins that help cells absorb glucose, were consistently elevated compared with cells that had the normal, or “wild-type,” forms of the genes. Cancer cells with these genetic mutations showed enhanced glucose uptake and glycolysis, a preferential mechanism by which cancer cells metabolize glucose.

Colorectal cancer cell lines with KRAS or BRAF mutations (the former mutation being present in nearly half of colorectal tumors) and wild-type forms of the genes fared equally well in a lab dish with normal glucose levels. However, when they were placed together in a low-glucose environment, like the types of environments that can exist within and around tumors, the cell lines with mutated KRAS or BRAF grew, whereas cell lines with the wild-type genesdid not. Eliminating GLUT1 in cell lines with the mutations eliminated this advantage.

In addition, the cancer cells with wild-type KRAS or BRAF that did survive under low-glycemic conditions had permanent increased expression of GLUT1, and a small percentage of these cells developed KRAS mutations.

“We think increased GLUT1 is a survival adaptation that makes cancer cells very efficient at gathering what little sugar exists in these areas,” said study co-author Dr. Bert Vogelstein, director of the Ludwig Center for Cancer Genetics and Therapeutics at the Johns Hopkins Kimmel Cancer Center, in a news release.

The findings, added the study’s lead investigator, Dr. Nickolas Papadopoulos, suggest that low-glucose environments favor the development of KRAS mutations “and maybe mutations yet to be identified in the same pathway.”

Finally, the researchers showed that low doses of an experimental compound that inhibits glycolysis, called 3-bromopyruvate (3-BrPA), could significantly inhibit tumor growth in animal models of colorectal cancer that harbor KRAS or BRAF mutations. In addition, 3-BrPA was far more toxic to cell lines that bore these mutations than to those that did not. The compound is one of several such glycolytic inhibitors being investigated as anti-cancer agents. The findings, the researchers wrote, “provide proof of principle that glycolytic inhibitors can retard tumor growth at doses that are nontoxic to normal tissues in vivo.”


Review Finds No Firm Evidence that Green Tea Prevents Cancer

Firm recommendations on the use of green tea in liquid or extract form to prevent cancer cannot be made based on the available evidence from published studies, according to the authors of a new review published last month in the Cochrane Database of Systematic Reviews. The conflicting evidence from the available studies, lead author Dr. Katja Boehm and colleagues concluded, means “that drinking green tea remains unproven in cancer prevention, but appears to be safe at moderate, regular, and habitual use.”

Fifty-one studies involving approximately 1.6 million people were included in the review, and 45 of those studies were conducted in Japan and China. Approximately half of the studies focused on gastrointestinal (GI) cancers, mostly those in the upper GI tract (e.g., pancreas, esophagus, liver). While a single case-control study showed a benefit of green tea consumption for the reduction of liver cancer risk, the studies looking at other GI cancer sites had “highly contradictory” results, the authors explained.

Other cancers covered by the review included lung, breast, ovarian, bladder, prostate, and oral cancer.

The review itself has limitations, the authors acknowledged, including the fact that the studies included were of varying methodological quality and were largely confined to Asian populations. Only one randomized clinical trial, for prostate cancer prevention, was available for the review (the trial found a decreased risk of prostate cancer among high-risk men who received a green tea extract compared with those who received placebo).

“In our view, the possibility of measuring the therapeutic effect of green tea based on isolated case-control or cohort studies is not very likely as other confounding variables come into place,” the authors wrote. If the potential preventive effects of green tea are to be established, they continued, large, well-designed randomized clinical trials will be needed.

Despite the findings, said Dr. John Milner, chief of the Nutritional Science Research Group in NCI’s Division of Cancer Prevention, green tea is a food item worth investigating further. It’s likely, he noted, that “exposures and interactions with a host of environmental and genetic factors influence individuals’ response to green tea.”


Cancer Incidence in U.S. Hispanics Varies by Country of Origin

In the first study to estimate cancer rates for U.S. Hispanics based on their country of origin, substantial variability was found in the rates and the predominant types of cancer for several different Hispanic subpopulations. Overall, cancer rates were 40 percent higher for first-generation Hispanics in the U.S. than populations in their countries of origin. These results were published in the August Cancer Epidemiology, Biomarkers & Prevention.

Researchers led by Dr. Paulo Pinheiro from the University of Miami Miller School of Medicine collected data on 301,944 people diagnosed with cancer in Florida between 1999 and 2001, using the Florida Cancer Data System. These individuals were classified as non-Hispanic white, non-Hispanic black, Hispanic, or mixed race and other non-Hispanic. Hispanics were further classified as Mexican, Puerto Rican, Cuban, or New Latino (including immigrants from Central and South America).

Overall cancer incidence rates were lower in Hispanics than non-Hispanic whites and blacks. However, Hispanics had higher incidence rates of some individual cancer types, including stomach and liver cancers. Rates of prostate, colorectal, and endometrial cancers were similar between Hispanics and whites, which contrasts with the results of many previous studies.

Cancer rates for U.S. Hispanics in Florida varied substantially by country of origin. Puerto Ricans had much higher cancer rates than Mexicans (53 percent higher for men and 30 percent higher for women). Cubans had lower overall cancer rates than Puerto Ricans but higher than Mexicans. The incidence rates for individual cancer types also differed between the Hispanic subpopulations.

“Targeted interventions for cancer prevention and control should take into account the specificity of each Hispanic subgroup,” said Dr. Pinheiro in an accompanying press release.


SATURN Trial Shows Small Improvement in Lung Cancer Survival

Maintenance therapy with erlotinib (Tarceva) results in a small but statistically significant improvement in overall survival in patients with advanced non-small cell lung cancer, researchers reported last week. The updated survival results from the international SATURN trial were presented at the World Conference on Lung Cancer in San Francisco. Patients who were randomly assigned to receive erlotinib following standard first-line chemotherapy had a median overall survival of 12 months, compared with 11 months for patients in the placebo arm. The SATURN trial is one of several recent trials testing the maintenance therapy approach in this patient population.

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