Putting Knowledge to Work - The Genetics of Cancer

Newswise — Knowledge of the human genome continues to provide tools in the fight against cancer as scientists work to understand diagnosis and prognosis at earlier stages. Data presented at the AACR 100th Annual Meeting 2009 illustrate this progress.

John S. Witte, Ph.D., professor in the Institute for Human Genetics at the University of California, San Francisco, will moderate a press conference at the Annual Meeting on Tuesday, April 21, 2009, at 10:00 a.m. MST in room 108 of the Colorado Convention Center. Reporters who cannot attend in person can dial in using the following number:

"¢ U.S./Canada Dial-In: (888) 282-7404"¢ International Dial-In: (763) 488-9184"¢ Access Code:88613002Witte said the increasing knowledge about genetics and cancer is beneficial for patients concerned about their risk.

"The specific details depend on the type of cancer, but in general if a person has several relatives with a certain type of cancer, they should consider seeing a genetic counselor and make environmental adjustments that will decrease their risk," he said.

LB-92. Frequent JAK Mutations in Pediatric Acute Lymphoblastic Leukemia (ALL) with Poor Outcome: A New Therapeutic Target in Resistant DiseaseEmbargo: 8:10 a.m. MST, Monday, April 20, 2009

Children with acute lymphoblastic leukemia (ALL) who have mutations in the JAK tyrosine kinase gene tend to have very poor outcomes and a higher rate of recurrence of their leukemia, which suggests a potential diagnostic tool and a new therapeutic target in high-risk disease.

This important research discovery was produced by the first TARGET (Therapeutically Applicable Research to Generate Effective Treatments) initiative sponsored by the National Cancer Institute (NCI) and coordinated by the Children's Oncology Group (COG). A team of physicians from COG worked with researchers at St. Jude Children's Research Hospital in Memphis, Tenn., the University of New Mexico Cancer Center and the NCI to conduct this research.

The researchers performed a genetic analysis in 221 children with B-progenitor ALL at high risk for relapse derived from a clinical trial conducted by COG. This analysis included genomic resequencing of JAK1, JAK2, JAK3 and TYK2 in 187 cases of ALL. JAK mutations, which were not previously known to occur in children with ALL, were found in 10 percent of patients. The presence of JAK mutations was associated with a deletion of the genes IKZF1 and CDKN2A/B and poor outcome. The four-year incidence of relapse was 71 percent for patients with JAK and IKZF1 alterations, compared with 23 percent for patients with neither alteration.

"These mutations can currently be identified using standard genetic testing. Drugs are being developed that can be used against these JAK kinases, and JAK inhibition clearly warrants clinical evaluation in this subset of patients," said Charles G. Mullighan, M.B.B.S. (Hons), M.Sc., M.D., assistant member of St. Jude and a lead author of the study.

Gregory Reaman, M.D., COG chair, added, "Developing clinical trials of JAK inhibitors in ALL is one of our highest priorities. This is an example of how clinical trials conducted by COG can translate an important laboratory discovery to potential new therapies for patients identified to be at very high risk for relapse."

1905. Genetic Variants in MicroRNA Processing Pathway Genes and Ovarian Cancer RiskEditor's Note: Late breaking data on this abstract not included in this release will be presented during the press conferenceEmbargo: 2:25 p.m. MST, Sunday, April 19, 2009

Genetic variants in the microRNA processing pathway may predict risk of ovarian cancer, according to research conducted at the University of Texas M. D. Anderson Cancer Center.

Xifeng Wu, M.D., Ph.D., a professor in the department of epidemiology at the University of Texas M. D. Anderson Cancer Center and lead author of the study, said ovarian cancer risk is understudied, but information obtained in this study could help clinicians build a risk prediction model similar to the Gail model in breast cancer.

"With this information, coupled with other genetic and potential lifestyle risk factors, we could develop a quantitative risk prediction model," said Wu. "Previous studies mainly focused on the tumor tissue of ovarian cancer, but few have attempted the risk prediction."

For the current study, Wu and colleagues evaluated 70 potential functional single nucleotide polymorphisms (SNP) in eight microRNA biogenesis pathway genes. This genetic information was gathered from 526 ovarian cancer cases and healthy controls.

The researchers identified 16 SNPs that had a predictive effect on ovarian cancer risk. A genetic makeup may be constructed based on these SNPs. Those patients who carried no more than five of these SNPs were considered to be at low risk for ovarian cancer.

Patients carrying between six and seven SNPs were at more than two-fold increased risk, while those carrying eight or more had a more than five-fold increased risk.

"People are born with these types of variants, so if this is confirmed in larger studies it could greatly enhance our understanding of the etiology of ovarian cancer, with potential applications in screening, cancer prevention and early detection," said Wu.

96. Confirmation of a Set of Genetic Susceptibility Variants for Chronic Lymphocytic Leukemia (CLL) Embargo: 8:00 a.m. MST, Sunday, April 19, 2009

Researchers from the Mayo Clinic have confirmed a set of genetic variants that put a person at greater risk for chronic lymphocytic leukemia, which is known to have a genetic component to disease risk.

"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," said Susan L. Slager, Ph.D., associate professor of biostatistics at the Mayo Clinic in Rochester, Minn. "We have validated genetic variants that may help explain why."

Slager said the findings of this study add more pieces to the puzzle that may lead to better prevention and prognosis.

"This will help us understand the disease better and, hopefully, help us to develop better drug targets," she said.

A previous genome-wide analysis study identified seven single nucleotide polymorphisms (SNP) that could possibly lead to chronic lymphocytic leukemia. Slager and colleagues validated these in an independent sample of patients.

All but one of the SNPs was significant predictors of risk. The strongest association was for rs735665 on 11q24, where the risk was 50 percent higher. This was closely followed by a 39 percent increased risk associated with rs9378805 on 6p25.

LB-99. Association of UGT2B17, UGT2B7 and UGT2B28 Gene Copy Number with Prostate Cancer RiskEmbargo: 1:00 p.m., Monday, April 20, 2009

Researchers found no association between UGT2B17 and the risk of prostate cancer when examined both individually and in combination with other genetic variables, according to research conducted at Weill Cornell Medical School in New York and Brigham and Women's Hospital in Boston.

"Prior to this study, we had two studies that reported this gene was linked with prostate cancer risk and two studies that did not. Our comprehensive study suggests that there is no significant association among the Europeans studied," said Sunita Setlur, Ph.D., an instructor in pathology at the Brigham and Women's Hospital and Harvard Medical School.

Reports like this, which scientists call a null finding, are critical to building a knowledge base from the ever-growing information derived from the mapping of the human genome. Prostate cancer affects one in six men in the United States and is known to have some sort of genetic component.

The researchers examined 269 individuals, including 156 men with prostate cancer and 113 men without prostate cancer who had PSA levels below 0.5 ng/ml for three years following a negative biopsy.

Copy number status analysis showed no changes for UGT2B7, while deletion patterns for UGT2B17 and UGT2B28 were between 3.4 percent and 19.9 percent depending on the analysis. No increased risk of prostate cancer was noted regardless of gene activity.

Setlur said the advantages of the current study were the identification of a strict cut-off point for PSA levels and the evaluation of copy number status of the gene of interest.

"This region is very interesting since it is involved in the regulation of testosterone. Therefore, delineating the association of genomic copy number status in this locus would help in understanding the biology of prostate cancer. Copy number status is fast becoming a standard measure of gene activity similar to what we can learn from single nucleotide polymorphisms," said Setlur.

LB-169. DNA Methylation Profiling Reveals a Field Defect in Bladders with Cancer and a Distinct Hypomethylated Pattern in Non-Invasive Bladder Tumors Embargo: 8:00 a.m. MST, Tuesday, April 21, 2009

Researchers have identified a DNA methylation pattern that may aid in the diagnosis of bladder cancer and the detection of those who may be at risk for recurrence.

Bladder cancer is currently the fifth most common cancer in the United States. It is characterized by a high rate of tumor recurrence that generally happens three to six months following treatment.

"Current clinical practice is to use invasive methods to diagnose and monitor these tumors, but we have uncovered a possible way to gather this information through a simple molecular assay," said Gangning Liang, M.D., Ph.D., associate professor of research in the department of urology at the University of Southern California.

DNA methylation is a process by which genes can be abnormally silenced or activated in cancer. Working with the knowledge from the human genome, scientists have been gaining a greater understanding of how methylation leads to measurable clinical outcomes.

For the current study, Liang and colleagues 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.

When comparing the cancerous tissue with normal bladder tissue, they found 158 hypermethylated locations and 366 hypomethylated locations. In addition, the researchers identified 21 loci that were hypermethylated in the normal appearing bladder tissue in patients with bladder cancer.

"These loci may provide markers for the identification of individuals at risk for developing bladder cancer, as they are only methylated in bladders with cancer," said Liang.

When the researchers further subdivided their analysis, they found that non-invasive tumors had a distinct pattern of hypomethylation when compared with invasive tumors, further supporting the notion that these two forms of bladder cancer develop along different molecular pathways.

The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, AACR is the world's oldest and largest professional organization dedicated to advancing cancer research. The membership includes more than 28,000 basic, translational and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and nearly 90 other countries. The AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants. The AACR Annual Meeting attracts more than 17,000 participants who share the latest discoveries and developments in the field. Special conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment and patient care. The AACR publishes six major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; Cancer Epidemiology, Biomarkers & Prevention; and Cancer Prevention Research. The AACR also publishes CR, a magazine for cancer survivors and their families, patient advocates, physicians and scientists. CR provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship and advocacy.