Genomics Researchers Discover Predictors for Chronic Lymphocytic Leukemia

Tuesday, April 04, 2006

ROCHESTER, Minn. — Mayo Clinic researchers have identified two key markers that may aid in the quest for earlier diagnosis of chronic lymphocytic leukemia (CLL). The findings can be found in the Journal of Clinical Oncology, Vol. 24, No. 6.

The investigators discovered that serum B-lymphocyte stimulator (BLyS) levels are elevated in patients with B-cell chronic lymphocytic leukemia (B-CLL) who have a family history of lymphoproliferative disorders. In these same patients, they also found a single nucleotide polymorphism (SNP) in the BLyS promoter, a region of the gene that regulates its expression.

"Our data indicate that people who have a familial history of B-cell malignancies are more likely to have elevated BLyS levels and the BLyS SNP compared to healthy individuals," says Anne Novak, Ph.D., Mayo Clinic hematology researcher. "We believe that identification of individuals with elevated BLyS levels or the BLyS SNP may allow for identification of individuals who are predisposed to development of B-cell malignancies — and the findings encourage us in our search for early diagnosis tools." The SNP (a genetic variation in the DNA) identified by the group was found in a region of the BLyS gene that may be responsible for regulation of its expression. BLyS is a protein that influences the growth and survival of B-cells and plays an important role in antibody production.

More than 92,000 people will be diagnosed in 2006 with lymphoma and other B-cell lymphoproliferative cancers, according to the American Cancer Society. Over 30 percent of them will die from the disease. This study's findings increase the ability to individualize medicine — establishing a more precise risk profile and improving the physician's ability for early diagnosis.

Researchers have long known that early diagnosis makes most cancer treatment more effective, and Dr. Novak and her fellow investigators continue to study ways to pinpoint individual risk and develop affordable and efficient screening tests. "We hope these findings will lead to the first effective screening tool for CLL," she says. "It is the next step to earlier and better treatment, prevention and hopefully someday a cure."

The study group included 70 untreated patients diagnosed with B-CLL. Twenty-four had familial CLL, with first- or second-degree relatives diagnosed with a B-cell lymphoproliferative malignancy including B-CLL, non-Hodgkin's lymphoma, multiple myeloma or Hodgkin's lymphoma. The control group consisted of serum samples from 41 age- and sex-matched patients with no personal or family history of a B-cell malignancy.

The average BLyS level in the normal controls was 6.68 nanograms per milliliter (ng/mL), and in CLL patients it was 11.93 ng/mL. Elevated levels were considered to be those greater than 20 ng/mL, and were found in two (5 percent) of the control patients and 13 (19 percent) of the CLL patients.

In the SNP analysis, the wild-type (normal) BLyS promoter was found in one (4 percent) of the 24 individuals with familial CLL compared to 14 (30 percent) of the 46 sporadic CLL patients and 10 (24 percent) of the disease-free control group. Only one (7 percent) of the 15 individuals with high BLyS levels had the wild-type genetic sequence, compared to 24 (25 percent) of the 96 individuals with normal BLyS levels. A large-scale analysis of the presence of this SNP in the general population and individuals with a B-cell lymphoproliferative disorder is under way at Mayo Clinic.

Other Mayo Clinic researchers involved with this study include: Deanna Grote; Steven Ziesmer; Michael Kline, Ph.D.; Michelle Manske; Susan Slager, Ph.D.; Thomas Witzig, M.D.; Tait Shanafelt, M.D.; Timothy Call, M.D.; Neil Kay, M.D.; Diane Jelinek, Ph.D.; James Cerhan, M.D., Ph.D.; and Stephen Ansell, M.D., Ph.D. They collaborated with Jane Gross, Ph.D.; Stacey Dillon, Ph.D.; and Brandon Harder from Zymogenetics, Seattle, Wash.

This research was funded in part by grants from the National Institutes of Health and the Leukemia and Lymphoma Society, with additional support from Zymogenetics. It is the result of ongoing studies conducted under the auspices of a National Cancer Institute (NCI) SPORE grant — Specialized Programs of Research Excellence, jointly held by the University of Iowa and Mayo Clinic. Mayo Clinic currently is conducting research within six SPOREs — brain, breast, lymphoma, myeloma, pancreas and prostate cancers. For more information on SPORE projects at Mayo Clinic, visit mayoresearch.mayo.edu.

To find out more about Mayo Clinic's hematological malignancies research, visit cancercenter.mayo.edu.

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