Printer-friendly format

Dr. James Downing, scientific director and chair of the pathology department at St. Jude

In 2005, the Human Genome Project was completed and since then has provided an exhaustive characterization of the whole genome, accelerating research into the mechanisms of disease. St. Jude Children's Research Hospital excels in specialized cancer research and recently published data from a study utilizing the whole genome that suggests new discoveries for both childhood and adult cancers.

Researchers discovered previously unsuspected lesions that contribute to the formation of pediatric acute lymphoblastic leukemia (ALL), the most common cancer in children. Investigators utilized advanced DNA microarray technology which produces a very high resolution analysis of the genome that is markedly greater than any previous resolution. This study analyzed leukemia samples from 242 pediatric patients with ALL. The St. Jude team of scientists, informaticists and biostatisticians used these microarrays, postage-stamp-sized chips that contain DNA fragments, to investigate more than 350,000 markers called single nucleotide polymorphisms, or SNPs ("snips") for short. Snips are individual variations in DNA that are spaced across the human chromosomes. These snips function as flags for researchers, enabling them to detect precise deletions of DNA in a gene or an increase in the number of specific genes. The high resolution provided a view of 100,000 snips per microarray which allowed scientists to look for such genetic alterations.

"Using these high resolutions called 'comparative genomic hybridization analysis,'we really can see a level of resolution at the genome-wide level that wasn't possible in the past," explained Dr. James Downing, scientific director and chair of the pathology department at St. Jude. "This study provides a new view of the molecular pathology of pediatric leukemia and this view is going to ultimately have a major impact on our ability to diagnose and treat this disease."

Pediatric ALL is the disease that spurred the impetus for St. Jude's existence and due to years of research it is one of the best characterized cancers at the molecular level. It's a disease that develops in the cells of the immune system, typically in the B lineage lymphocytes which make antibodies. In pediatric ALL the lymphocytes don't mature to become fully functional cells, proliferating defective cells that are uncontrolled by normal mechanisms. Upwards of 90 percent of pediatric ALL patients are cured, but it is a prevalent disease. Despite all the progress made, relapsed ALL is still one of the major causes of death from cancer in the pediatric population.

"We wanted to know, would this platform that provides this higher resolution actually give us new insight or had the standard approaches of molecularly characterizing ALL provided us a pretty good idea of what's going on with the disease?" Downing explained. "We thought that would answer a very important question in the overall field of cancer. From the best characterized cancer, let's apply this methodology and see, do we actually find something new?"

In fact, researchers did find something new. The study identified an unexpectedly high frequency of lesions involving genes that function as master regulators of normal B-cell development and differentiation. According to St. Jude literature, the study found that 40 percent of cases had deletions or mutations in one of three "master genes" that control the normal differentiation of immature progenitor cells into mature B lymphocytes. The most prevalent mutation was the PAX 5 gene, a master regulator of a specific pathway. The mutation disrupts the pathway and contributes to a block in differentiation (the founding feature of pediatric ALL). Mutations were also found in other genes with important roles in B-cell differentiation, EBF1 and Ikaros. Downing said until this study, scientists didn't know these mutations existed and now they pose rational targets for future therapeutic developments. Additionally, there was little evidence that PAX 5 was involved in pediatric ALL, which this data confirms is the most frequently mutated gene in the disease.

Follow-up studies have utilized an increased resolution of 500,000 snips per microarray for further analysis. The database generated from these studies has made available to scientists about 1 billion data points from which they can compare and contrast different kinds of cancers to locate unidentified culprit lesions.

"I think the entire field is very excited about the results because it says there are new lesions," Downing said. "[This] gives us new insights into the pathways that are disrupted in cancer and that is definitely going to give us new ways of diagnosing cancer, [make us] better at classifying cancer, and ultimately at developing therapies that are better targeted to cancer and afford a better chance for a cure."


May 2007

Tags:

None