Study identifies potential link between Gilbert's Syndrome, childhood acute lymphoblastic leukemia

Scientists from the Barbara Ann Karmanos Cancer Institute and Wayne State University School of Medicine, both in Detroit, and the Children's Hospital of Michigan/Detroit Medical Center, presented preliminary data that identified a potential link between Gilbert's Syndrome and the development of a specific subtype of childhood acute lymphoblastic leukemia (ALL). The findings were announced today at the 2010 American Society of Clinical Oncology Annual Meeting.

The research team is led by Yaddanapudi Ravindranath, M.B., B.S., senior member at the Karmanos Cancer Institute, as well as the Georgie Ginopolis Chair for Pediatric Cancer and Hematology at the Children's Hospital of Michigan. Dr Ravindranath and his staff were assisted by faculty from the Wayne State University School of Medicine's Center for Molecular Medicine and Genetics, under the direction of Gerald Feldman, M.D., Ph.D. They were also assisted by Fatimah Nahhas, Ph.D., and Anwar Mohammed, M.S., M.D., of the Detroit Medical Center University Laboratories and Richard K. Severson, Ph.D., program leader of Epidemiology and Population Studies Program at Karmanos and the department of Family Medicine and Public Health Sciences at Wayne State University School of Medicine.

Researchers are attempting to understand that potential link as a way of determining whether chemical carcinogens may be responsible for the onset of a subset of B precursor childhood ALL, the most common form of leukemia in children. Treatability of B precursor ALL in children is very good, with a cure rate of about 80 percent.

Gilbert's Syndrome is a major cause of neonatal jaundice and is present at conception, inherited by the fetus as a recessive trait from both parents. There is no treatment necessary for the syndrome since after the first month of life it causes only mild jaundice – mostly during extended periods of fasting – and this level of jaundice causes no ill effects, according to Dr. Ravindranath.

"Gilbert's Syndrome is a very common condition," said Dr. Ravindranath. "It's present in approximately 11 percent of the U.S. white population and approximately 16 to 20 percent in the African-American population."

The syndrome is caused by the decreased activity of specific enzymes (referred to as UGT1A1) that normally assist the liver's detoxification process, enabling it to filter and eliminate environmental carcinogens such as those found in the diet, as well as steroids, synthetic drugs and flavonoids.

"Until recently, it was thought that Gilbert's Syndrome in most cases had no health consequences except in newborn babies, with jaundice being the most notable symptom," Dr. Ravindranath said. "In 1995, a molecular defect was identified, which now specifically indicates the presence of Gilbert's Syndrome. Because UGTs are important in the elimination of carcinogens, it is suspected that Gilbert's Syndrome may increase cancer risk, but this has yet to be proven".

"Our findings have not yet been validated in other studies and even if validated Gilbert's Syndrome may not be the direct cause of leukemia or cancer because most cancers are caused by multiple gene interactions."

Researchers at Karmanos, Wayne State and the Detroit Medical Center studied 80 children with ALL at Children's Hospital of Michigan. Out of the 30 children who possessed a specific "fusion" gene, known as ETV6/RUNX1, the frequency of Gilbert's Syndrome was 30 percent. In other words, among the 80 total samples that were tested, nine of 30 children with ETV6/RUNX1-positive ALL had Gilbert's syndrome, in contrast to four of 50 ETV6/RUNX1-negative ALL children.

Dr. Ravindranath said that though Gilbert's Syndrome is common in the general population, the number of children with ETV6/RUNX1-positive childhood ALL is very small.

"We can't give an estimate on the fraction of the Gilbert's Syndrome population that would be susceptible to the development of childhood ALL," he said.

Dr. Ravindranath said the next step for researchers is to expand the study to other institutions and to study a wider sample of blood and bone marrow samples from children with B precursor ALL.  

"No one has studied this in detail before. We want to confirm this finding and we have initiated some collaborative studies," he said. "If we can confirm the link between Gilbert's Syndrome and ALL, this would be a major observation. We would have for the first time a risk factor that can be easily detected."