Writing in the Proceedings of the National Academy of Sciences, the research team reports that when a gene called TFEB is split off from its chemical "throttle," the gene becomes overactive in PRCC cells. The disease is considered one of the more difficult childhood tumors to treat, because other than surgery, no therapy has been found effective, and scientists don't have a good understanding of the tumor's molecular origins. The study will be published on the journal's website, www.pnas.org, during the week of April 28.
"The discovery of this oncogene [or cancer-causing gene] is an example of research that encompasses the clinic as well as the laboratory," says the study's senior author, David Fisher, MD, PhD, an oncologist at Dana-Farber and Children's. "By bridging these two areas, we've made a connection that may result in better diagnosis and treatment of people with this disease, demonstrating the potential and importance of translational research."
The discovery grew out of the Dana-Farber team's previous research into MITF, a gene that controls the activity of a group of genes in skin cells known as melanocytes. Fisher and his colleagues identified several of these target genes, which are used as "markers" in blood tests for diagnosing whether an individual has the skin cancer melanoma.
Several years ago, the researchers discovered that MITF is one of a family of genes that plays similar roles in different types of cells. Three other genes in this family are called TFE3, TFEB, and TFEC.
In recent years, scientists have found several cases of papillary renal cell carcinoma in which TFE3 was fused abnormally to a variety of different genes. "While TFE3 was clearly important in these tumors, the precise function of the fusion partners has not been clear," says Fisher, who is also an associate professor of pediatrics at Harvard Medical School. "It was a hint, though, that other members of the MITF family may be involved in PRCC."
The next step came with a young patient who had undergone surgery at Children's for PRCC came to Dana-Farber's Jimmy Fund Clinic for a routine check-up. As part of the exam, Fisher checked the pathology report on the patient's tumor, expecting to find that it harbored a TFE3 mutation.
"The report indicated the tumor cells did not have an abnormality at the TFE3 gene's location, but instead had an abnormality on chromosome 6," Fisher relates. "We knew from our earlier research that TFEB is located on chromosome 6 at that same general location. While it could have been a coincidence, it raised the possibility that a TFEB mutation was linked to the cancer."
The pathology report, produced by the study's lead pathologist and co-author Sara Vargas, MD, of Children's Hospital and her colleagues, contained another hint of TFEB's involvement. The tumor cells had tested positive for one of the 'marker' genes controlled by MITF, Fisher explains. Because TFEB and MITF appear to control many of the same genes, this further supported the possibility that TFEB was the culprit gene behind the tumor's growth.
To find out for sure, Ian Davis, MD, PhD, of Dana-Farber and Children's, an instructor in pediatric oncology working in Fisher's lab, performed molecular tests on the tumor cells and found the TFEB gene was indeed split apart, with the main region being fused to the "gearbox" - the on-and-off switch - of a gene on a completely different chromosome. The error causes TFEB to function abnormally and implicates TFEB in the development of cancerous growth. "This mutation was convincing evidence that TFEB functions as an oncogene in this tumor," Davis, first author of the study, remarks.
The finding was confirmed when investigators at Memorial Sloan-Kettering Cancer Center and Johns Hopkins University sent Dana-Farber scientists PRCC tumor cells from their patient populations that contained virtually the identical chromosomal irregularity.
The discovery will give focus to researchers' efforts to develop effective drug therapies for PRCC. Although no TFEB-blocking drugs currently exist, investigators hope to devise treatments capable of blocking some of the gene "targets" of TFEB - the genes it switches on that carry the cancer process forward.
"The finding will not only help doctors make more precise diagnoses of this disease, but may influence treatment as well," Fisher remarks. "It will put us in a position to prescribe treatments that are known to work best for each specific tumor type."
Other co-authors of the study are Albert Yeh, MD, and Antonio Perez-Atayde, MD, of Children's Hospital Boston, Jonathan Fletcher, MD, of Brigham and Women's Hospital, Marc Ladanyi, MD, of Memorial Sloan-Kettering Cancer Center, and Pedram Argani, MD, of Johns Hopkins Medical School.
Dana-Farber Cancer Institute is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.
Children's Hospital Boston is the nation's premier pediatric medical center. Children's has been ranked #1 among the country's pediatric hospitals in U.S. News and World Report for 13 years in a row. Founded in 1869 as a 20-bed hospital for children, today it is a 300-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's Hospital Boston is the primary pediatric teaching affiliate of Harvard Medical School, home to the world's leading pediatric research enterprise, and the largest provider of health care to the children of Massachusetts.
Dana-Farber Cancer Institute
Children's Hospital Boston