Chromatin May Explain How Few Genetic Changes Lead to Pediatric Kidney Cancer

In adults, tumors display hundreds of genetic mutations that have led the way to cancer. Yet among children, just a few mutations can unleash abnormal cells that cause tumors to grow. Scientists have long been intrigued by this disparity.

Now a new study suggests that a pediatric kidney cancer called Wilms tumor can, with just a few genetic changes, hijack pathways that ordinarily drive development of normal kidney tissue. "Wilms tumor typically shows up only between the ages of one and five, and we think it arises from a population of stem cells that don't need many mutations to become tumors," explains Miguel Rivera, an assistant professor at Massachusetts General Hospital and an HHMI physician scientist early career awardee. Rivera, HHMI scientists Bradley Bernstein and Daniel Haber, and their colleagues at Massachusetts General Hospital published their research on June 4, 2010 in the journal Cell Stem Cell.

"Wilms tumor typically shows up only between the ages of one and five, and we think it arises from a population of stem cells that don't need many mutations to become tumors." said Miguel Rivera.

Wilms tumor is the most common childhood kidney cancer, afflicting roughly 500 children in the United States each year. In most cases, surgery combined with chemotherapy can kill these cells, but not all cases of Wilms tumor respond to current therapies. "We don't have many other options when standard therapy fails," Rivera says.

Rivera was a postdoctoral fellow in the lab of HHMI investigator Haber, who has had a longstanding interest in Wilms tumor genetics, when he found that the cancer has a relatively "flat" genomic profile. In other words, from a genetic perspective, Wilms tumor looks oddly normal compared to adult tumors, which are littered with genetic deletions, amplifications, and other signs of DNA damage. To better understand the cancer's biology, Rivera decided he needed to use a different type of analysis. "We wanted to look at the essential molecular pathways that keep the tumor going," he explains.

That's where Bernstein, an HHMI early career scientist at Mass General, came into the picture. Bernstein studies molecular pathways by looking at chromatin, structures composed of histone proteins that serve as spools to wind DNA into small packages. Every cell in the body has the same genes, but which genes are active depends on what kind of tissue it is. Chemical tags on histones are part of that process. They change the way the chromatin is organized and allow the right combination of genes to be turned on in each tissue. Bernstein uses a technique called chromatin profiling to learn about the organization of individual genes within a cell- information that can reveal whether a gene is turned on or off, or is poised to be activated at a later stage.

During their investigation, Bernstein, Rivera, Haber, and other members of the team used chromatin profiling to study three types of cells: Wilms tumor cells, embryonic stem cells, and normal kidney cells. Chromatin profiling had been used with embryonic stem cells and cancer cell lines grown in culture, but until this study, it had never been applied comprehensively to primary tumors. When they looked at the data, "the first thing that jumped out was a pattern of active chromatin signatures over a set of about 100 genes," Bernstein says. "We showed them to [Rivera], and he realized they were master regulators of kidney development." This told the group that the tumor was mimicking the behavior of a stem cell, which has the ability to develop into any mature cell type found in the kidney.

Of the 100 genes identified, 26 are known to be essential for renal development and the rest are a new set of potentially critical genes, Rivera says. Ordinarily, normal development leads kidney stem cells to become adult kidney cells. But in Wilms tumor, that process gets stuck. This leaves a glut of immature cells that self-renew and create a tumor. Rivera wants to use what they learned about these overactive genes to develop new therapies that can reset the cells to normal development. "Looking at [Wilms tumor] from a developmental biology perspective should shed light on new therapeutic targets," he says. Some interesting candidates have already emerged, he says. "We have to validate them first and then identify which ones are amenable to therapy."

For Bernstein, the findings indicate that chromatin profiling can be a useful tool to study other types of cancer as well. "It was by looking at the chromatin landscape that we were able to precisely illuminate the molecular architecture of these cells," he says. "That's how we determined their character, and found out that they look a lot like renal stem cells. Now we need to look at whether similar phenomena may account for other pediatric cancers."

Contact: Andrea Widener
(301) 215-8807