Chromosomal Fragile Sites: The Relationship with Hepatitis B Virus and Liver Cancers

    • September 30, 2008

The Problem: How cancer develops and progresses is one of medicine's most challenging areas of research. What could the Hepatitis B virus and its link to liver cancer reveal about the development, growth and spread of cancer?

Grantee Background: As a young boy growing up in Ghana, West Africa, Lewis Rowland Roberts, MB, ChB, PhD, was exceptionally inquisitive. "I've always been a very curious person-sometimes to my parents' chagrin because I would take things apart and not be able to put them back together," he recalls.

Today, Roberts trains his curiosity on the pieces of a scientific puzzle that will one day more fully explain how cancer develops. His particular focus is on the connections between liver cancer and a disease—Hepatitis B—that is widespread in the sub-Saharan region of his native country. "I would see patients during my training who were young people with liver cancer from Hepatitis B," he recalls.

Roberts' father was a physician, his mother a nurse, and other relatives had medical careers as well. That background was a strong influence for Roberts, but so was his family's commitment to education. "Both of my grandfathers were teachers and started high schools in Ghana," he says. "My dad taught at his dad's school before he went to medical school. So there is a strong undercurrent of medicine, education and service."

After medical school, Roberts worked as a teaching and research fellow in Ghana. He then took a detour—working with young people for two years in a ministry organization in Kenya—before returning to medicine. He came to the University of Iowa, Iowa City, to conduct his PhD research on gene expression in the liver and how liver cells responded to stress hormones. Though he had originally planned to return to Ghana, the high cost of research kept him here. "It became clear to me that I could not run a research program in Ghana," he says. "The economy was very depressed there at the time."

Committed by then to both research and clinical practice, Roberts sought out a special residency program at the Mayo Clinic that allowed him to do both. He soon developed a special interest in liver cell injury and cell death, and secured a fellowship in gastroenterology after his residency. He accepted an offer to join Mayo's faculty with one caveat: "If I can't be in West Africa, I will try to study something that is of relevance to Africa and other underserved areas—liver cancer."

From 2000 to 2004, Roberts was able to do that with an award from the Robert Wood Johnson Foundation's Harold Amos Medical Faculty Development Program. Working at Mayo Clinic with cancer geneticist David Smith, Ph.D., Roberts became immersed in Smith's specialty, known as "chromosomal fragile sites," which are areas of a genome that are less stable and more prone to breakage. According to Roberts, cancer geneticists are very interested in the relationship of these sites to the development of cancer. Through his Harold Amos award, Roberts zeroed in on viruses associated with cancer—including Hepatitis B—armed with a list of questions:

"If these viruses were more likely to integrate into a fragile site, is this the way the viruses have their carcinogenic effects? Would the Hepatitis B virus—already known to integrate into the human genome—integrate into fragile sites? When it does integrate, does it integrate into places within the genome that give the cells a growth advantage and promote the development of cancer?"

During his four-year participation in the Harold Amos program, Roberts was able to essentially answer "Yes" to each question. In a series of complicated steps, Roberts identified and characterized the genetic alterations that occur at the site of integration of Hepatitis B virus into the host liver cell genome. He also discovered that integration is not necessarily random—a finding that Roberts says some scientists still resist. "Hepatitis B virus integration occurs in over 90 percent of Hepatitis B virus-induced primary liver cancers," Roberts says, "and is thought to contribute to the development of cancer in most cases."

Today, Roberts continues to study liver cancer and to benefit from his Harold Amos experience, even recruiting others to apply to the program. "They have the cream of the crop of scientists who offer to serve as mentors," he says. "That is a unique part of the program, having such accomplished mentors be role models for fellows."

And true to his word, Roberts has not forgotten his native country. Because of Minnesota's large population of African immigrants, Roberts is pushing for development of a medical surveillance program to help provide early detection of liver cancer in immigrants with hepatitis B virus infection. And about eight years ago, Roberts started a series of continuing education courses for physicians, nurses and medical students in Nigeria and now Ghana, the perfect combination for a physician seeking to combine family legacies in both medicine and education.

RWJF Perspective: The Harold Amos Program is one of RWJF's oldest programs, having started in 1983 as the Minority Faculty Development Program. It was renamed in 2004 to honor the first African American to chair a department at Harvard Medical School; he was also a former director of the program. The program provides four-year postdoctoral research awards to historically disadvantaged physicians who are committed to developing careers in academic medicine.

"One of the assumptions of the program," says J.A. Grisso, MD, MSc, a senior program officer at RWJF, "is that if you give leadership opportunities to individuals from underrepresented and disadvantaged groups that they, in their career trajectories, are more likely to take on the issues that are particularly important to vulnerable populations. That has been true for the Harold Amos Faculty Development Program. Individuals who could be outstanding scholars in any world and for any issue have very often chosen to address these important issues that we care about at RWJF.

"This is a long-standing program that is very forward-thinking," says Grisso. "It has uniquely engaged individuals who do basic science research as well as those who do health services research and clinical research. People who are completely basic science-oriented are now getting trained in or exposed to epidemiology and public health and then are starting to talk about the social issues as they might affect biological systems. They are asking questions that are unique in my experience with basic science."

Lewis Rowland Roberts, MB, ChB, PhD

Lewis Rowland Roberts, MB, ChB, PhD
Harold Amos Medical Faculty Development Program