Investigative Instincts Guided Vogelstein's Journey of Discovery

OncologyLive, August 2014, Volume 15, Issue 8

In Partnership With:

Partner | Cancer Centers | <b>Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins</b>

Revelations About Cancer Mutations Predate Technological Advances

Bert Vogelstein, MD

Bert Vogelstein had no idea that a young girl would start him on a journey that would forever change humanity’s understanding of cancer. He was an intern fresh out of medical school when the girl’s parents brought their daughter to Johns Hopkins to find out why she’d grown so pale and started bruising so easily. The tests revealed cancer. When Vogelstein delivered the news to the stunned parents, they asked how and why a preteen could develop cancer.

Decades later, Vogelstein can still remember how terrible it was to be unable to provide an answer. “I just threw up my hands and said, ‘I don’t know. Nobody knows. It’s just this total black box, this thing that just strikes people randomly, when they shouldn’t be struck.’ And, right then and there, it became clear to me that if I wanted to spend my life on a puzzle, on a problem that I could apply my skills toward, that was going to be a good one,” he recalled.

Vogelstein’s epiphany launched a lifelong hunt for the root causes of cancer, a hunt that unveiled in 1989 the most important cancer suppressor gene, and went on to unearth much of what we know about the mutations found in many tumor types.

Choosing a Path

Vogelstein has published more than 450 papers since 1976, and those papers have been cited more than 200,000 times—a tally that illustrates their incredible impact. Vogelstein’s work not only launched a wave of genetic research around the globe, but also helped lay the groundwork for today’s era of targeted assays and therapeutics.Vogelstein was born in Baltimore, Maryland, in 1949 and raised in the city, which then, as now, saw much of its scholarly life dominated by the various arms of Johns Hopkins University.

He came from a long line of rabbis, starting with his grandfather and going back 13 generations. His father, however, was a lawyer, as were many other men in his family, and, law—not medicine—was what appealed to Vogelstein in grade school. It wasn’t until high school that he developed a love of science and mathematics that determined the course of his life.

He left Baltimore after high school for the University of Pennsylvania in Philadelphia, majoring in math and graduating summa cum laude. (He also, perhaps to appease his rabbinical ancestors, won the school’s Rosenbaum Award for undergraduate work in Semitic languages and literature.)

After briefly pursuing graduate studies in mathematics, Vogelstein felt called upon to pursue a career path that would help others more directly. Vogelstein returned to Baltimore to study medicine at Johns Hopkins, receiving his medical degree in 1974 and remaining at Johns Hopkins for his internship and pediatrics residency. He was serving that residency, wondering what he wanted to do with his professional life, when he diagnosed that little girl’s cancer and struggled to explain it to her parents.

He soon undertook a postdoctoral fellowship at the National Cancer Institute, where he learned the basic principles of molecular biology, and then returned to Johns Hopkins, where he has remained ever since.

The Tumor Suppressor Gene Theory

“I still had to decide whether I should continue to see patients and practice medicine, or devote all of my energies to research, so I tried doing both,” he said. “I found myself during the days seeing patients and during the nights going to the lab and trying to do a little bit of research. And I found at night I was really happy. I felt stimulated. I couldn’t wait to get to the lab at night so I could start experiments.”Vogelstein’s is one of the great careers in medical research—and it nearly ended before it began. The first two grant proposals he ever submitted to the National Institutes of Health (NIH) were rejected.

“I was getting really worried, because there’s only a limited time you can go in science without getting funded, or else you’re going to be driving a cab or something,” he said. But once money began flowing into his lab, Vogelstein focused his attention on colon cancer. He amassed a large collection of tissue samples at each step in the progression from fully healthy to malignant carcinoma, and found that colon cancer, rather than developing uniquely in each patient, went through similar genetic steps in many patients.

In a 1988 article published in The New England Journal of Medicine (NEJM), Vogelstein posited that the progression required two different types of genetic mutations: (1) the activation of oncogenes (such as the Ras gene that had already been identified); and (2) the inactivation of tumor suppressors.

The existence of tumor suppressors— genes that prevent cells from multiplying too quickly—had always struck Vogelstein as logical, particularly in light of the observation that tumor cells were almost always missing specific chunks of DNA that were present in normal cells.

The tumor suppressor theory also explained why cancer is relatively rare in the general public despite the frequency of cell mutations: most people have two copies of each tumor suppressor (one inherited from each parent), and thus would need both copies incapacitated before developing serious problems.

Zeroing in on TP53

The theory made sense, but it suffered from one big problem. Neither Vogelstein nor anyone else had ever identified a tumor suppressor gene. Given technology at the time, there was no way scientists could scour the entire human genome for tumor suppressors, but Vogelstein realized he didn’t need to cast such a broad net. He looked instead at the far smaller chunks of DNA that tumors often lacked, reasoning that some of the relatively small number of genes therein must be tumor suppressors.Vogelstein found his quarry almost immediately and, just a year after his NEJM article, he published evidence that TP53—a gene long thought to stimulate rather than inhibit cell growth—was a tumor-suppressing gene. Indeed, Vogelstein’s paper noted that both copies of TP53 were always missing or mutated in colon cancer cells.

Further research by Vogelstein and his team revealed that TP53 and its mutations play a similar role in many human cancers. In fact, subsequent research has shown that tumor growth does not hinge upon one particular mutation of TP53. A mass of analyses that was initiated by Vogelstein’s paper has found more than 20,000 possible different mutations, many of which reduce or eliminate its tumor-suppressing qualities. TP53 is now recognized as the most commonly mutated gene in human cancers, virtually operating as their common denominator.

Finding More Genes in Colon Cancer

All of these discoveries conformed to what Vogelstein had hypothesized before the first tumor suppressor had been found, a fact that Vogelstein believes illustrates how science really works. “You have hunches. There’s some gut feeling you have that something is right, or can be done, or is ripe for investigation. That’s not methodical at all, or analytical. The analytical part only comes later,” he said. “Once you make that connection, once you have that hunch, that insight, then you have to provide evidence supporting it, or to disprove it. That’s an execution process, rather than a discovery process per se.”After documenting the function of TP53, Vogelstein joined forces with Kenneth W. Kinzler, PhD, a onetime grad student in Vogelstein’s lab who is now a fellow professor at Johns Hopkins. Working together, the researchers identified additional genes involved in colon cancers, genes such as APC. Vogelstein and Kinzler showed that mutations of APC occurring in single colorectal epithelial cells start the entire sequence of changes that lead from healthy tissues to adenomas, the benign tumors.

The pair also identified genes such as PIK3CA, which, when mutated, are responsible for the next step in the process, creating malignant tumor cells from the adenoma cells.

Forging Ahead in Cancer Genetics

All told, Vogelstein and his protégé have documented much of the genetic activity surrounding a host of cell mutations in the colorectal tract, including how patients with inherited APC mutations develop a disease called familial adenomatous polyposis and grow hundreds or thousands of benign tumors in their colons and rectums. Much of Vogelstein’s recent research has focused on making early diagnosis tools less invasive. For example, his lab has developed sensitive blood tests that are now used in the clinic to identify patients with inherited mutations in genes known to be involved in colorectal cancer.

Vogelstein has also worked to create therapies that exploit the knowledge of cancer genetics that researchers like him have recently uncovered. He and his team have used an oxygen-hating, soil-dwelling bacterium to kill tumor cells—which often develop faster than their blood supply, and are thus low in oxygen —in animal cancers. (This last concept also draws heavily on the work of the cancer pioneer Judah Folkman, MD, who uncovered much of what we know about how tumors recruit blood vessels to spur growth. Folkman was honored posthumously with a Giant in Cancer Care award in 2013.)

Vogelstein has also used new tools to speed up his exploration of cancer genes. Beginning in 2004, Vogelstein and Kinzler, working with Victor Velculescu, MD, PhD, and Nickolas Papadopoulos, PhD, and others in their group, began to perform large-scale experiments to identify mutations throughout the human genome. They were the first to perform exomic sequencing, the determination of the sequence of every protein-encoding gene in the human genome. The first analyzed tumors included colon, breast, pancreas, and brain tumors. In the process of analyzing protein-encoding genes within cancers, Vogelstein and his colleagues discovered several novel genes that play a pivotal role in cancer, such as IDH1, IDH2, ARID1A, ARID2, ATRX, DAXX, MLL2, MLL3, CIC, and RNF43.

That work has enabled Vogelstein and his team to create and publish genomic maps of cancer for breast, colon, and many other cancers. “Cancer is, in essence, a genetic disease,” he said. “Mutations are just clocks. Every time a cell divides it mutates at a low rate, and those changes are recorded in the cancer genome.”

Bert Vogelstein, MD: Sampling of Journal Articles

  • Vogelstein B, Papadopoulos N, Velculescu VE, et al. Cancer genome landscapes. Science. 2013;339(6127):1546-1558.
  • Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors [published online January 20, 2011]. Science. 2011;331(6021):1199-1203.
  • Leary RJ, Kinde I, Diehl F, et al. Development of personalized tumor biomarkers using massively parallel sequencing. Sci Transl Med. 2010;2(20):2014.
  • Wood LD, Parsons DW, Jones S, et al. The genomic landscapes of human breast and colorectal cancers [published online October 11, 2007]. Science. 2007;318(5853):1108-1113.
  • Diehl F, Schmidt K, Choti MA, et al. Circulating mutant DNA to assess tumor dynamics [published online July 31, 2007]. Nat Med. 2008;14(9):985-990.
  • Papadopoulos N, Kinzler KW, Vogelstein B. The role of companion diagnostics in the development and use of mutation-targeted cancer therapies. Nat Biotechnol. 2006;24(8):985-995.
  • Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med. 2004;10(8):789-799.
  • Komarova NL, Lengauer, C, Vogelstein B, Nowak MA. Dynamics of genetic instability in sporadic and familial colorectal cancer. Cancer Biol Ther. 2002;1(6):685-692.
  • Lengauer, C., Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature.1998;396(6712):643-649.
  • Kinzler KW, Vogelstein B. Cancer-susceptibility genes: gatekeepers and caretakers. Nature.1997;386(6627):761-763.
  • Vogelstein B, Kinzler KW. p53 function and dysfunction. Cell.1992;70(4): 523-526.
  • Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988;319(9):525-532.

Vogelstein still has much to discover before he will be able to give a fully satisfactory answer to questions such as those asked by the parents of that little girl all those years ago, but he has gotten far closer.