Bert Vogelstein, M.D.
Bert Vogelstein ranks today, as he has for more than a decade, as the pre-eminent international scientist. Many of the discoveries that led the world to understand that cancer is a genetic disease unfolded one by one in his laboratory.
Vogelstein and his student Ken Kinzler discover the GLI gene through its amplification in advanced forms of brain tumors. The GLI gene and related genes later found by Kinzler and Vogelstein are now known to be the central components of a signaling transduction pathway that contributes to the development of many different forms of tumors.
In a now classic paper published in the New England Journal of Medicine, Vogelstein lays out a model for the development of colorectal neoplasia. The model posited that cancer was a genetic disease driven by sequential mutations in oncogenes and tumor suppressor genes. It has since become the standard icon for understanding human tumors in general.
Vogelstein identifies mutations of p53 in colon cancers and shows that it is a tumor suppressor gene. He later demonstrates that p53 is a common denominator underlying many forms of human tumors. These discoveries initiated a revolution in cancer research that continues today, with ramifications for epidemiology, biochemistry, molecular biology and clinical medicine in addition to genetics. There have been more than 20,000 mutations of p53 discovered since the first one reported by Vogelstein. The p53 gene is the most commonly mutated of all genes, including both suppressor genes and oncogenes, ever found in human tumors.
Their studies of inherited colon cancer syndromes leads Vogelstein and Kinzler to identify the cause of an inherited colon cancer syndrome called Familial Adenmomatous Polyposis (FAP). They find that this syndrome is the result of hereditary mutations of the APC gene. They soon show that non-inherited (somatic) mutations of this gene initiate colorectal tumors in the general population, causing normal cells to form the precancerous growths known as polyps.
1993 - 1994:
The Vogelstein lab, working with that of Albert de la Chapelle in Finland, discovers that the other major form of hereditary colorectal cancer, hereditary non-polyposis colon cancer (HNPCC), is caused by a gene on chromosome 3 that disrupts normal DNA repair processes. This seminal finding leads Vogelstein’s team and other researchers to clone and identify what are now known as the human mismatch repair genes.
1993 - 1999:
With these discoveries, cancer gene testing was catapulted into mainstream medicine. The Vogelstein lab developed novel tests that could accurately detect the hereditary mutations in a cost-effective and sensitive fashion. This testing is now part of the routine management of patients with strong family histories of colon cancer and has dramatically altered how these patients are diagnosed and treated.
1992 - 2000:
The Vogelstein lab discovers the genes that mediate the effects of the tumor suppressor genes p53, APC, and others. These include genes involved in controlling cell growth, such as p21, 14-3-3 sigma, and b-catenin, as well as genes controlling cell death, such as PUMA. These studies prove enormously valuable for understanding how genetic alterations are translated into tumor development.
1999 - 2004:
The Vogelstein lab initiates another field of cancer research when they describe chromosomal instability (CIN) as a major underlying feature of most human tumors. In addition to outlining the concept, they discover several genes that promote it in various tumor types.
The Vogelstein lab discovers mutations in PIK3CA, a gene whose product modifies lipids. They show that mutations in this gene occur not only in colorectal cancers but also in breast, stomach, brain and other tumors. The PIK3CA is now recognized to be the most highly mutated oncogene yet identified in human cancers.
The Vogelstein lab develops new tests to detect pre-symptomatic colorectal tumors on the basis of mutant genes that escape into the stool or blood. They develop highly sophisticated technologies that can detect one mutant DNA molecule among 10,000 normal copies derived from non-cancer cells. These tests have the capacity to revolutionize non-invasive testing for colon and other cancers and prevent hundreds of thousands of needless deaths.
Close to 200 breast and colon cancer genes are identified by the Vogelstein lab in a landmark study that detailed the first draft of the genetic code for these two deadly cancers. The data is expected to be the foundation of future genetic discoveries that may improve prevention, detection and treatment of cancer.
1995 - 2005:
ScienceWatch names Vogelstein as the most frequently cited scientist in the world, in all fields of science. His work has become the benchmark not only for cancer research but for biomedical research in general.
Vogelstein and colleagues decode the genomes for pancreatic cancer and glioblastoma multiforme, a brain cancer. The findings point to a group of key pathways in both cancers that can be targets for future therapies. In 2011, the scientists also cracked the genomic code for a rare form of pancreatic cancer, called neuroendocrine or islet cell tumors, and pancreatic cysts, which can be precursors to pancreatic cancer. Investigators working with Vogelstein have also mapped the genomes of ovarian cancer, oligodendrogliomas (a common form of brain cancer), liver cancer, and ovarian clear cell cancer.
Vogelstein and colleagues at the Sol Goldman Pancreatic Cancer Research Center used "personalized genome" sequencing on an individual with a hereditary form of pancreatic cancer to locate a mutation in a gene called PALB2 that is responsible for initiating the disease. The discovery marks their first use of a genome scanning system to uncover suspect mutations in normal inherited genes. The findings, they say, underscore the value of so-called "personalized genome" sequencing, which decodes a person's genes and compares the changes to those found in healthy people.
With colleagues in his laboratory, Vogelstein discovered how two cancer-promoting genes enhance a tumor’s capacity to grow and survive under conditions where normal cells die. The knowledge, they say, may offer new treatments that starve cancer cells of a key nutrient – sugar.
Pancreatic cancer develops and spreads much more slowly than scientists have thought, according to research from Vogelstein and colleagues. The finding indicates that there is a potentially broad window for diagnosis and prevention of the disease.
Vogelstein developed a gene-based test to distinguish harmless from precancerous pancreatic cysts. The test may eventually help some patients avoid needless surgery to remove the harmless variety.
A study involving data of thousands of identical twins by Vogelstein and colleagues found that whole genome sequencing fails to provide informative guidance to most people about their risk for most common diseases, and warns against complacency born of negative genome test results.
In a study of 28 advanced colon cancer patients treated with a targeted therapy called panitumumab, Vogelstein and colleagues found that drug resistance mutations appear in the blood of patients about five to seven months after treatment, and low levels of these mutations exist before the therapy begins, making the cancers predestined to recur.