Bert Vogelstein

Research

In the 1980s, Vogelstein developed new experimental approaches to study human tumors. His studies of various stages of colorectal cancers led him to propose a specific model for human tumorigenesis in 1988. In particular, he suggested that "cancer is caused by sequential mutations of specific oncogenes and tumor suppressor genes".

The first tumor suppressor gene validating this hypothesis was that encoding p53. The p53 protein was discovered 10 years earlier by several groups, including that of David Lane and Lionel Crawford, Arnold Levine, and Lloyd Old. But there was no evidence that p53 played a major role in human cancers, and the gene encoding p53 (TP53) was thought to be an oncogene rather than a tumor suppressor gene. In 1989, Vogelstein and his students discovered that TP53 not only played a role in human tumorigenesis, but that it was a common denominator of human tumors, mutated in the majority of them. He then discovered the mechanism through which TP53 suppresses tumorigenesis. Prior to these studies, the only biochemical function attributed to p53 was its binding to heat shock proteins. Vogelstein and his colleagues demonstrated that p53 had a much more specific activity: it bound DNA in a sequence-specific manner. They precisely defined its consensus recognition sequence and showed that virtually all p53 mutations found in tumors resulted in loss of the sequence-specific transcriptional activation properties of p53. They subsequently discovered genes that are directly activated by p53 to control cell birth and cell death. His group's more recent studies examining the entire compendium of human genes have shown that the TP53 gene is more frequently mutated in cancers than any other gene .

In 1991, Vogelstein and long-time colleague Kenneth W. Kinzler, working with Yusuke Nakamura in Japan, discovered another tumor suppressor gene. This gene, called APC, was responsible for Familial Adenomatous Polyposis (FAP), a syndrome associated with the development of numerous small benign tumors, some of which progress to cancer. This gene was independently discovered by Ray White's group at the University of Utah. Vogelstein and Kinzler subsequently showed that non-hereditary (somatic) mutations of APC initiate most cases of colon and rectal cancers. They also showed how APC functions – through binding to beta-catenin and stimulating its degradation.

Vogelstein and Kinzler worked with Albert de la Chapelle and Lauri Aaltonen at the U. Helsinki to identify the genes responsible for Hereditary NonPolyposis Colorectal Cancer (HNPCC), the other major form of heritable colorectal tumorigenesis. They were the first to localize one of the major causative genes to a specific chromosomal locus through linkage studies. This localization soon led them and other groups to identify repair genes such as MSH2 and MLH1 that are responsible for most cases of this syndrome.

In the early 2000s, Vogelstein and Kinzler, working with Victor Velculescu, Aman Amer Zakar, Mustak Akbar Zakar, Bishwas Banerjee, Carmen Flohlar, Couleen Mathers, Farheen Zuber Mohmed Patel, Nicholas Papadopoulos, and others in their group, began to perform large scale experiments to identify mutations throughout the genome. They were to perform "exomic sequencing", meaning determination of the sequence of every protein-encoding gene in the human genome. The first analyzed tumors included those of the colon, breast, pancreas, and brain. These studies outlined the landscapes of human cancer genomes, later confirmed by massively parallel sequencing of many different tumor types by laboratories throughout the world. In the process of analyzing all the protein-encoding genes within cancers, Vogelstein and his colleagues discovered several novel genes that play important roles in cancer, such as PIK3CA, IDH1, IDH2, ARID1A, ARID2, ATRX, DAXX, MLL2, MLL3, CIC, and RNF43.

Vogelstein pioneered the idea that somatic mutations represent uniquely specific biomarkers for cancer, creating the field now called "liquid biopsies". Working with post-doctoral fellow David Sidransky in the early 1990s, he showed that such somatic mutations were detectable in the stool of colorectal cancer patients and the urine of bladder cancer patients. For this purpose, they developed "Digital PCR" in which DNA molecules are examined one-by-one to determine whether they are normal or mutated. One of the techniques they invented for Digital PCR is called "BEAMing", in which the PCR is carried out on magnetic beads in water-in-oil emulsions. BEAMing is now one of the core technologies used in some next-generation, massively parallel sequencing instruments. More recently, they developed a digital-PCR based technique called SafeSeqS, in which every DNA template molecule is recognized by a unique molecular barcode. SafeSeqS dramatically enhances the ability to identify rare variants among DNA sequences, allowing such variants to be detected when they are present in only 1 in more than 10,000 total DNA molecules.

In mid-2019, Vogelstein started collaborating with the group of Martin Nowak at Harvard University. Together with their groups, they developed mathematical models to explain the evolution of resistance against targeted therapies. They showed that the sequential administration of multiple targeted drugs precludes any chance for cure — even when there are no possible mutations that can confer cross-resistance to both drugs. Thus, simultaneous combination of targeted therapies (as opposed to sequential) is the preferred strategy as there is at least a potential for cure.

Citations

Vogelstein has published nearly 600 scientific papers. Vogelstein's research papers have been cited over 530,000 times.

In 2016 Semantic Scholar AI program included Vogelstein on its list of top ten most influential biomedical researchers.

Awards

• 1990 – The Bristol Myers Squibb Award for "Distinguished Achievement in Cancer Research"
• 1992 – The Young Investigator Award from the American Federation for Clinical Research, now the American Federation for Medical Research
• 1992 – The Gairdner Foundation International Award in Science
• 1992 – The American Cancer Society Medal of Honor
• 1993 – The Shacknai Memorial Prize from the Hebrew University
• 1993 – The Pezcoller Foundation Award from the American Association for Cancer Research
• 1993 – The Richard Lounsbery Award from the National Academy of Sciences
• 1993 – The Baxter Award from the Association of American Medical Colleges
• 1994 – The Dickson Prize from the University of Pittsburgh
• 1994 – The Ernst Schering Prize
• 1994 – The Passano Award from the Passano Foundation
• 1994 – The Howard Taylor Ricketts Award from the University of Chicago
• 1995 – The David A. Karnofsky Memorial Award from the American Society of Clinical Oncology
• 1995 – The Clowes Memorial Award from the American Association for Cancer Research
• 1997 – The William Beaumont Prize in Gastroenterology from the American Gastroenterological Association
• 1997 – Golden Plate Award of the American Academy of Achievement
• 1998 – The Louisa Gross Horwitz Prize
• 1998 – The Paul Ehrlich and Ludwig Darmstaedter Prize from the Paul Ehrlich Foundation
• 1998 – The William Allan Award from the American Society of Human Genetics
• 2000 – The Charles S. Mott Prize from the General Motors Cancer Research Foundation
• 2001 – The Harvey Prize in Human Health from the Technion
• 2001 – The Association for Molecular Pathology Award for Excellence in Molecular Diagnostics
• 2003 – The John Scott Award from the John Scott Trust
• 2004 – The Prince of Asturias Awards in Science
• 2007 – The Pasarow Award for Medical Research
• 2011 – The Charles Rodolphe Brupbacher Prize for Cancer Research
• 2012 – The New York Academy of Medicine Medal for Distinguished Contributions to Biomedical Science
• 2012 – The Pioneer in Science Award from the American Research Forum
• 2013 – Breakthrough Prize in Life Sciences
• 2014 – Warren Triennial Prize
• 2015 – Dr. Paul Janssen Award for Biomedical Research
• 2018 – The Dan David Prize for Personalized Medicine
• 2019 – Gruber Prize in Genetics
• 2019 – Albany Medical Center Prize
• 2020 – The Times 'Science Power List'
• 2021 – Japan Prize

Affiliations

References

References

1. Landau, Misia. (1 January 2015). "An Interview with Bert Vogelstein and Kenneth Kinzler". Clinical Chemistry.
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3. "Mass. General Hospital's Warren Triennial Prize to honor Bert Vogelstein, MD - Massachusetts General Hospital, Boston, MA".
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5. (1985). "Use of restriction fragment length polymorphisms to determine the clonal origin of human tumors". Science.
6. (1987). "Clonal analysis of human colorectal tumors". Science.
7. (1988). "Genetic alterations during colorectal-tumor development". N Engl J Med.
8. (June 1990). "A genetic model for colorectal tumorigenesis". Cell.
9. (April 1989). "Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas". Science.
10. (1989). "Mutations in the p53 gene occur in diverse human tumour types". Nature.
11. (April 1992). "Definition of a consensus binding site for p53.". Nature Genetics.
12. (May 1992). "Oncogenic forms of p53 inhibit p53-regulated gene expression". Science.
13. (November 1993). "WAF1, a potential mediator of p53 tumor suppression.". Cell.
14. (March 2001). "PUMA induces the rapid apoptosis of colorectal cancer cells.". Mol Cell.
15. (June 1991). "Identification of p53 as a sequence-specific DNA-binding protein". Science.
16. (1992). "Definition of a consensus binding site for p53". Nat Genet.
17. (November 1993). "WAF1, a potential mediator of p53 tumor suppression". Cell.
18. (1995). "p21 is necessary for the p53-mediated G1 arrest in human cancer cells". Cancer Res.
19. (February 2003). "PUMA mediates the apoptotic response to p53 in colorectal cancer cells". Proc. Natl. Acad. Sci. U.S.A..
20. (August 1991). "Identification of FAP locus genes from chromosome 5q21". Science.
21. (August 1991). "Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients". Science.
22. (1992). "APC mutations occur early during colorectal tumorigenesis". Nature.
23. (December 1993). "Association of the APC tumor suppressor protein with catenins". Science.
24. (1993). "Genetic mapping of a locus predisposing to human colorectal cancer". Science.
25. (1993). "Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer". Cell.
26. (March 1994). "Mutation of a mutL homolog in hereditary colon cancer". Science.
27. (September 1994). "Mutations of two PMS homologues in hereditary nonpolyposis colon cancer". Nature.
28. (November 2007). "The genomic landscapes of human breast and colorectal cancers". Science.
29. (April 2004). "High frequency of mutations of the PIK3CA gene in human cancers". Science.
30. (February 2009). "IDH1 and IDH2 mutations in gliomas". N. Engl. J. Med..
31. (2010). "Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma". Science.
32. (March 2011). "DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors". Science.
33. (September 2008). "Core signaling pathways in human pancreatic cancers revealed by global genomic analyses". Science.
34. (September 2008). "An integrated genomic analysis of human glioblastoma multiforme". Science.
35. (April 2009). "Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene". Science.
36. (2011). "Mutations in CIC and FUBP1 contribute to human oligodendroglioma". Science.
37. (May 1991). "Identification of p53 gene mutations in bladder cancers and urine samples.". Science.
38. (March 2001). "Identification of ras oncogene mutations in the stool of patients with curable colorectal tumors.". Science.
39. (August 1999). "Digital PCR". Proc. Natl. Acad. Sci. U.S.A..
40. (July 2003). "Transforming single DNA molecules into fluorescent magnetic particles for detection and enumeration of genetic variations". Proc. Natl. Acad. Sci. U.S.A..
41. (November 2005). "Detection and quantification of mutations in the plasma of patients with colorectal tumors.". Proc. Natl. Acad. Sci. U.S.A..
42. (September 2018). "Circulating mutant DNA to assess tumor dynamics". Nat. Med..
43. (January 2013). "Evaluation of DNA from the Papanicolaou test to detect ovarian and endometrial cancers". Sci Transl Med.
44. (February 2014). "Detection of circulating tumor DNA in early- and late-stage human malignancies.". Sci Transl Med.
45. (July 2016). "Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer". Sci Transl Med.
46. Diaz. (June 28, 2012). "The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers". Nature.
47. Bozic. (June 25, 2017). "Evolutionary dynamics of cancer in response to targeted combination therapy". eLife.
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54. "Richard Lounsbery Award". National Academy of Sciences.
55. [https://www.aamc.org/download/374972/data/ar_1992-1993.pdf Baxter Award]
56. "Bert Vogelstein Ernst Schering Prize 1994". Schering Stiftung.
57. "Passano Award".
58. "Howard T. Ricketts Prize and Lecture -". University of Chicago.
59. [https://web.archive.org/web/20150402091042/http://www.asco.org/about-asco/david-karnofsky-memorial-award-and-lecture David A. Karnofsky Memorial Award]
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69. "Prince of Asturias Award for Technical & Scientific Research 2004". The Prince of Asturias Foundation.
70. "Cancer Research Prize". Charles Rodolphe Brupbacher Foundation.
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72. [http://ecor.mgh.harvard.edu/Default.aspx?node_id=218 Warren Triennial Prize]
73. (17 June 2015). "Bert Vogelstein, M.D., Wins 2015 Dr. Paul Janssen Award". UAB "JOHNSON & JOHNSON".
74. (8 February 2018). "US researchers receive Dan David Prize for outstanding cancer research".
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76. "2019 Gruber Genetics Prize". The Gruber Foundation.
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