Bert Vogelstein

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Bert Vogelstein
Bert Vogelstein giving the Trent Lecture.jpg
Born (1949-06-02) June 2, 1949 (age 67)
Baltimore, Maryland
Institutions Johns Hopkins School of Medicine
Alma mater University of Pennsylvania
Johns Hopkins School of Medicine
Known for p53, Vogelgram, somatic evolution in cancer
Notable awards Breakthrough Prize in Life Sciences (2013)[1]
Warren Triennial Prize (2014)[2]
Spouse Ilene
Website
www.hhmi.org/research/investigators/vogelstein_bio.html

Bert Vogelstein (born 1949) is Director of the Ludwig Center, Clayton Professor of Oncology and Pathology and a Howard Hughes Medical Institute investigator at The Johns Hopkins Medical School and Sidney Kimmel Comprehensive Cancer Center.[3] A pioneer in the field of cancer genomics, his studies on colorectal cancers revealed that they result from the sequential accumulation of mutations in oncogenes and tumor suppressor genes. These studies now form the paradigm for modern cancer research and provided the basis for the notion of the somatic evolution of cancer. Together with Martin Nowak at Harvard University, he developed many mathematical models to understand the evolutionary process of cancer which lead to various hypotheses about mechanisms and timing of progression and seeding of metastases.

Research[edit]

In the 1980s, Vogelstein developed new experimental approaches to study human tumors.[4] 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".[5][6][7]

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.[8][9] 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.[10][11][12][13][14][15]

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.[16][17] 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.[18][19]

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.[20][21][22][23]

Beginning in 2004, Vogelstein and Kinzler, working with Victor Velculescu, Nicholas Papadopoulos and others in their group, began to perform large scale experiments to identify mutations throughout the genome. They were the first 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.[24] 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,[25] IDH1,[26] IDH2,[26] ARID1A,[27] ARID2, ATRX,[28] DAXX,[28] MLL2, MLL3, CIC, and RNF43.[29][30][31][32]

Vogelstein and Kinzler concomitantly, in collaboration with Luis Diaz, developed ways to use these mutations as biomarkers in cancer patients, either for early diagnosis or for monitoring the extent of disease in cancer patients.[33][34] For this purpose, they developed "Digital PCR" in which DNA molecules are examined one-by-one to determine whether they are normal or mutated.[35] 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.[36] BEAMing is now one of the core technologies used in some next-generation, massively parallel sequencing instruments.

In the mid 2000s, 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.[37] 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.[38]

Citations[edit]

Vogelstein has published more than 450 scientific papers since 1976. According to the Institute for Scientific Information (now Thomson-Reuter Essential Science Indicators), Vogelstein's papers have been cited more than 200,000 times, more than those of any other scientist publishing during that time period.

Awards[edit]

Affiliations[edit]

  • Alpha Epsilon Delta (1968)
  • Phi Beta Kappa (1969)
  • The American Academy of Arts & Sciences (1992)
  • The National Academy of Sciences, USA (1992)
  • Alpha Omega Alpha (1995)
  • The American Philosophical Society (1995)
  • The Institute of Medicine (2001)
  • European Molecular Biology Organization (EMBO) (2005)

References[edit]

  1. ^ https://breakthroughprize.org/Laureates/2/L34
  2. ^ a b http://www.massgeneral.org/about/pressrelease.aspx?id=1766
  3. ^ Interview with Bert Vogelstein
  4. ^ Vogelstein B, Fearon ER, Hamilton SR, Feinberg AP. "Use of restriction fragment length polymorphisms to determine the clonal origin of human tumors". Science. 227: 642–5. doi:10.1126/science.2982210. PMID 2982210. 
  5. ^ Fearon ER, Hamilton SR, Vogelstein B. "Clonal analysis of human colorectal tumors". Science. 238: 193–7. doi:10.1126/science.2889267. PMID 2889267. 
  6. ^ Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AM, Bos JL. "Genetic alterations during colorectal-tumor development". N Engl J Med. 319: 525–32. doi:10.1056/NEJM198809013190901. PMID 2841597. 
  7. ^ Fearon ER, Vogelstein B (June 1990). "A genetic model for colorectal tumorigenesis". Cell. 61: 759–67. doi:10.1016/0092-8674(90)90186-i. PMID 2188735. 
  8. ^ Baker SJ, Fearon ER, Nigro JM, et al. (April 1989). "Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas". Science. 244: 217–21. doi:10.1126/science.2649981. PMID 2649981. 
  9. ^ Nigro JM, Baker SJ, Preisinger AC, Jessup JM, Hostetter R, Cleary K, Bigner SH, Davidson N, Baylin S, Devilee P. "Mutations in the p53 gene occur in diverse human tumour types". Nature. 342: 705–8. doi:10.1038/342705a0. PMID 2531845. 
  10. ^ Kern SE, Kinzler KW, Bruskin A, et al. (June 1991). "Identification of p53 as a sequence-specific DNA-binding protein". Science. 252: 1708–11. doi:10.1126/science.2047879. PMID 2047879. 
  11. ^ el-Deiry WS, Kern SE, Pietenpol JA, Kinzler KW, Vogelstein B. "Definition of a consensus binding site for p53". Nat Genet. 1: 45–9. doi:10.1038/ng0492-45. PMID 1301998. 
  12. ^ Kern SE, Pietenpol JA, Thiagalingam S, Seymour A, Kinzler KW, Vogelstein B. "Oncogenic forms of p53 inhibit p53-regulated gene expression". Science. 256: 827–30. doi:10.1126/science.1589764. PMID 1589764. 
  13. ^ el-Deiry WS, Tokino T, Velculescu VE; et al. (November 1993). "WAF1, a potential mediator of p53 tumor suppression". Cell. 75: 817–25. doi:10.1016/0092-8674(93)90500-P. PMID 8242752. 
  14. ^ Waldman T, Kinzler KW, Vogelstein B. "p21 is necessary for the p53-mediated G1 arrest in human cancer cells". Cancer Res. 55: 5187–90. PMID 7585571. 
  15. ^ Yu J, Wang Z, Kinzler KW, Vogelstein B, Zhang L (February 2003). "PUMA mediates the apoptotic response to p53 in colorectal cancer cells". Proc. Natl. Acad. Sci. U.S.A. 100: 1931–6. doi:10.1073/pnas.2627984100. PMC 149936Freely accessible. PMID 12574499. 
  16. ^ Kinzler KW, Nilbert MC, Su LK, et al. (August 1991). "Identification of FAP locus genes from chromosome 5q21". Science. 253: 661–5. doi:10.1126/science.1651562. PMID 1651562. 
  17. ^ Nigro JM, Baker SJ, Preisinger AC, Jessup JM, Hostetter R, Cleary K, Bigner SH, Davidson N, Baylin S, Devilee P. "Mutations in the p53 gene occur in diverse human tumour types". Nature. 342: 705–8. doi:10.1038/342705a0. PMID 2531845. 
  18. ^ Powell SM, Zilz N, Beazer-Barclay Y, Bryan TM, Hamilton SR, Thibodeau SN, Vogelstein B, Kinzler KW. "APC mutations occur early during colorectal tumorigenesis". Nature. 359: 235–7. doi:10.1038/359235a0. PMID 1528264. 
  19. ^ Su LK, Vogelstein B, Kinzler KW (December 1993). "Association of the APC tumor suppressor protein with catenins". Science. 262: 1734–7. doi:10.1126/science.8259519. PMID 8259519. 
  20. ^ Peltomäki P, Aaltonen LA, Sistonen P, Pylkkänen L, Mecklin JP, Järvinen H, Green JS, Jass JR, Weber JL, Leach FS. "Genetic mapping of a locus predisposing to human colorectal cancer". Science. 260: 810–2. doi:10.1126/science.8484120. PMID 8484120. 
  21. ^ Leach FS, Nicolaides NC, Papadopoulos N, Liu B, Jen J, Parsons R, Peltomäki P, Sistonen P, Aaltonen LA, Nyström-Lahti M. "Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer". Cell. 75: 1215–25. doi:10.1016/0092-8674(93)90330-s. PMID 8261515. 
  22. ^ Papadopoulos N, Nicolaides NC, Wei YF, et al. (March 1994). "Mutation of a mutL homolog in hereditary colon cancer". Science. 263: 1625–9. doi:10.1126/science.8128251. PMID 8128251. 
  23. ^ Nicolaides NC, Papadopoulos N, Liu B, et al. (September 1994). "Mutations of two PMS homologues in hereditary nonpolyposis colon cancer". Nature. 371: 75–80. doi:10.1038/371075a0. PMID 8072530. 
  24. ^ Wood LD, Parsons DW, Jones S, et al. (November 2007). "The genomic landscapes of human breast and colorectal cancers". Science. 318: 1108–13. doi:10.1126/science.1145720. PMID 17932254. 
  25. ^ Samuels Y, Wang Z, Bardelli A, et al. (April 2004). "High frequency of mutations of the PIK3CA gene in human cancers". Science. 304: 554. doi:10.1126/science.1096502. PMID 15016963. 
  26. ^ a b Yan H, Parsons DW, Jin G, et al. (February 2009). "IDH1 and IDH2 mutations in gliomas". N. Engl. J. Med. 360: 765–73. doi:10.1056/NEJMoa0808710. PMC 2820383Freely accessible. PMID 19228619. 
  27. ^ Jones S, Wang TL, Shih IeM Mao TL, Nakayama K, Roden R, Glas R, Slamon D, Diaz LA Jr, Vogelstein B, Kinzler KW, Velculescu VE, Papadopoulos N. "Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma". Science. 330: 228–31. doi:10.1126/science.1196333. PMC 3076894Freely accessible. PMID 20826764. 
  28. ^ a b Jiao Y, Shi C, Edil BH, et al. (March 2011). "DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors". Science. 331: 1199–203. doi:10.1126/science.1200609. PMC 3144496Freely accessible. PMID 21252315. 
  29. ^ Jones S, Zhang X, Parsons DW, et al. (September 2008). "Core signaling pathways in human pancreatic cancers revealed by global genomic analyses". Science. 321: 1801–6. doi:10.1126/science.1164368. PMC 2848990Freely accessible. PMID 18772397. 
  30. ^ Parsons DW, Jones S, Zhang X, et al. (September 2008). "An integrated genomic analysis of human glioblastoma multiforme". Science. 321: 1807–12. doi:10.1126/science.1164382. PMC 2820389Freely accessible. PMID 18772396. 
  31. ^ Jones S, Hruban RH, Kamiyama M, et al. (April 2009). "Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene". Science. 324: 217. doi:10.1126/science.1171202. PMC 2684332Freely accessible. PMID 19264984. 
  32. ^ Bettegowda C, Agrawal N, Jiao Y, Sausen M, Wood LD, Hruban RH, Rodriguez FJ, Cahill DP, McLendon R, Riggins G, Velculescu VE, Oba-Shinjo SM, Marie SK, Vogelstein B, Bigner D, Yan H, Papadopoulos N, Kinzler KW. "Mutations in CIC and FUBP1 contribute to human oligodendroglioma". Science. 333: 1453–5. doi:10.1126/science.1210557. PMC 3170506Freely accessible. PMID 21817013. 
  33. ^ Diehl F, Schmidt K, Choti MA, Romans K, Goodman S, Li M, Thornton K, Agrawal N, Sokoll L, Szabo SA, Kinzler KW, Vogelstein B, Diaz LA (2008). "Circulating mutant DNA to assess tumor dynamics". Nat. Med. 14: 985–90. doi:10.1038/nm.1789. PMC 2820391Freely accessible. PMID 18670422. 
  34. ^ Kinde I, Bettegowda C, Wang Y, Wu J, Agrawal N, Shih IeM Kurman R, Dao F, Levine DA, Giuntoli R, Roden R, Eshleman JR, Carvalho JP, Marie SK, Papadopoulos N, Kinzler KW, Vogelstein B, Diaz LA Jr. "Evaluation of DNA from the Papanicolaou test to detect ovarian and endometrial cancers". Sci Transl Med. 5: 167ra4. doi:10.1126/scitranslmed.3004952. PMC 3757513Freely accessible. PMID 23303603. 
  35. ^ Vogelstein B, Kinzler KW (August 1999). "Digital PCR". Proc. Natl. Acad. Sci. U.S.A. 96: 9236–41. doi:10.1073/pnas.96.16.9236. PMC 17763Freely accessible. PMID 10430926. 
  36. ^ Dressman D, Yan H, Traverso G, Kinzler KW, Vogelstein B (July 2003). "Transforming single DNA molecules into fluorescent magnetic particles for detection and enumeration of genetic variations". Proc. Natl. Acad. Sci. U.S.A. 100: 8817–22. doi:10.1073/pnas.1133470100. PMC 166396Freely accessible. PMID 12857956. 
  37. ^ Diaz; et al. (June 28, 2012). "The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers". Nature. 486. doi:10.1038/nature11219. 
  38. ^ Bozic; Reiter; Allen; et al. (June 25, 2013). "Evolutionary dynamics of cancer in response to targeted combination therapy". eLife. 2 (e00747). doi:10.7554/eLife.00747. 
  39. ^ "Past Recipients / Bert Vogelstein". Canada Gairdner Award web site. 
  40. ^ Team BCPS: creating a culture of deliberate excellence, Baltimore County Public Schools
  41. ^ "John Scott Award recipients". 
  42. ^ "Prince of Asturias Award for Technical & Scientific Research 2004". 
  43. ^ "Cancer Research Prize". Charles Rodolphe Brupbacher Foundation. 

External links[edit]