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Bert Vogelstein
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 Institutions.〔(Interview with Bert Vogelstein )〕 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 much of modern cancer research.
==Research==
In the 1980s, Vogelstein developed new experimental approaches to study human tumors.〔(Vogelstein, B., Fearon, E. R., Hamilton, S. R., and Feinberg, A. P. Use of restriction fragment length polymorphisms to determine the clonal origin of human tumors. Science 227, 642-645, 1985. )〕 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".〔(Fearon, E. R., Hamilton, S. R., and Vogelstein, B. Clonal analysis of human colorectal tumors. Science 238, 193-197, 1987. )〕〔(Vogelstein, B., Fearon, E. R., Hamilton, S. R., Kern, S. E., Preisinger, A. C., Leppert, M., Nakamura, Y., White, R., Smits, A. M., and Bos, J. L. Genetic alterations during colorectal tumor development. N Engl J Med 319, 525-532, 1988. )〕〔(Fearon, E. R., and Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759-767, 1990. )〕
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.〔(Baker, S. J., Fearon, E. R., Nigro, J. M., Hamilton, S. R., Preisinger, A. C., Jessup, J. M., vanTuinen, P., Ledbetter, D. H., Barker, D. F., Nakamura, Y., White, R., and Vogelstein, B. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science 244, 217-221, 1989. )〕〔(Nigro, J. M., Baker, S. J., Preisinger, A. C., Jessup, J. M., Hostetter, R., Cleary, K., Bigner, S. H., Davidson, N., Baylin, S., Devilee, P., Glover, T., Collins, F. S., Weston, A., Modali, R., Harris, C. C., and Vogelstein, B. Mutations in the p53 gene occur in diverse human tumour types. Nature 342, 705-708., 1989. )〕 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.〔(Kern, S. E., Kinzler, K. W., Bruskin, A., Jarosz, D., Friedman, P., Prives, C., and Vogelstein, B. Identification of p53 as a sequence-specific DNA-binding protein. Science 252, 1708-1711, 1991. )〕〔(el-Deiry, W. S., Kern, S. E., Pietenpol, J. A., Kinzler, K. W., and Vogelstein, B. Definition of a consensus binding site for p53. Nat Genet 1, 45-49, 1992. )〕〔(Kern, S. E., Pietenpol, J. A., Thiagalingam, S., Seymour, A., Kinzler, K. W., and Vogelstein, B. Oncogenic forms of p53 inhibit p53-regulated gene expression. Science 256, 827-830, 1992. )〕〔(El-Deiry, W. S., Tokino, T., Velculescu, V. E., Levy, D. B., Parsons, R., Trent, J. M., Lin, D., Mercer, W. E., Kinzler, K. W., and Vogelstein, B. Waf1, a potential mediator of p53 tumor suppression. Cell 75, 817-825, 1993. )〕〔(Waldman, T., Kinzler, K. W., and Vogelstein, B. P21 is necessary for the p53-mediated G1 arrest in human cancer cells. Cancer Res 55, 5187-5190, 1995. )〕〔(Yu, J., Wang, Z., Kinzler, K. W., Vogelstein, B., and Zhang, L. PUMA mediates the apoptotic response to p53 in colorectal cancer cells. Proc Natl Acad Sci U S A 100, 1931-1936, 2003. )〕
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.〔(Kinzler, K. W., Nilbert, M. C., Su, L. K., Vogelstein, B., Bryan, T. M., Levy, D. B., Smith, K. J., Preisinger, A. C., Hedge, P., McKechnie, D., Finniear, R., Markham, A., Groffen, J., Boguski, M. S., Altschul, S. F., Horii, A., Ando, H., Miyoshi, Y., Miki, Y., Nishisho, I., and Nakamura, Y. Identification of FAP locus genes from chromosome 5q21. Science 253, 661-665, 1991. )〕〔(Nishisho, I., Nakamura, Y., Miyoshi, Y., Miki, Y., Ando, H., Horii, A., Koyama, K., Utsunomiya, J., Baba, S., Hedge, P., Markham, A., Krush, A. J., Petersen, G., Hamilton, S. R., Nilbert, M. C., Levy, D. B., Bryan, T. M., Preisinger, A. C., Smith, K. J., Su, L.-K., Kinzler, K. W., and Vogelstein, B. Mutations of chromosome 5q21 genes in fap and colorectal cancer patients. Science 253, 665-669, 1991. )〕 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.〔(Powell, S. M., Zilz, N., Beazer-Barclay, Y., Bryan, T. M., Hamilton, S. R., Thibodeau, S. N., Vogelstein, B., and Kinzler, K. W. APC mutations occur early during colorectal tumorigenesis. Nature 359, 235-237, 1992. )〕〔(16. Su, L. K., Vogelstein, B., and Kinzler, K. W. Association of the APC tumor suppressor protein with catenins. Science 262, 1734-1737, 1993. )〕
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.〔(Peltomaki, P., Aaltonen, L. A., Sistonen, P., Pylkkanen, L., Mecklin, J. P., Jarvinen, H., Green, J. S., Jass, J. R., Weber, J. L., Leach, F. S., Petersen, G. M., Hamilton, S. R., de la Chapelle, A., and Vogelstein, B. Genetic mapping of a locus predisposing to human colorectal cancer. Science 260, 810-812, 1993. )〕〔(Leach, F. S., Nicolaides, N. C., Papadopoulos, N., Liu, B., Jen, J., Parsons, R., Peltomaki, P., Sistonen, P., Aaltonen, L. A., Nystrom-Lahti, M. Guan, X-Y., Zhang, J., Meltzer, P.S., Yu, J-W., Kao, F-T., Chen, D.J., Cerosaletti, K.M., Fournier, R.E.K., Todd, S., Lewis, T., Leach, R.J., Naylor, S.L., Weissenbach, J., Mecklin, J-P., Jarvinen, H., Petersen, G.M., Hamilton, S.R., Green, J., Jass, J., Watson, P., Lynch, H.T., Trent, J.M., de la Chapelle, A., Kinzler, K.W., and Vogelstein, B., Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75, 1215-1225, 1993. )〕〔(Papadopoulos, N., Nicolaides, N. C., Wei, Y. F., Ruben, S. M., Carter, K. C., Rosen, C. A., Haseltine, W. A., Fleischmann, R. D., Fraser, C. M., Adams, M. D., Venter, J.C., Hamilton, S.R., Petersen, G.M., Watson, P., Lynch, H.T., Peltomaki, P., Mecklin, J-P., de la Chapelle, A., Kinzler, K.W., Vogelstein, B. Mutation of a mutL homolog in hereditary colon cancer. Science 263, 1625-1629, 1994. )〕〔(23. Nicolaides, N. C., Papadopoulos, N., Liu, B., Wei, Y. F., Carter, K. C., Ruben, S. M., Rosen, C. A., Haseltine, W. A., Fleischmann, R. D., Fraser, C. M., Adams, M. D., Venter, J. C., Dunlop, M. G., Hamilton, S. R., Petersen, G. M., De la Chapelle, A., Vogelstein, B., and Kinzler, K.W. Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 371, 75-80, 1994. )〕
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.〔(Wood, L. D., Parsons, D. W., Jones, S., Lin, J., Sjoblom, T., Leary, R. J., Shen, D., Boca, S. M., Barber, T., Ptak, J., Silliman, N., Szabo, S., Dezso, Z., Ustyanksky, V., Nikolskaya, T., Nikolsky, Y., Karchin, R., Wilson, P. A., Kaminker, J. S., Zhang, Z., Croshaw, R., Willis, J., Dawson, D., Shipitsin, M., Willson, J. K., Sukumar, S., Polyak, K., Park, B. H., Pethiyagoda, C. L., Pant, P. V., Ballinger, D. G., Sparks, A. B., Hartigan, J., Smith, D. R., Suh, E., Papadopoulos, N., Buckhaults, P., Markowitz, S. D., Parmigiani, G., Kinzler, K. W., Velculescu, V. E., and Vogelstein, B. The genomic landscapes of human breast and colorectal cancers. Science 318, 1108-1113, 2007. )〕 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,〔(Samuels, Y., Wang, Z., Bardelli, A., Silliman, N., Ptak, J., Szabo, S., Yan, H., Gazdar, A., Powell, S.M., Riggins, G.J., Willson, J.K., Markowitz, S., Kinzler, K.W., Vogelstein, B. and Velculescu, V.E. High frequency of mutations of the PIK3CA gene in human cancers. Science 304: 554, 2004. )〕 IDH1,〔(Yan, H., Parsons, D.W., Genglin, J., McLendon, R., Rasheed, B.A., Yuan, W., Kos, I., Batinic-Haberle, I., Jones, S., Riggins, G.J., Friedman, H., Friedman, A., Reardon, D., Herndon, J., Kinzler, K.W., Velculescu, V.E., Vogelstein, B. and Bigner, D.D. IDH1 and IDH2 Mutations in Gliomas. New England Journal of Medicine 360: 765-773, 2009. )〕 IDH2,〔 ARID1A,〔(Jones, S., Wang, T.L., Shih,I.M., Mao, T.L., Nakayama, K., Roden, R., Glas, R., Slamon, D., Diaz, L.A. Jr., Vogelstein, B., Kinzler, K.W., Velculescu, V.E. and Papadopoulos, N. Frequent Mutations of Chromatin Remodeling Gene ARID1A in Ovarian Clear Cell Carcinoma. Science, 363: 1532-1543, 2010. )〕 ARID2, ATRX,〔(Jiao, Y., Shi, C., Edil, B.H., de Wilde, R.F., Klimstra, D.S., Maitra, A., Schulick, R.D., Tang, L.H., Wolfgang, C.L., Choti, M.A., Velculescu, V.E., Diaz, L.A. Jr., Vogelstein, B., Kinzler, K.W., Hruban, R.H. and Papadopoulos, N. DAXX/ATRX, MEN1, and mTOR Pathway Genes Are Frequently Altered in Pancreatic Neuroendocrine Tumors. Science,331:1199-2030, 2011. )〕 DAXX,〔 MLL2, MLL3, CIC, and RNF43.〔(Jones, S., Zhang, X., Parsons, D.W., Lin, J.C., Leary, R.J., Angenendt, P., Mankoo, P., Carter, H., Kamiyama, H., Jimeno, A., Hong, S.M., Fu, B., Lin, M.T., Calhoun, E.S., Kamiyama, M., Walter, K., Nikolskaya, T., Nikolsky, Y., Hartigan, J., Smith, D.R., Hidalgo, M., Leach, S.D., Klein, A.P., Jaffee, E.M., Goggins, M., Maitra, A., Iacobuzio-Donahue, C., Eshleman, J.R., Kern, S.E., Hruban, R.H., Karchin, R., Papadopoulos, N., Parmigiani, G., Vogelstein, B., Velculescu, V.E. and Kinzler, K.W. Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses. Science 321:1801-1806, 2008. )〕〔(Parsons, D.W., Jones, S., Zhang, X., Lin, J.C., Leary, R.J., Angenendt, P., Mankoo, P., Carter, H., Siu, I.M., Gallia, G.L., Olivi, A., McLendon, R., Rasheed, B.A., Keir, S., Nikolskaya, T., Nikolsky, Y., Busam, D.A., Tekleab, H., Diaz, L.A. Jr, Hartigan, J., Smith, D.R., Strausberg, R.L., Marie, S.K., Shinjo, S.M., Yan, H., Riggins, G.J., Bigner, D.D., Karchin, R., Papadopoulos, N., Parmigiani, G., Vogelstein, B., Velculescu, V.E. and Kinzler K.W. An Integrated Genomic Analysis of Human Glioblastoma Multiforme. Science 321:1807-1812 2008. )〕〔(Jones, S., Hruban, R.H., Kamiyama, M., Borges, M., Zhang, X., Parsons, D.W., Lin, Cheng-Ho, J., Palmisano, E., Brune, K., Jaffee, E.M., Iacobuzio-Donahue, C.A., Maitra, A., Parmigini, G., Kern, S.E., Velculescu, V.E., Kinzler, K.W., Vogelstein, B., Eshleman, J.R., Goggins, M. and Klein, A. Exomic Sequencing Identifies PALB2 as a Pancreatic Cancer Susceptibility Gene. Science 324: 217, 2009. )〕〔(Bettegowda, C., Agrawal, N., Jiao, Y., Sausen, M., Wood, L.D., Hruban, R.H., Rodriguez, F.J., Cahill, D.P., McLendon, R., Riggins, G., Velculescu, V.E., Oba-Shinjo, S.M., Marie, S.K.N, Vogelstein, B., Bigner, D., Yan, H., Papadopoulos, N., Kinzler, K.W. Mutations in CIC and FUBP1 contribute to human oligodendrogliomas. Science, 333: 1453-1455, 2011. )〕
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.〔(Diehl, F., Schmidt, K., Choti, M.A., Romans, K., Goodman, S., Li, M., Thornton, K., Agrawal, N., Sokoll, L., Szabo, S.A., Kinzler, K.W., Vogelstein, B. and Diaz Jr., L.A. Circulating mutant DNA to assess tumor dynamics. Nature Medicine 14: 985-990, 2008. )〕〔(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: 167-172, 2013. )〕 For this purpose, they developed "Digital PCR" in which DNA molecules are examined one-by-one to determine whether they are normal or mutated.〔(Vogelstein, B. and Kinzler, K.W. Digital PCR. Proceedings of the National Academy of Sciences, U.S.A. 96: 9236-9241, 1999. )〕 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.〔(Dressman, D., Yan, H., Traverso, G., Kinzler, K.W. and Vogelstein, B. Transforming single DNA molecules into fluorescent magnetic particles for detection and enumeration of genetic variations. Proceedings of the National Academy of Sciences, U.S.A. 100: 8817-8822, 2003. )〕 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. 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.
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