About The Expert

Our Experts

Victor Velculescu, M.D., Ph.D.

Interests:

Molecular genetics of human cancer

Titles

Associate Professor of Oncology

Schools/Degrees

M.D., Medicine, The Johns Hopkins University
Ph.D., Human Genetics and Molecular Biology, The Johns Hopkins University

Training

Postdoctoral Fellowship, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Research Summary

Since joining the faculty, Dr. Velculescu has focused on identifying the genetic basis of colorectal cancer. Over the past several years, he has developed approaches, including high-throughput genomic sequencing, serial analysis of gene expression (SAGE), and a novel method called digital karyotyping, to elucidate the genetic and gene expression differences important in neoplasia. Using these approaches, he has begun to systematically examine the colorectal cancer genome, starting with gene families involved in signal transduction. Members of these gene families have been implicated in human cancer, and the encoded enzymes represent attractive therapeutic targets.

These efforts have recently identified frequent activating mutations in protein and lipid kinases (Bardelli et al, 2003; Samuels et al, 2004) and inactivating mutations in protein phosphatases not previously linked to neoplasia (Wang et al, 2004). For example, he has found genetic alterations in phosphatidylinositol 3-kinase PIK3CA in 30 percent of colon, brain and breast tumors, making this one of the most highly mutated oncogenes yet identified in human cancer. The identification of such genetic alterations provides insight into the pathogenesis of cancer and opens up novel possibilities for diagnostic and therapeutic intervention.

Journal Citations

Yan, H., Parsons, W., Jin, G., McLendon, R., Rasheed, A.B., 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. (2009). IDH1 and IDH2 Mutations in Gliomas. NEJM. 360, 765-773.

Barber, T.D., McManus, K., Yuen, K.W., Reis, M., Parmigiani, G., Shen, D., Barrett, I., Nouhi, Y., Spencer, F., Markowitz, S., Velculescu, V.E., Kinzler, K.W., Vogelstein, B., Lengauer, C., and Hieter, P. (2008). Chromatid cohesion defects may underlie chromosome instability in human colorectal cancers. Proc Natl Acad Sci U S A 105, 3443-3448.

Chan, T.A., Glockner, S., Yi, J.M., Chen, W., Van Neste, L., Cope, L., Herman, J.G., Velculescu, V., Schuebel, K.E., Ahuja, N., and Baylin, S.B. (2008). Convergence of mutation and epigenetic alterations identifies common genes in cancer that predict for poor prognosis. PLoS Med 5, e114

He, Y., Vogelstein, B., Velculescu, V.E., Papadopoulos, N., and Kinzler, K.W. (2008). The antisense transcriptomes of human cells. Science 322, 1855-1857.

Jones, S., Chen, W.D., Parmigiani, G., Diehl, F., Beerenwinkel, N., Antal, T., Traulsen, A., Nowak, M.A., Siegel, C., Velculescu, V.E., Kinzler, K.W., Vogelstein, B., Willis, J., and Markowitz, S.D. (2008). Comparative lesion sequencing provides insights into tumor evolution. Proc Natl Acad Sci U S A 105, 4283-4288.

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. (2008). Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science (New York, N.Y 321, 1801-1806.

Parmigiani, G., Boca, S., Lin, J., Kinzler, K.W., Velculescu, V., and Vogelstein, B. (2009). Design and analysis issues in genome-wide somatic mutation studies of cancer. Genomics 93, 17-21.

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. (2008). An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807-1812.

Velculescu, V.E. (2008). Defining the blueprint of the cancer genome. Carcinogenesis 29, 1087-1091.

Huang, C. H., D. Mandelker, O. Schmidt-Kittler, Y. Samuels, V. E. Velculescu, K. W. Kinzler, B. Vogelstein, S. B. Gabelli, and L. M. Amzel. 2007. The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations. Science 318:1744-8.

Leary, R. J., J. Cummins, T. L. Wang, and V. E. Velculescu. 2007. Digital karyotyping. Nat Protoc 2:1973-86.

Lin, J., C. M. Gan, X. Zhang, S. Jones, T. Sjoblom, L. D. Wood, D. W. Parsons, N. Papadopoulos, K. W. Kinzler, B. Vogelstein, G. Parmigiani, and V. E. Velculescu. 2007. A multidimensional analysis of genes mutated in breast and colorectal cancers. Genome Res 17:1304-18.

Peters, B. A., B. St Croix, T. Sjoblom, J. M. Cummins, N. Silliman, J. Ptak, S. Saha, K. W. Kinzler, C. Hatzis, and V. E. Velculescu. 2007. Large-scale identification of novel transcripts in the human genome. Genome Res 17:287-92.

Rago, C., D. L. Huso, F. Diehl, B. Karim, G. Liu, N. Papadopoulos, Y. Samuels, V. E. Velculescu, B. Vogelstein, K. W. Kinzler, and L. A. Diaz, Jr. 2007. Serial assessment of human tumor burdens in mice by the analysis of circulating DNA. Cancer Res 67:9364-70.

Wood, L. D., D. W. Parsons, S. Jones, J. Lin, T. Sjoblom, R. J. Leary, D. Shen, S. M. Boca, T. Barber, J. Ptak, N. Silliman, S. Szabo, Z. Dezso, V. Ustyanksky, T. Nikolskaya, Y. Nikolsky, R. Karchin, P. A. Wilson, J. S. Kaminker, Z. Zhang, R. Croshaw, J. Willis, D. Dawson, M. Shipitsin, J. K. Willson, S. Sukumar, K. Polyak, B. H. Park, C. L. Pethiyagoda, P. V. Pant, D. G. Ballinger, A. B. Sparks, J. Hartigan, D. R. Smith, E. Suh, N. Papadopoulos, P. Buckhaults, S. D. Markowitz, G. Parmigiani, K. W. Kinzler, V. E. Velculescu, and B. Vogelstein. 2007. The genomic landscapes of human breast and colorectal cancers. Science 318:1108-13.

Bettegowda, C., Huang, X., Lin, J., Cheong, I., Kohli, M., Szabo, S. A., Zhang, X., Diaz, L. A., Jr., Velculescu, V. E., Parmigiani, G., Kinzler, K. W., Vogelstein, B. & Zhou, S. (2006). The genome and transcriptomes of the anti-tumor agent Clostridium novyi-NT. Nat Biotechnol.

Blades, N., Parmigiani, G., and Velculescu, V. (2006). Error Estimation in SAGE Libraries. Genome Biology.

Cummins, J. M. & Velculescu, V. E. (2006). Implications of micro-RNA profiling for cancer diagnosis. Oncogene 25, 6220-7.

Cummins, J. M., He, Y., Leary, R. J., Pagliarini, R., Diaz, L. A., Jr., Sjoblom, T., Barad, O., Bentwich, Z., Szafranska, A. E., Labourier, E., Raymond, C. K., Roberts, B. S., Juhl, H., Kinzler, K. W., Vogelstein, B. & Velculescu, V. E. (2006). The colorectal microRNAome. Proc Natl Acad Sci U S A 103, 3687-92.

Nakayama, K., Nakayama, N., Davidson, B., Katabuchi, H., Kurman, R. J., Velculescu, V. E., Shih Ie, M. & Wang, T. L. (2006). Homozygous deletion of MKK4 in ovarian serous carcinoma. Cancer Biol Ther 5, 630-4.

Nakayama, K., Nakayama, N., Kurman, R. J., Cope, L., Pohl, G., Samuels, Y., Velculescu, V. E., Wang, T. L. & Shih Ie, M. (2006). Sequence mutations and amplification of PIK3CA and AKT2 genes in purified ovarian serous neoplasms. Cancer Biol Ther 5, 779-85.

Parsons, D. W., Wang, T. L., Samuels, Y., Bardelli, A., Cummins, J. M., DeLong, L., Silliman, N., Ptak, J., Szabo, S., Willson, J. K., Markowitz, S., Kinzler, K. W., Vogelstein, B., Lengauer, C. & Velculescu, V. E. (2005). Colorectal cancer: mutations in a signalling pathway. Nature 436, 792.

Samuels, Y., Diaz, L. A., Jr., Schmidt-Kittler, O., Cummins, J. M., Delong, L., Cheong, I., Rago, C., Huso, D. L., Lengauer, C., Kinzler, K. W., Vogelstein, B. & Velculescu, V. E. (2005). Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 7, 561-73.

Sjoblom, T., Jones, S., Wood, L. D., Parsons, D. W., Lin, J., Barber, T. D., Mandelker, D., Leary, R. J., Ptak, J., Silliman, N., Szabo, S., Buckhaults, P., Farrell, C., Meeh, P., Markowitz, S. D., Willis, J., Dawson, D., Willson, J. K., Gazdar, A. F., Hartigan, J., Wu, L., Liu, C., Parmigiani, G., Park, B. H., Bachman, K. E., Papadopoulos, N., Vogelstein, B., Kinzler, K. W. & Velculescu, V. E. (2006). The consensus coding sequences of human breast and colorectal cancers. Science 314, 268-74.

Wood, L. D., Calhoun, E. S., Silliman, N., Ptak, J., Szabo, S., Powell, S. M., Riggins, G. J., Wang, T. L., Yan, H., Gazdar, A., Kern, S. E., Pennacchio, L., Kinzler, K. W., Vogelstein, B. & Velculescu, V. E. (2006). Somatic mutations of GUCY2F, EPHA3, and NTRK3 in human cancers. Hum Mutat 27, 1060-1.

Bachman, K. E., Argani, P., Samuels, Y., Silliman, N., Ptak, J., Szabo, S., et al. 2004. The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol. Ther. 3:772-775.

Barber, T. D., Vogelstein, B., Kinzler, K. W., & Velculescu, V. E. 2004. Somatic mutations of EGFR in colorectal cancers and glioblastomas. New Engl. J. Med. 351:2883.

Bentires-Alj, M., Paez, J. G., David, F. S., Keilhack, H., Halmos, B., Naoki, K., et al. 2004. Activating mutations of the noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. Cancer Res. 64:8816-8820.

Broderick, D. K., Di, C., Parrett, T. J., Samuels, Y. R., Cummins, J. M., Mclendon, R. E., et al. 2004. Mutations of PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas and medulloblastomas. Cancer Res. 64:5048-5050.

Rajagopalan, H., Jallepalli, P., Rago, C., Velculescu, V. E., Kinzler, K. W., Vogelstein, B., et al. 2004. Inactivation of hCDC4 can cause chromosomal instability. Nature. 428:77-81.

Samuels, Y., & Velculescu, V. E. 2004. Oncogenic mutations of PIK3CA in human cancers. Cell Cycle. 3:1221-1224.

Samuels, Y., Wang, Z., Bardelli, A., Silliman, N., Ptak, J., Szabo, S., et al. 2004. High frequency of mutations of the PIK3CA gene in human cancers. Science. 304:554.

Wang, T. L., Diaz, L. A., Romans, K., Bardelli, A., Saha, S., Glizia, G., et al. 2004. Digital karyotyping identifies thymidylate synthase amplification as a mechanism of resistance to 5-FU in metastatic colorectal cancer patients. Proc. Natl. Acad. Sci. USA. 101:3089-3094.

Wang, Z., Cummins, J. M., Shen, D., Cahill, D. P., Jallepalli, P. V., Wang, T. L., et al. 2004. Three classes of genes mutated in colorectal cancers with chromosomal instability. Cancer Res. 64:2998-3001.

Wang, Z., Shen, D., Parsons, D. W., Bardelli, A., Sager, J., Szabo, S., et al. 2004. Mutational analysis of the tyrosine phosphatome in colorectal cancers. Science. 304:1164-1166.