Joseph Costello PhD

Associate Professor in Residence of Neurological Surgery

Principal Investigator, Brain Tumor Research Center

Program Member, UCSF Comprehensive Cancer Center Programs in Neurologic Oncology, Cancer Genetics, and Breast Oncology

Read About Dr. Costello's Current Research ►

Dr. Costello's laboratory investigates the role of genetic and epigenetic alterations in the development of sporadic cancers, with a focus on brain tumors. Most sporadic cancers have been described by molecular pathways involving gain and loss of chromosomal regions corresponding to oncogene activation and tumor suppressor gene inactivation, respectively. Such genetic characterizations of sporadic tumors do not take into account epigenetic alterations that may similarly result in abnormal loss or gain of gene activity. Methylation of cytosine in DNA is such a modification that can influence gene expression and chromosome stability. Although DNA methylation patterns can be significantly altered in human cancers, such changes are not detected by typical genetic screening methods.

The Costello lab uses a DNA fingerprinting technique termed Restriction Landmark Genomic Scanning (RLGS) to simultaneously assess the genetic and epigenetic (methylation) status of thousands of gene-associated CpG islands. Their studies have shown that in many human tumor types, the pattern of methylation of CpG island-containing genes is non-random and displays distinct tumor type-specificity. Further results suggested that there are a large number of genes in which methylation, rather than genetic alteration, is the primary mechanism of inactivation. These findings support the proposal that many potentially important cancer genes have remained undiscovered for decades due to the exclusively genetic screening methods used. It is now critically important to identify these genes to determine how the aberrant methylation contributes to malignancy.

Education, Training, and Previous Positions

1994: PhD, Loyola University
1994-1999: Postdoctoral Fellow, Ludwig Institute for Cancer Research, San Diego
2000-Present: Department of Neurological Surgery, UCSF

Selected Honors and Awards

2003: Board of Directors, Epigenetics Society
2005: Director, Epigenetics Division of the UCSF CCC Program in Cell Cycling and Signaling
2005: Karen Osney Brownstein Endowed Chair in Molecular Neuro-Oncology
2005: Human Epigenome Project
2006: Scientific Advisory Council, Brain Tumor Society
2006: External Advisory Board, University of Tokyo; UAB Heflin Center for Human Genetics
2007: International Epigenome Project (AHEAD), committee member
2008: Nature, Invited Reader Panelist

Selected Recent Publications

Silber J, Lim DA, Petritsch C, Persson AI, Maunakea AK, Yu M, Vandenberg SR, Ginzinger DG, James CD, Costello JF, Bergers G, Weiss WA, Alvarez-Buylla A, Hodgson JG. miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med 2008;6:14.
 
Costello JF. Stem cells: Tips for priming potency. Nature 2008;454(7200):45-6.
 
Yi JM, Tsai HC, Glöckner SC, Lin S, Ohm JE, Easwaran H, James CD, Costello JF, Riggins G, Eberhart CG, Laterra J, Vescovi AL, Ahuja N, Herman JG, Schuebel KE, Baylin SB. Abnormal DNA methylation of CD133 in colorectal and glioblastoma tumors. Cancer Res 2008;68(19):8094-103.
 
Smith JF, Mahmood S, Song F, Morrow A, Smiraglia D, Zhang X, Rajput A, Higgins MJ, Krumm A, Petrelli NJ, Costello JF, Nagase H, Plass C, Held WA. Identification of DNA methylation in 3' genomic regions that are associated with upregulation of gene expression in colorectal cancer. Epigenetics 2007;2(3):161-72.
 
Carvalho LH, Smirnov I, Baia GS, Modrusan Z, Smith JS, Jun P, Costello JF, McDermott MW, Vandenberg SR, Lal A. Molecular signatures define two main classes of meningiomas. Mol Cancer 2007;6:64.
 
Brena RM, Costello JF. Genome-epigenome interactions in cancer [Review]. Hum Mol Genet 2007;16 Spec No 1:R96-105.
 
Hong C, Moorefield KS, Jun P, Aldape KD, Kharbanda S, Phillips HS, Costello JF. Epigenome scans and cancer genome sequencing converge on WNK2, a kinase-independent suppressor of cell growth. Proc Natl Acad Sci U S A. 2007;104(26):10974-9.
 
Brena RM, Plass C, Costello JF. Mining methylation for early detection of common cancers. PLoS Med 2006;3(12):e479.
 
Cadieux B, Ching TT, VandenBerg SR, Costello JF. Genome-wide hypomethylation in human glioblastomas associated with specific copy number alteration, methylenetetrahydrofolate reductase allele status, and increased proliferation. Cancer Res 2006;66(17):8469-76.
 
Reynolds PA, Sigaroudinia M, Zardo G, Wilson MB, Benton GM, Miller CJ, Hong C, Fridlyand J, Costello JF, Tlsty TD. Tumor suppressor p16INK4A regulates polycomb-mediated DNA hypermethylation in human mammary epithelial cells. J Biol Chem 2006;281(34):24790-802.
 
Smith JS, Costello JF. A broad band of silence. Nat Genet 2006;38(5):504-6.
 
Feltus FA, Lee EK, Costello JF, Plass C, Vertino PM. DNA motifs associated with aberrant CpG island methylation. Genomics 2006;87(5):572-9.
 
Cuevas IC, Slocum AL, Jun P, Costello JF, Bollen AW, Riggins GJ, McDermott MW, Lal A. Meningioma transcript profiles reveal deregulated Notch signaling pathway. Cancer Res 2005;65(12):5070-5.
 
Ching TT, Maunakea AK, Jun P, Hong C, Zardo G, Pinkel D, Albertson DG, Fridlyand J, Mao JH, Shchors K, Weiss WA, Costello JF. Epigenome analyses using BAC microarrays identify evolutionary conservation of tissue-specific methylation of SHANK3. Nat Genet 2005;37(6):645-51.
 
Hong C, Maunakea A, Jun P, Bollen AW, Hodgson JG, Goldenberg DD, Weiss WA, Costello JF. Shared epigenetic mechanisms in human and mouse gliomas inactivate expression of the growth suppressor SLC5A8. Cancer Res 2005;65(9):3617-23.
 
Stokoe D, Costello JF. Phosphatase and tensin homologue growth suppression without phosphatase. Proc Natl Acad Sci U S A 2005;102(8):2677-8.
 
Costello JF. Comparative epigenomics of leukemia.Nat Genet 2005;37(3):211-2.