Last Updated: 7/25/2009

Research Interests
Cancer is fundamentally a disease of genomic aberrations: tumor genomes harbor mutations in key genes that lead to uncontrolled proliferation. With new developments in sequencing technologies, we can now survey the complete list of mutations in an individual tumor. My research group will develop bioinformatics tools to decipher the phenotypic effects of mutations in tumor genomes. Our overarching goal is to identify oncogenic mutations in tumor genomes that represent genetic vulnerabilities, and thus targets for individualized cancer therapy.

1) Oncogene discovery in hepatocellular carcinoma
Hepatocellular carcinomas (HCC) represents the third most lethal malignancy worldwide, causing over 600,000 deaths each year. More than 85% of HCC result from chronic infection with hepatitis B or C virus. In previous work, we characterized copy number alterations in the genomes of 103 tumors from hepatitis C virus positive patients. We found amplifications and overexpression of VEGFA in a subset of tumors, thus representing a novel mechanism for stimulating angiogenesis. In addition, we identified a new molecular class of HCC defined by the polysomy of chromosome 7. We are continuing to pioneer new sequencing technologies to discover mutations and copy number alterations in HCC from different etiologies. The oncogenic roles of these mutations will be assessed with both gain-of-function and loss-of-function experiments.

2) Genomic predictors of therapeutic response
In some cases, mutations in certain genes represent critical genetic dependencies for specific tumor types. In recent years, a handful of molecular inhibitors have emerged as effective therapies in tumors with genetic alterations in tyrosine kinases. One of these inhibitors, sorafenib, was reported to significantly extend the survival of advanced hepatocellular carcinoma patients. However, the physiological target of sorafenib remains unknown. Furthermore, its modest clinical benefit suggests that either patient stratification or combination therapies will increase the efficacy of sorafenib. We will investigate the genetic determinants of response to sorafenib by characterizing mutations in patient samples and cell line models.

3) Copy number alterations in tumor genomes
Tumor genomes harbor dozens of chromosomal gains, losses and rearrangements that often affect oncogenes or tumor suppressors. We developed a segmentation algorithm that maps chromosomal breakpoints that demarcate regions of amplification and deletion in tumor genomes. This computational method achieved 2-fold higher precision than microarrays for mapping the boundaries of copy number gain and loss, while also yielding more accurate measurements of high-level amplifications. We will continue to develop computational tools to find recurrent regions of copy number gains and losses from tumor genome sequencing projects.

Recent Accomplishments and Honors
1996-2000 John Motley Morehead Award, University of North Carolina, Chapel Hill
2000 Phi Beta Kappa, Venable Medal, Walter Spearman Award, University of North Carolina
2000-2001 National Sciences and Engineering Research Council of Canada Scholarship
2001-2005
Howard Hughes Medical Institute Predoctoral Fellowship
2006-2007
Davies Charitable Foundation Research Fellowship Award
2007 American Association for Cancer in Research Scholar-in-Training Award

Training
University of North Carolina, Chapel Hill B.S. 2000 Biochemistry
University of California, Berkeley Ph.D. 2005 Molecular & Cell Biology

Publications
Chiang DY, Getz G, Jaffe DB, O'Kelly MJ, Zhao X, Carter SL, Russ C, Nusbaum C,Meyerson M, Lander ES (2009). High-resolution mapping of copy-number alterations with massively parallel sequencing. Nature Methods 6:99-103.

Chiang DY, Villanueva A, Hoshida Y, Peix J, Newell P, Minguez B, LeBlanc AC, Donovan DJ, Thung SN, Sol M, Tovar V, Alsinet C, Ramos AH, Barretina J, Roayaie S, Schwartz M, Waxman S, Bruix J, Mazzaferro V, Ligon AH, Najfeld V, Friedman SL, Sellers WR, Meyerson M, Llovet JM (2008). Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Research 68:6779-88.

Cancer Genome Atlas Research Network (2008). Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061-8.

E-mail: chiang@med.unc.edu
Telephone: (919) 843-7887
Address: 11-129 Lineberger Cancer Center, 450 West Drive CB #7295, Chapel Hill, NC 27599

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