Bio

Professional Education


  • Doctor of Philosophy, Stanford University, GENE-PHD (2015)
  • Bachelor of Science, University of California Davis, Genetics (2010)

Research & Scholarship

Lab Affiliations


Publications

All Publications


  • Discovery and functional characterization of a neomorphic PTEN mutation PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Costa, H. A., Leitner, M. G., Sos, M. L., Mavrantoni, A., Rychkova, A., Johnson, J. R., Newton, B. W., Yee, M., De La Vega, F. M., Ford, J. M., Krogan, N. J., Shokat, K. M., Oliver, D., Halaszovich, C. R., Bustamante, C. D. 2015; 112 (45): 13976-13981

    Abstract

    Although a variety of genetic alterations have been found across cancer types, the identification and functional characterization of candidate driver genetic lesions in an individual patient and their translation into clinically actionable strategies remain major hurdles. Here, we use whole genome sequencing of a prostate cancer tumor, computational analyses, and experimental validation to identify and predict novel oncogenic activity arising from a point mutation in the phosphatase and tensin homolog (PTEN) tumor suppressor protein. We demonstrate that this mutation (p.A126G) produces an enzymatic gain-of-function in PTEN, shifting its function from a phosphoinositide (PI) 3-phosphatase to a phosphoinositide (PI) 5-phosphatase. Using cellular assays, we demonstrate that this gain-of-function activity shifts cellular phosphoinositide levels, hyperactivates the PI3K/Akt cell proliferation pathway, and exhibits increased cell migration beyond canonical PTEN loss-of-function mutants. These findings suggest that mutationally modified PTEN can actively contribute to well-defined hallmarks of cancer. Lastly, we demonstrate that these effects can be substantially mitigated through chemical PI3K inhibitors. These results demonstrate a new dysfunction paradigm for PTEN cancer biology and suggest a potential framework for the translation of genomic data into actionable clinical strategies for targeted patient therapy.

    View details for DOI 10.1073/pnas.1422504112

    View details for Web of Science ID 000364470300071

  • Transcriptome sequencing from diverse human populations reveals differentiated regulatory architecture. PLoS genetics Martin, A. R., Costa, H. A., Lappalainen, T., Henn, B. M., Kidd, J. M., Yee, M., Grubert, F., Cann, H. M., Snyder, M., Montgomery, S. B., Bustamante, C. D. 2014; 10 (8)

    Abstract

    Large-scale sequencing efforts have documented extensive genetic variation within the human genome. However, our understanding of the origins, global distribution, and functional consequences of this variation is far from complete. While regulatory variation influencing gene expression has been studied within a handful of populations, the breadth of transcriptome differences across diverse human populations has not been systematically analyzed. To better understand the spectrum of gene expression variation, alternative splicing, and the population genetics of regulatory variation in humans, we have sequenced the genomes, exomes, and transcriptomes of EBV transformed lymphoblastoid cell lines derived from 45 individuals in the Human Genome Diversity Panel (HGDP). The populations sampled span the geographic breadth of human migration history and include Namibian San, Mbuti Pygmies of the Democratic Republic of Congo, Algerian Mozabites, Pathan of Pakistan, Cambodians of East Asia, Yakut of Siberia, and Mayans of Mexico. We discover that approximately 25.0% of the variation in gene expression found amongst individuals can be attributed to population differences. However, we find few genes that are systematically differentially expressed among populations. Of this population-specific variation, 75.5% is due to expression rather than splicing variability, and we find few genes with strong evidence for differential splicing across populations. Allelic expression analyses indicate that previously mapped common regulatory variants identified in eight populations from the International Haplotype Map Phase 3 project have similar effects in our seven sampled HGDP populations, suggesting that the cellular effects of common variants are shared across diverse populations. Together, these results provide a resource for studies analyzing functional differences across populations by estimating the degree of shared gene expression, alternative splicing, and regulatory genetics across populations from the broadest points of human migration history yet sampled.

    View details for DOI 10.1371/journal.pgen.1004549

    View details for PubMedID 25121757