<html> <head> <title>David Quigley - UCSF - Cancer Genetics</title> <style> p { font-family: "Arial", Sans-serif; } .div { font-family: "Arial", Sans-serif; } div.breadcrumbs { font-family: "Arial", Sans-serif; font-size:100%; font-weight:bold; background-color:#C2E0FF; padding: 5px; margin-bottom: 5px; } div.header{ font-family: "Arial", Sans-serif; font-size:125%; font-weight:bold } div.header_divider { font-family: "Gill Sans", "Arial", Sans-serif; font-size:150%; font-weight:bold; border-bottom: solid #C2E0FF; padding-bottom: 2px; margin-top: 5px; margin-bottom: 5px; } div.body{ font-family: "Arial", Sans-serif; } div.summary{ font-family: "Arial", Sans-serif; margin-left: 120px; background-color: #efefef; padding: 4px; width: 50% } div.citation{ margin-left: 100px; margin-right: 100px; margin-top: 30px; margin-bottom: 5px; } </style> </head> <body> <div class="header">David Quigley, PhD</div> <div class="breadcrumbs"> Research Summary &nbsp;&nbsp;-&nbsp;&nbsp; <a href="CV_David_Quigley_2018.pdf">CV</a> &nbsp;&nbsp;-&nbsp;&nbsp; <a href="publications.html">Publications</a> &nbsp;&nbsp;-&nbsp;&nbsp; <a href="/carmen">CARMEN</a> &nbsp;&nbsp;-&nbsp;&nbsp; <a href="equalizer.html">equalizer</a> &nbsp;&nbsp;-&nbsp;&nbsp; <a href="prostate.html">Prostate Cancer</a> </div> <br /> <div class="header_divider">The genomics of prostate cancer</div> <div class="body"> I am a translational geneticist focused on understanding metastatic cancer, with a focus on prostate cancer. My research in <a href="http://cancer.ucsf.edu/people/profiles/ashworth_alan.5757">Alan Ashworth s laboratory</a> at the <a href="http://cancer.ucsf.edu">UCSF Helen Diller Comprehensive Cancer Center</a>, and in collaboration with the UCSF SU2C/PCF West Coast Dream Team, focuses on: <ol> <li>how alterations in DNA repair genes affect tumor genomes</li> <li>detecting and overcoming resistance to targeted therapy</li> </ol> Our <a href="https://www.ncbi.nlm.nih.gov/pubmed/28450426">2017 paper in Cancer Discovery</a> provided the first demonstration of multi-clonal <i>BRCA2</i> reversion mutations in metastatic prostate cancer patients who developed resistance to talazoparib and olaparib using liquid biopsy</a>. More recently, I was a lead author on a large whole genome study of metastatic prostate cancer. This study was <a href=" https://www.cell.com/cell/fulltext/S0092-8674(18)30842-0">recently published in Cell</a>. Key findings from this paper include: <ul> <li>Deep whole genome and transcriptome sequencing of 101 prostate cancer metastases</li> <li>Tandem duplication affects intergenic regulatory loci upstream of <i>AR</i> and <i>MYC</i></li> <li>Inactivation of <i>CDK12</i>, <i>TP53</i>, and <i>BRCA2</i> affect distinct classes of structural variants</li> <li>Androgen receptor is affected by mutation or structural variation in 85% of mCRPC</li> </ul> Data and analysis from this paper are <a href="/prostate.html">available on this website</a>. </div> <br> <div class="header_divider">Contact</div> <div class="body"> <table width="100%" border="0" cellpadding="1" cellspacing="0"> <tr><td class="contact" width="75">Email</td><td><i>David.Quigley</b></i> at <i>ucsf.edu</i></td></tr> <tr><td class="contact" valign="top">Address</td> <td>UCSF Helen Diller Comprehensive Cancer Center<BR> 1450 Third St. Room 207<BR> Box 0128<BR> San Francisco, CA 94143-0875</td></tr> </table> </div> <br /> <div class="header_divider">Genetics and Genomics of cancer susceptibility</div> <img src="images/figure1.png" align="right"> <div class="body"> The first step in understanding the genetic architecture of human disease is to identify germline and acquired genetic variants associated with disease initiation or progression. <br /><br /> A cancer susceptibility locus may encompass hundreds of genes. To identify the relevant targets of the variant we have taken a <b>systems genetics</b> approach that measures the influence of that locus on intermediate phenotypes such as mRNA expression or DNA copy number changes. This influence is then synthesized through a data-driven approach guided by a biological understanding of the affected tissue. I have used genetically heterogeneous mouse models of skin cancer to identify networks of <b>expression Quantitative Trait Loci (QTL)</b> associated with sets of genes that are functionally related because they produce proteins that are part of a common structure or because they are steps in a gene pathway. This approach is reviewed in (<a href="http://www.ncbi.nlm.nih.gov/pubmed/19636343">Quigley et al. Nature Reviews: Cancer 2009</a>). <br /><br /> Combining these networks with phenotype QTL identified plausible candidate genes under common genetic control with matched phenotypes (e.g., hemoglobin pathway genes that share common genetic control with the Red Blood Cell count phenotype). We used this method to identify the stem cell marker <i>Lgr5</i> as a candidate driver of normal hair follicle activity and the vitamin D receptor as a driver of skin tumor development (<a href="http://www.ncbi.nlm.nih.gov/pubmed/19136944" alt="Pubmed">Quigley et al. Nature 2009</a>). </div> <br /> <div class="header_divider"> Tumor context interacts with germline and somatic variation </div> <div class="body"> As tumors develop, germline influence on gene expression is supplanted by the effects of <b>somatic genome alterations and changes in the tumor microenvironment</b>. The DMBA/TPA mouse skin tumor system develops frequent trisomy on chromosome seven. I showed that genes on this chromosome have a disproportionate loss of significant eQTL and corresponding increase in expression of Cyclin D1, a driver of tumorigenesis located on chromosome seven (<a href="http://www.ncbi.nlm.nih.gov/pubmed/21244661">Quigley et al. Genome Biology 2011</a>). I have also used network eQTL methods to identify genetic variants only relevant in the context of a tumor. In my thesis work with Anne-Lise Brresen Dale and Vessela Kristensen at the University of Oslo, I identified a candidate mechanism for the breast cancer susceptibility locus at 5p12 (<a href="http://www.ncbi.nlm.nih.gov/pubmed/24388359">Quigley et al. Molecular Oncology 2014</a>). We showed the risk genotype was associated with increased expression and decreased promoter methylation of <i>MRPS30</i>, a mitochondrial ribosomal protein. This association was exclusive in ER-positive breast tumors and not found in normal breast tissue. In an analysis of somatic <i>TP53</i> mutation in the 2000 tumor METABRIC cohort, we showed that lymphocyte invasion in IC10/Basal-like breast tumors is associated with wild-type <i>TP53</i> (<a href="http://www.ncbi.nlm.nih.gov/pubmed/25351767">Quigley <i>et al.</i>, Molecular Cancer Research 2014</a>). </div> <br /> <div class="header_divider">Collaborations</div> <div class="body"> <p> <a href="http://fenglaboratory.com">Dr. Felix Feng</a>, Genetics of Prostate Cancer<br> <a href="http://cancer.ucsf.edu/people/profiles/small_eric.3671">Dr. Eric Small</a>, Genetics of Prostate Cancer<br> <a href="http://cancer.ucsf.edu/people/profiles/balmain_allan.3777">Dr. Allan Balmain, PhD</a>, Genetics of skin cancer<br> <a href="http://www.ous-research.no/borresen/">Dr. Anne-Lise Brresen-Dale, PhD</a>, Genetics of breast cancer<br> <a href="https://bms.ucsf.edu/faculty/anders-persson-phd">Dr. Anders Persson, PhD</a>, neural stem cells and glioma<br> <a href="http://www.ous-research.no/kristensen/">Dr. Vessela Kristensen, PhD</a>, Genetics of breast cancer<br> <a href="http://bms.ucsf.edu/directory/faculty/anders-persson-phd">Dr. Anders Persson, PhD</a>, Glioblastoma<br> <a href="http://cancer.ucsf.edu/people/weiss_william.php">Dr. William Weiss, MD, PhD</a>, Genetic models of neuroblastoma<br> <a href="http://cancer.ucsf.edu/people/akhurst_rosemary.php">Dr. Rosemary Akhurst, PhD</a>, the role of TGF-Beta in squamous cell carcinomas<br> <a href="http://cancer.ucsf.edu/people/jablons_david.php">Dr. David Jablons, MD</a>, lung adenocarcinoma genetic network analysis<br> <a href="http://www.ncmm.uio.no/research/groups/breast-cancer/hurtado-bio/">Dr. Toni Hurtado, PhD</a>, Estrogen signaling in breast cancer<br> <a href="http://proctor.ucsf.edu/faculty/mcnamara">Dr. Nancy Mcnamera, OD PhD</a>, Inflammatory diseases in the eye<br> <a href="http://proctor.ucsf.edu/faculty/lietman">Dr. Tom Lietman, MD</a>, stochastic modeling of trachoma<br> </p> </div> <div class="body"><i>Updated July 2017</i></div> </body> </html>