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Systematic Interrogation of 3Q26 Identifies TLOC1 and SKIL As Cancer Drivers

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Systematic Interrogation of 3Q26 Identifies TLOC1 and SKIL As Cancer Drivers Published OnlineFirst June 13, 2013; DOI: 10.1158/2159-8290.CD-12-0592 RESEARCH ARTICLE Systematic Interrogation of 3q26 Identifi es TLOC1 and SKIL as Cancer Drivers Daniel Hagerstrand 1 , Alexander Tong 1 , Steven E. Schumacher 2 , 5 , Nina Ilic 1 , Rhine R. Shen 1 , Hiu Wing Cheung 1 , 5 , Francisca Vazquez 1 , 5 , Yashaswi Shrestha 1 , 5 , So Young Kim 1 , 6 , Andrew O. Giacomelli 1 , Joseph Rosenbluh 1 , 5 , Anna C. Schinzel 1 , Nicole A. Spardy 1 , David A. Barbie 1 , 5 , Craig H. Mermel 1 , 5 , Barbara A. Weir 5 , Levi A. Garraway 1 , 3 , 5 , Pablo Tamayo 5 , Jill P. Mesirov 5 , Rameen Beroukhim 1 , 2 , 3 , 5 , and William C. Hahn 1 , 3 , 4 , 5 Downloaded from cancerdiscovery.aacrjournals.org on September 29, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst June 13, 2013; DOI: 10.1158/2159-8290.CD-12-0592 ABSTRACT 3q26 is frequently amplifi ed in several cancer types with a common amplifi ed region containing 20 genes. To identify cancer driver genes in this region, we inter- rogated the function of each of these genes by loss- and gain-of-function genetic screens. Specifi cally, we found that TLOC1 (SEC62 ) was selectively required for the proliferation of cell lines with 3q26 amplifi cation. Increased TLOC1 expression induced anchorage-independent growth, and a second 3q26 gene, SKIL (SNON ), facilitated cell invasion in immortalized human mammary epithelial cells. Expres- sion of both TLOC1 and SKIL induced subcutaneous tumor growth. Proteomic studies showed that TLOC1 binds to DDX3X, which is essential for TLOC1-induced transformation and affected protein translation. SKIL induced invasion through upregulation of SLUG (SNAI2 ) expression. Together, these studies identify TLOC1 and SKIL as driver genes at 3q26 and more broadly suggest that cooperating genes may be coamplifi ed in other regions with somatic copy number gain. SIGNIFICANCE: These studies identify TLOC1 and SKIL as driver genes in 3q26. These observations provide evidence that regions of somatic copy number gain may harbor cooperating genes of different but complementary functions. Cancer Discov; 3(9); 1044–57. ©2013 AACR. INTRODUCTION RESULTS The most common alterations found in cancer genomes are recurrent somatic copy number alterations (SCNA; refs. 1, 3q26 Is Frequently Amplifi ed in Ovarian, Breast, 2 ). Although some of these SCNAs harbor known oncogenes and Non–Small Cell Lung Cancers or tumor suppressor genes, the gene(s) targeted by most of We previously used the Genomic Identifi cation of Signifi - these SCNAs remain unclear. For example, a recent study cant Targets in Cancer (GISTIC) analytic approach to identify of more than 3,000 cancer samples identifi ed 158 recurrent recurrent regions of SCNA in a set of 3,131 tumor samples SCNAs in several cancer types, of which 122 did not harbor a ( 1 ). Many of the most frequently amplifi ed regions harbored known oncogene or tumor suppressor gene ( 1 ). known oncogenes, but the identity of specifi c driver genes was 3q26 has been reported to be amplifi ed in several cancer unknown for several recurrently amplifi ed regions. Specifi - types including breast, prostate, ovarian, non–small cell lung, cally, 3q26 was amplifi ed in 22% of these tumor samples, and and head and neck squamous carcinomas. The distal arm 8.4% of tumors harbored focal amplifi cations, as defi ned as a of 3q also contains other oncogene candidates including region less than half a chromosome arm long. The minimal PIK3CA , SOX2 , and TP63 ( 3–5 ). However, the analysis of a common amplifi ed region contained 20 protein-coding genes. large number of human cancers showed that the minimal When we investigated the specifi c cancer types in Tumorscape common amplifi ed region at 3q26 contains 20 genes, which ( 6 ) that harbor this amplicon, we found that 3q26 is ampli- frequently does not include the neighboring genes PIK3CA , fi ed in 43.7% of ovarian, 31.7% of breast, and 31.2% of non– SOX2 , or TP63 . small cell lung carcinomas (NSCLC; ref. 1 ; Fig. 1A ). When we Here, we applied both gain- and loss-of-function approaches interrogated the current Cancer Genome Atlas (TCGA; 5,547 to interrogate the 20 genes resident in the minimal common samples; refs. 2 , 7 ), we found that 3q26 is amplifi ed in lung amplifi ed region of 3q26 for effects on proliferation, anchor- squamous cell (31.5%), serous ovarian (19.3%), cervical squa- age-independent growth, and invasion. We found two genes mous cell (11.8%), head and neck (11.5%), pancreatic (7.1%), that cooperated to confer a tumorigenic phenotype: TLOC1 uterine corpus endometrial (7.1%), and stomach adenocarci- and SKIL . noma cancers (6.1%). Amplifi cation of 3q26 often extends to include larger regions of 3q. Because PIK3CA , SOX2 , and TP63 also reside on Authors’ Affi liations: 1 Departments of Medical Oncology and 2 Cancer 3q, we investigated at what frequency these genes are ampli- Biology; 3 Center for Cancer Genome Discovery, Dana-Farber Cancer Insti- fi ed in conjunction with 3q26. Of more than 3,000 cancer 4 tute; Department of Medicine, Brigham and Women’s Hospital, Harvard samples in Tumorscape, 718 (22%) displayed amplifi cation Medical School, Boston; 5 Broad Institute of Harvard and MIT, Cambridge, Massachusetts; and 6 Department of Molecular Genetics and Microbiology, of 3q26. Of these 718 samples, 59 did not include PIK3CA , Duke University Medical Center, Durham, North Carolina SOX2 , or TP63 ( Fig. 1B ). To investigate whether PIK3CA is Note: Supplementary data for this article are available at Cancer Discovery mutated at a higher frequency in samples that lack amplifi ca- Online (http://cancerdiscovery.aacrjournals.org/). tion of the minimal common amplifi ed region, we analyzed Corresponding Author: William C. Hahn, Dana-Farber Cancer Institute, 450 data from 3,953 samples from the TCGA ( 2 ) for which both Brookline Avenue, Boston, MA 02215. Phone: 617-632-2641; Fax: 617- copy number and mutation information were available. We 632-4005; E-mail: [email protected] found no signifi cant enrichment of PIK3CA mutations in doi: 10.1158/2159-8290.CD-12-0592 samples that either harbor or lack amplifi cation of 3q26 ©2013 American Association for Cancer Research. ( P = 0.37, χ 2 test). Together these observations confi rm that SEPTEMBER 2013CANCER DISCOVERY | 1045 Downloaded from cancerdiscovery.aacrjournals.org on September 29, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst June 13, 2013; DOI: 10.1158/2159-8290.CD-12-0592 RESEARCH ARTICLE Hagerstrand et al. A Samples Ovarian Breast NSCLC EVI1 MDS1 ARPM1 m MYNN ar LRRC34 p 3 LRRC31 SAMD7 e TLOC1 GPR160 PHC3 PRKCI entromer SKIL C CLDN11 SLC7A14 RPL22L1 arm EIF5A2 q 3 SLC2A2 3q26 TNIK PIK3CA PLD1 SOX2 FNDC3B TP63 43.7% 31.7% 31.2% 3q26 Amplification B 3p arm Centromere 3q arm Chromosome 3 170 mb 1801 mb 190 mb 3q region 3q26 PIK3CA SOX2 TP63 Samples Figure 1. 3q26 is frequently amplifi ed in ovarian cancer , breast cancer, and NSCLC. A, copy number plots of the samples in Tumorscape for the q arm of chromosome 3. A vertical line represents each sample, where red represents a high chromosomal copy number ratio, blue represents low, and white represents neutral. Chromosomal bands are shown to the left. Two horizontal blue lines indicate the minimal common amplifi ed region, and the genes are listed to the right. B, illustration of samples with 3q26 amplifi cation. Samples that did not exhibit copy number gain of the PIK3CA , SOX2 , or TP63 locus are shown at the top. The 3q distal regions have been magnifi ed to show the position of these in relation to each other. (continued on following page) 3q26 is frequently amplifi ed in several cancer types in a in 11 cell lines that do or fi ve cell lines that do not harbor manner that is independent of copy number alterations of amplifi cation of 3q26 ( Fig. 1D ). We used RNA interference PIK3CA , SOX2 , or TP63 . (RNAi) Gene Enrichment Ranking (RIGER) analysis ( 8 ) to identify genes that were selectively essential for proliferation Systematic Interrogation of 3q26 Identifi es of cell lines with 3q26 amplifi cation. This method takes the TLOC1 and SKIL as Transforming Genes effect of all shRNAs for one gene into account and compares To identify genes resident in 3q26 that contribute to the score for each gene to other genes. Specifi cally, we sum- malignant transformation, we interrogated the function of marized the effects of multiple shRNAs (fi ve on average) the genes in the region by conducting systematic gain- and targeting each gene into a single fi nal score called normalized loss-of-function studies ( Fig. 1C ). Specifi cally, we suppressed enrichment score (NES), which considers the relative ranking or overexpressed each of the 20 genes present in the minimal of and the magnitude of gene-specifi c suppression effects of common amplifi ed region and assessed the effects on prolif- the shRNAs (Supplementary Table S1). The enrichment score eration, anchorage-independent growth, and invasion. refl ects the degree to which the shRNAs targeting each gene To identify genes whose expression was necessary for the are overrepresented at the top or bottom of the ranked list. proliferation of cell lines that harbored the 3q26 amplicon, The scores are further normalized to account for the size of we conducted an arrayed short hairpin RNA (shRNA) screen each set of shRNAs against each gene to yield a NES. Using 1046 | CANCER DISCOVERYSEPTEMBER 2013 www.aacrjournals.org Downloaded from cancerdiscovery.aacrjournals.org on September 29, 2021. © 2013 American Association
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