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Retention of Interstitial Genes Between TMPRSS2 and ERG Is Associated with Low-Risk Prostate Cancer Stephen J

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Retention of Interstitial Genes Between TMPRSS2 and ERG Is Associated with Low-Risk Prostate Cancer Stephen J Published OnlineFirst November 10, 2017; DOI: 10.1158/0008-5472.CAN-17-0529 Cancer Tumor and Stem Cell Biology Research Retention of Interstitial Genes between TMPRSS2 and ERG Is Associated with Low-Risk Prostate Cancer Stephen J. Murphy1, Farhad Kosari1, R. Jeffrey Karnes2, Aqsa Nasir1, Sarah H. Johnson1, Athanasios G. Gaitatzes1,3, James B. Smadbeck1, Laureano J. Rangel4, George Vasmatzis1, and John C. Cheville1,5 Abstract TMPRSS2-ERG gene fusions occur in over 50% of prostate interstitial sequences occurred more frequently in very low-risk cancers, but their impact on clinical outcomes is not well tumors. These tumors also frequently displayed ERG gene understood. Retention of interstitial genes between TMPRSS2 fusions involving alternative 50-partners to TMPRSS2,specifi- and ERG hasbeenreportedtoinfluence tumor progression in cally SLC45A3 and NDRG1 and other ETS family genes, which an animal model. In this study, we analyzed the status of retained interstitial TMPRSS2/ERG sequences. Lastly, tumors TMPRSS2-ERG fusion genes and interstitial genes in tumors displaying TMPRSS2-ERG fusions that retained interstitial from a large cohort of men treated surgically for prostate cancer, genes were less likely to be associated with biochemical recur- associating alterations with biochemical progression. Through rence (P ¼ 0.028). Our results point to more favorable clinical whole-genome mate pair sequencing, we mapped and classified outcomes in patients with ETS family fusion-positive prostate rearrangements driving ETS family gene fusions in 133 cases of cancers, which retain potential tumor-suppressor genes in the very low-, low-, intermediate-, and high-risk prostate cancer interstitial regions between TMPRSS2 and ERG. Identifying from radical prostatectomy specimens. TMPRSS2-ERG gene these patients at biopsy might improve patient management, fusions were observed in 44% of cases, and over 90% of these particularly with regard to active surveillance. Cancer Res; 77(22); fusions occurred in ERG exons 3 or 4. ERG fusions retaining 1–11. Ó2017 AACR. Introduction of patients with prostate cancer has remained limited. In the largest cohorts of prostate cancer patients tested to date involving While large advances have been made in the understanding of a combined total of over 5,500 cases, ERG overexpression was not the biology of prostate cancer, there remain significant gaps in our prognostic for biochemical recurrence (BCR) or disease-specific understanding of prostate cancer initiation and progression, and mortality following radical prostatectomy (3–6). In addition, the this affects the management of prostate cancer patients. Clinically, presence of TMPRSS-ERG fusion has not been predictive of biomarkers are needed to better stratify patients that have prostate improved response to radiotherapy, although a link between ETS cancer with a low risk of progression from those at higher risk. This fusions and altered DNA repair mechanisms has been proposed is critically important as many patients are choosing active sur- (7, 8). However, clinical associations have been predicted with veillance with presumptive low-risk disease based on limited ETS fusion status and response to hormonal therapies (3, 9). In sampling of their prostate cancer. Even though more than a several cohorts of active surveillance patients, men whose tumors decade has passed since the discovery of TMPRSS2-ERG gene were ERG fusion positive at diagnosis were more than twice as fusion (1, 2), the impact of this fusion in the clinical management likely to require treatment compared with men with ERG-negative tumors. (10). The ETS-family of transcription factors currently comprises 29 1Biomarker Discovery Program, Center of Individualized Medicine, Mayo Clinic, unique genes in humans, including ERG(21q22), ETV1(7p21), 2 Rochester, Minnesota. Department of Urology, Mayo Clinic, Rochester, Minne- and ETV4(17q21) (11). Conserved ETS DNA-binding domains sota. 3Genomics Systems Unit, Mayo Clinic, Rochester, Minnesota. 4Department define the family members, with additional basic helix-loop-helix of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. 5Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. pointed domains, transcriptional activation and/or inactivation domain variably present, instilling specific cellular functions (12). Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Overexpression of ETS family proteins in prostate cancer is com- monly initiated through the positioning of androgen-responsive S.J. Murphy and F. Kosari contributed equally to this article. promoters in frame with ETS-family member genes, resulting in Corresponding Authors: J.C. Cheville, Mayo Clinic, 200 First St., SE, Rochester, disease-driven oncogenic functions. The androgen-responsive MN 55905. Phone: 507-284-3867; Fax: 507-284-1599; E-mail: gene, TMPRSS2 (21q22), is principally observed fused near its [email protected]; or G. Vasmatzis, [email protected] first exon, placing its promoter in frame with foremost 50-exons of doi: 10.1158/0008-5472.CAN-17-0529 ETS-family transcription factors, retaining their characteristic 0 Ó2017 American Association for Cancer Research. functional domains (1). Although less numerous, additional 5 www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst November 10, 2017; DOI: 10.1158/0008-5472.CAN-17-0529 Murphy et al. fusion partners include other prostate-responsive genes, stitial sequence between TMPRSS2 and ERG is more commonly SLC45A3, NDRG1, HERV-K 22q11.23, and C15orf21, as well as found in low-risk prostate cancer. a strongly expressed housekeeping gene (HNRNPA2B1) with no prostate specificity or androgen-responsiveness (13, 14). Materials and Methods The prevalence of ETS-family fusions in prostate cancer suggests Microarray expression data a significant role in prostate cancer development (1, 15, 16). The Expression analyses used an Affymetrix (U133PLUS2) micro- elucidation of the oncogenic activation of members of the ETS- array dataset from a prior study (29) that included expression family of transcription factors was envisioned to have significant profiles of laser capture microdissected-derived collections of clinical impact in the treatment of prostate cancer and provided prostate tumor cells from Mayo patients including 28 cases of rational therapeutic targets (2). However, although recurrent gene Gleason score 6 (low-risk) and 36 cases of Gleason score 7 and fusions involving ALK, ROS, MET, and ABL have been tremen- higher prostate cancer (intermediate- and high-risk) as well as dously successful therapeutic targets in other cancers, fusions lymph node metastases. Normalized expression values were involving ETS-family of transcription factors have proven noto- computed by the "gcrma" R/Bioconductor package (https:// riously difficult to target (2, 17). ETS members are associated with www.bioconductor.org/). The ERG status of tumors was based the regulation of cell growth, proliferation, differentiation, and on the log intensity values of "213541_s_at" probeset above or apoptosis, through activation or repression of target genes (18). 2 below a threshold of 6. Associations of fusion and BCR status with However, in vivo studies recapitulating ERG or ETV1 expression in gene expression levels were calculated by group t tests and mice fell short of generating carcinoma, resulting only in the corrected for multiple hypotheses testing using the "qvalue" development of prostatic intraepithelial neoplasia (PIN; refs. 12, package in R. Reported values are P values after multiple hypoth- 19, 20). Thus although early acquisition of the fusion suggests a esis correction (q values). role in prostate cancer initiation, ETS fusions could potentially be primers to tumorigenesis, with other subsequent driver muta- tions, such as PTEN loss (21), dictating cancer progression. With Tissue collection and processing no consistent association of TMPRSS2-ERG gene fusion with Consecutive cases selected from the Mayo Clinic prostate clinicopathologic features nor cancer outcome, the prognostic cancer–frozen repository from radical prostatectomy specimens role of TMPRSS2-ERG gene fusions in prostate cancer remains were initially grouped according to Gleason grade group (30), limited (22). with 78 cases of grade group 1 (Gleason 3þ3), 15 cases of grade Although significant biological differences have been observed group 2 (Gleason 3þ4), 13 cases of grade group 3 (Gleason 4þ3), among different ETS family fusions, the clinical impact is still 8 cases of grade group 4 (Gleason 4þ4), and 17 cases of grade emerging (3). The structures of TMPRSS2-ERG fusions have been group 5 (Gleason scores 9 and 10). Grade group 1 was addition- demonstrated to impart differing biological functions in vitro, ally subgrouped according to tumor volume as very low-risk which could potentially influence clinical responses (23, 24). The (clinically insignificant confined grade group 1 Gleason score 6 3 mechanism of the gene fusion may additionally influence prog- cancer with tumor volume less than 0.7 cm ; INS GS6; 53 cases) nosis (25, 26). Two mechanisms of TMPRSS2-ERG fusion have and low-risk larger volume grade group 1 Gleason score 6 (tumor 3 been described that while resulting in structurally identical fusion volume greater than 0.7 cm ; LV GS6; 26 cases). Grade groups 2 products,
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