Citations

Abstract The gene KDM6A/UTX was recently identified as a putative tumor suppressor (van Haaften et al). The gene is frequently lost in a variety of malignancies but most commonly in esophageal squamous cell carcinomas (8%) and multiple myeloma (10%). The initial characterization of UTX abnormalities in multiple myeloma utilized a mixture of 58 cell lines and patient samples. To establish the frequency of UTX inactivation in multiple myeloma we studied the copy number profiling dataset (n=239) available from the Multiple Myeloma Genomics Initiative (MMGI) and our internal dataset of 68 human myeloma cell lines which were characterized by array-based CGH (Agilent 400k), whole exome sequencing, and mRNA sequencing. We identified homozygous deletions in 2.5% of patients and 26.5% of cell lines. There are no mutations in the available whole genome and exome sequencing data from 38 patients in the MMGI that partially overlaps the 239 copy number samples sequencing. However, in the cell lines another 14.3% of samples showed loss of UTX through a variety of mechanisms (missense, nonsense, frameshifts, single exon deletions and insertions of LINE elements) detected by exome and mRNA sequencing, bringing the total percentage of cell lines with UTX inactivation to 40.8%. The increased frequency of UTX inactivation in cell lines likely suggests that it is associated with a more aggressive disease or promotes the growth of the tumor outside of the normal bone marrow microenvironment. As part of the cell line characterization phase of the project we found that ARD has a homozygous deletion encompassing the entire UTX locus while its isogenic counterparts, ARP-1 and CAG, express wild-type UTX at a level comparable to other cell lines without UTX abnormalities. To ensure these isogenic cell lines represent the same tumor not different tumors from the same individual we cloned the immunoglobulin receptor rearrangements in all there lines, which confirmed these are derived from the same original tumor. To develop this model system we first generated single cell clones from each of the three cell lines. Six clones from each were randomly selected and their DNA content was determined by flow cytometry. In all cases the clones matched the parental population in ploidy (ARD 3.2N, ARP 3.3N, CAG 3.8N). We randomly select one subclone from each cell line to characterize in detail using spectral karyotyping, array-based CGH, whole exome sequencing, mRNA sequencing, and CHIP-seq for H3K4me3, H3K27ac, H3K27me1, H3K27me2, and H3K27me3. The detailed characterization of this isogenic model system will make it an excellent platform for future work aimed at understanding how UTX loss contributes to myelomagenesis. Citation Format: Kristi Allen, Venkata Yellapantula, Quan Zhao, David Edwards, Marta Chesi, Leif Bergsagel, John Carpten, Jonathan Keats. Characterization of an isogenic model system for KDM6A/UTX loss in multiple myeloma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5209. doi:10.1158/1538-7445.AM2013-5209

Abstract Matrix metalloproteinases (MMPs), a family of extracellular matrix degrading proteins, have been found to be upregulated in many human cancers and have been shown to contribute to cancer progression. There have been many aborted attempts to target MMPs therapeutically using small molecule inhibitors; the limited selectivity of most MMP inhibitors may be a major factor contributing to their poor effectiveness. As an alternative to small molecule MMP inhibitors, we are developing new methodology to create selective protein inhibitors of MMPs, based on the scaffold of the natural inhibitor TIMP-1, that may be used as protein therapeutics. Because TIMP-1 has a very short plasma half-life, we have developed methods for PEGylation that extend the plasma half-life to about 24h while preserving MMP inhibitory activity, rendering it more suitable for in vivo applications. We have also generated mutations in TIMP-1 that confer selective binding toward particular MMPs. The targets thus far pursued include MMP-9, MMP-3, and MMP-10, which represent therapeutic targets of interest in breast cancer and lung cancer. In the future, the methods developed here can be used to identify TIMP-1 variants selective toward additional MMPs, which may be of utility in the research and treatment of many human cancers. Citation Format: Christine Mehner, Jyotica Batra, Jessica Robinson, Derek C. Radisky, Evette S. Radisky. Engineering TIMP-1 for selective MMP inhibition and future use as a protein therapeutic. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5069. doi:10.1158/1538-7445.AM2013-5069

Abstract Pancreatic ductal adenocarcinoma (PDA) is the 4th leading cause of cancer related death in the U.S. This disease has a poor prognosis due to late detection and rapid progression to metastasis. ADAM10 is a membrane bound metalloproteinase responsible for shedding bioactive molecules and inducing regulated intra-membrane proteolysis of cell surface proteins such as Notch. Both ADAM10 and Notch are highly expressed in patients with PDA, with the latter being implicated in PDA progression. We have found that genetic ablation of ADAM10 in the KrasG12D/+;Ptf1aCre/+ mouse PDA model altered tumor character to favor a cystic phenotype, mixed with low grade pancreatic intraepithelial neoplasia (PanIN) and PDA. Though ADAM10 knockout mice retain the ability to form locally invasive cancer, they live 50% longer than control mice, essentially to a full 2-year life span. The phenotypes we observe closely mimic Notch-2 knockout mice, consistent with ADAM10’s role as the primary Notch activating proteinase. Further examination revealed that ADAM10 knockout mice did not show significant liver metastasis compared to control, despite their local invasiveness. The mechanism through which ADAM 10 controls a cancer cell's ability to establish distant metastases will be explored. Citation Format: Jason C. Hall, Howard C. Crawford. Ablation of a disintegrin and metalloproteinase 10 (ADAM 10) induces significant pancreatic tumor heterogeneity and blocks cancer metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5015. doi:10.1158/1538-7445.AM2013-5015

Abstract Background: Circadian rhythms of biological processes are regulated by endogenous clock genes and clock-controlled genes. Aberrant expression of circadian clock genes may have important consequences on the transactivation of downstream targets that control the cell cycle and cellular proliferation potentially promoting carcinogenesis. Animal models indicate that several circadian rhythm genes are expressed in the ovaries, where they influence and are influenced by estrous cycles. The goal of the current study was to examine the association of circadian gene variants and epithelial ovarian cancer (EOC) risk. Methods: Thirty-one SNPs from five circadian genes (i.e., ARNTL, CRY2, KLF10, NPAS2, PER3, TIMELESS) were genotyped in 14,736 cases and 23,448 control women of European ancestry from 43 studies in the Ovarian Cancer Association Consortium (OCAC), on a custom Illumina iSelect designed for the Collaborative Oncological Gene-Environment Study (COGS). Both invasive cancers combined and the four main histological subtypes (serous [n=8,372], endometroid [n=2,068], clear cell [n=1,025] and mucinous [n=943] were analyzed, SNP analyses were conducted using unconditional logistic regression under a log-additive model. All analyses were adjusted for study site and population substructure. Results: Eleven SNPs were found to be associated with ovarian cancer risk. The SNPs most associated with serous cancer risk were KLF10 rs2513928 (OR=.95 p=6.1x10−3), rs2513927 (OR=1.05 p=6.1x10−3), rs2511703 (OR=1.05 p=9.8x10−3), rs3191333 (OR=1.05, p=1.5x10−2) and NPAS2 rs13012930 (OR=.95, p=3.5x10−2). Endometroid cancer risk was significantly associated with ARNTL SNPs rs10732458 (OR=1.3, p=1.0x10−2) and rs7117836 (OR=1.2, p=4.6x10−2), while clear cell cancer risk was associated with ARNTL rs1562438 (OR=.88, p=1.5x10−2), rs1026071 (OR=.89, p=1.8x10−2), and rs3816360 (OR=.91, p=4.8x10−2) and KLF10 rs2388232 (OR=1.1, p=3.3x10−2). No variants were significantly associated with mucinous cancer risk. Four SNPs in KLF10 were associated with cancer invasiveness; they were rs2513928 (OR=.95, p=1.8x10−3), rs3191333 (OR=1.04, p=1.4x10−2), rs2513927 (OR=1.04, p=1.9x10−2), and rs2511703 (OR=1.03, p=2.8x10−2). Conclusions: Data from the current study suggest that polymorphisms in circadian genes ARNTL, KLF10, and NPAS2 are significantly associated with ovarian cancer histopathologic subtypes and invasiveness. These findings merit further investigation and replication. Funding: R01 CA149429 Citation Format: Heather Jim, Jonathan Tyrer, Hui-Yi Lin, Gang Han, Xiaotao Qu, Ellen L. Goode, Zhihua Chen, Ya-Yu Tsai, Julie M. Cunningham, Edward Iversen, Susan Ramus, Andrew Berchuck, Joellen Schildkraut, Alvaro Monteiro, Simon Gayther, Steven A. Narod, Thomas A. Sellers, Paul Pharoah, Catherine M. Phelan. Variation in circadian rhythm genes influence epithelial ovarian cancer risk and invasiveness. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4850. doi:10.1158/1538-7445.AM2013-4850 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

Abstract NSC 161128 is a phenylurea thiocarbamate that has shown differential activity in the NCI60 anticancer screen and in xenograft models. The best in vivo activity was observed against the DU-145 prostate cell line. Previous studies conducted by DTP/NCI demonstrated that NSC 161128 is rapidly metabolized after administration to mice or rats, with the major detected metabolite being N-methyl-N’-phenylurea (M10). The other putative metabolite(s) arising from cleavage of the N-S bond, dimethyldithiocarbamate (M85) and/or its disulfide [bis(dimethyldithiocarbamoyl)disulfide, M17] were not detected in animal plasma using available methodologies. NSC 161128 was also shown to be rapidly degraded in aqueous solution at low and high pH, forming M10 and M17. As part of the preclinical evaluation of NSC 161128, we developed a sensitive, specific LC/MS/MS method to quantitate NSC 161128, M10 and M17 in biological samples, explored the stability of NSC 161128 in cell culture medium, and characterized the pharmacokinetics and in vivo metabolism of NSC 161128 following i.p. administration to athymic nude mice. We developed and validated suitable positive ionization lc/ms/ms methodology for measuring NSC 161128, M10 and M17. The assay utilized liquid extraction with isopropanol:1-chlorobutane, 1:9 (v/v) and MS/MS detection with the 270>177, 151>94 and 241>120 transitions for NSC 161128, M10 and M17, respectively. Baseline separation was achieved on an Atlantis T3 column under a mobile phase consisting of 40:60 methanol:water containing 0.1% formic acid. Standard curves were linear over the concentration range 1.0-1000 ng/mL with a lower limit of detection of 1.0 ng/mL. The parent compound was stable under acidic and neutral conditions, but some degradation (<10%) was detected under basic conditions. NSC 161128 disappearance (∼20%) was also detected during 24-h incubation in RPMI medium +/- FBS. M10 was a minor product in those same incubations, suggesting that reactive metabolites are not formed in cell culture medium. Rapid degradation of NSC161128 and concomitant formation of M10 was observed in plasma at room temperature. While degradation was reduced by incubation on ice, substantial loss of drug (>40%) was noted within 30 minutes, and samples for pharmacokinetic studies were kept cold and processed quickly to prevent degradation. NSC 161128 pharmacokinetics were characterized in male CD1 mice after i.p. administration of a 200 mg/kg dose. The peak plasma concentration of 255 ng/ml was observed 5 minutes after drug administration and the plasma half-life was 138 min. The peak concentration of 14.7 μg/ml M10 was detected 15 min after the NSC 161128 dose and the half-life was 560 min. Analysis of the pharmacokinetics of the thiol metabolites will be presented. Supported by NCI contract N01-CM-2011-00014. Citation Format: Chad A. Walden, Joel M. Reid, Renee M. McGovern, Joseh M. Covey, Matthew M. Ames. LC/MS/MS assay and mouse pharmacokinetics of the phenylurea thiocarbamate NSC 161128. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4557. doi:10.1158/1538-7445.AM2013-4557

Abstract Resistance to temozolomide (TMZ) in the majority of glioblastoma multiforme (GBM) is mediated by O6-methylguanine methyltransferase (MGMT). In this study, the efficacy of TMZ, a mono-functional methylating agent, was compared to a bi-functional TMZ analog (DP68) and a corresponding mono-functional TMZ analog (DP86) in established glioma lines (T98, U251), primary GBM xenograft lines (GBM12, GBM22, GBM6) and a TMZ-resistant model with high level MGMT expression (GBM12TMZ). Using a combination of CyQuant and neurosphere assays, the IC50 with TMZ treatment for MGMT expressing lines (U251, GBM12, GBM22) was much lower than non-expressing lines (T98, G6, G12TMZ), while all lines were sensitive to DP68 regardless of MGMT status (see Table). In the same assays, cells were less sensitive to DP86, but cytotoxicity was also independent of MGMT status. In both U251 and T98, DP68 resulted in a time-and dose-dependent induction of markers for DNA damage and checkpoint activation (P-H2AX, ATM, KAP1, Chk1 and Chk2) and a pronounced S-phase arrest within 24 hours of treatment. Based on these results and the hypothesis that DP68 induces DNA cross-links, siRNA knockdown was used to further dissect the importance of the ATM and ATR signaling pathways and the Fanconi Anemia (FA) cross-link repair pathway for DP68 cytotoxicity. Compared to no treatment, 1 microM DP68 resulted in 100% relative absorbance in siCONtrol transfected U251 cells, 41% for siATR, 35% for siFANCD2 and 90% for siATM. In contrast, only siATR and not siFAND2 nor siATM sensitized U251 cells to DP86. Similarly, inhibition of ATR (VE-821), but not ATM (KU-60019) potently sensitized cells to DP68 (see Table). Taken together, the inhibitory effects of DP68 are superior to TMZ in the GBM cell lines tested, regardless of MGMT expression. Furthermore, the siRNA and western blotting suggest that recovery from DP68 is dependent on ATR and the FA repair pathway. TMZ (IC50, microM) DP68 (IC50, microM)) DP86 (IC50, microM)) CyQuant Ctrl 1uM VE-821 1uM KU-60019 Ctrl 1uM VE-821 1uM KU-60019 Ctrl 1uM VE-821 1uM KU-60019 U251 25 20 20 2.5 0.8 2.1 70 40 65 T98 >320 200 260 9 2 7 115 60 115 Neurosphere Ctrl VE-821 KU-60019 Ctrl VE-821 KU-60019 Ctrl VE-821 KU-60019 G12 4 3.2 4.2 0.9 0.08 0.7 18 6 18 G22 40 NA NA 1 NA NA 40 NA NA G6 160 NA NA 0.5 NA NA 15 NA NA G12TMZ >300 NA NA 2 NA NA 22 NA NA Citation Format: Ann C. Mladek Tuma, Yulian Ramirez, Dimitrios Pletsas, Richard T. Wheelhouse, Roger M. Phillips, Ross H. Alonzo, Kaitlyn Knudson, Jann N. Sarkaria. Cytotoxicity of a novel bi-functional temozolomide analog, DP68, is independent of MGMT status in glioblastoma models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4476. doi:10.1158/1538-7445.AM2013-4476

Abstract Increasing evidence points towards the importance of epigenetic changes in the pathogenesis of multiple myeloma (MM). The biochemical modifications that govern epigenetics are DNA methylation, and post-translational modifications of histone proteins. Histone methylation is catalyzed by histone methyltransferases (HMT) and histone demethylases (HDMT). The purpose of our study was to interrogate genomics data to identify HMT or HDMT genes that are altered in MM. We mined copy number, gene expression and whole genome sequencing data generated as part of the Multiple Myeloma Research Consortium Genomics Initiative. Collectively, the datasets converged on numerous alterations involving histone methylation of lysine 9 (H3K9). One of these genes, the HDMT JMJD1C, was over-expressed in approximately 15% of MM samples examined. We validated over-expression of JMJD1C expression by RT-PCR in over 50 clinical MM samples and 10 human myeloma cell lines (HMCLs). We also confirmed over-expression of JMJD1C by immunohistochemistry (IHC) in a tissue microarray (TMA) consisting of over 60 MM samples. Next we demonstrated a negative correlation between JMJD1C expression and H3K9 methylation by IHC and western blot in 6/10 HMCL and in over 60% of clinical samples examined on the TMA. This validates the H3K9 demethylase activity of JMJD1C. Furthermore, we demonstrated that, in general, H3K9 methylation, a repressive mark associated with heterochromatin, is low in a large percentage of samples. To study the functional significance, we generated a double knockout isogenic cell line pair in U266 cells using zinc finger nuclease technology. We performed ChIP-seq and RNA-seq analyses to identify genes affected by JMJD1C binding to H3K9. Our data indicate that loss of JMJD1C expression alleviates the repression conferred by H3K9 methylation in MM. Studies are ongoing to realize JMJD1C as a potential and novel therapeutic target in MM. Citation Format: Janine LoBello, Danielle DiPerna, Moly Gale, Aprill Watanabe, Galen Hostetter, Rafael Fonseca, Bodour Salhia. Regulation of H3K9 methylation by the demethyltransferase gene JMJD1C in multiple myeloma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4243. doi:10.1158/1538-7445.AM2013-4243

Abstract Glioblastoma (GB) is the highest grade and most common form of primary adult brain tumors. Despite surgical removal followed by concomitant radiation and chemotherapy with the alkylating agent temozolomide (TMZ), GB tumors develop treatment resistance and recur, invading brain tissue. Impaired response to treatment occurs rapidly conferring a median survival of just fifteen months. Thus, it is necessary to identify the genetic and signaling mechanisms that promote tumor resistance and spread in order to develop targeted therapies to combat this refractory setting. Our lab has previously published a role for the TWEAK-Fn14 ligand-receptor system in GB cell invasiveness and survival. Here we report that SGEF, a RhoG specific guanine nucleotide exchange factor (GEF), is overexpressed in GB tumors and we hypothesize that SGEF plays an important role in promoting TWEAK-Fn14 mediated glioma invasion and survival. We show that upon TWEAK binding to Fn14, SGEF is recruited to the Fn14 cytoplasmic tail. The Fn14-SGEF interaction requires TRAF2 recruitment and leads to activation of Rac1. Importantly, SGEF mRNA expression is elevated in TMZ-resistant primary GB tumor grafts compared to those with known TMZ sensitivity. SGEF mRNA and protein expression are regulated by the TWEAK-Fn14 signaling axis in an NF-κB dependent manner and inhibition of SGEF expression via shRNA shutdown sensitizes glioma cells to TMZ-induced apoptosis and impairs colony formation following TMZ insult. Furthermore, gene expression analysis of SGEF depleted GB cells revealed impaired expression of a network of DNA repair and survival genes including ATM, ATR, BRCA2, and XIAP among others, as well as increased expression of the pro-apoptotic gene BAD. Understanding the role of SGEF in promoting chemotherapeutic resistance may direct the development of novel targeted therapeutics for TMZ refractory, invasive GB cells. Citation Format: Shannon P. Fortin, Ian T. Mathews, Jonathan Rollo, Julianna T.D. Ross, Marc H. Symons, Jann N. Sarkaria, Nhan L. Tran. SGEF is overexpressed in glioblastoma and mediates TWEAK-Fn14 induced cell survival. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4108. doi:10.1158/1538-7445.AM2013-4108

Abstract Definitive radiotherapy combined with chemotherapy is associated with enhanced locoregional control and clinical outcomes in non-small cell lung cancer (NSCLC) patients who are not candidates for surgery. However, radiation-induced pneumonitis and esophagitis are common dose-limiting inflammatory conditions that occur in these patients. These events can compromise the effect of the overall treatment and reduce quality of life in these patients. It is not clear what factors contribute to differences in the development of toxicities among patients with same clinical or dosimetric parameters. In this study, we conducted a large scale pathway-based analysis to identify inflammation-related genetic variants associated with radiation-induced pneumonitis or esophagitis. In the initial discovery phase, 11,930 inflammation-related genetic variants were genotyped in 243 stage I-III NSCLC patients who were treated with definitive radiotherapy at MD Anderson Cancer Center. A fast-track validation was performed for the top candidate SNPs in an additional 212 NSCLC cases following the same criteria. A total of 14 SNPs and 12 SNPs were validated for pneumonitis and esophagitis, respectively. Meta-analysis was used to summarize the results from two phases. The most significant SNPs for esophagitis and pneumonitis mapped to chromosome 18p (OR=9.05, 95%CI=2.68-30.59, P-meta=3.90×10−4) and 14q (OR=4.75, 95%CI=2.17-10.41, P-meta =9.61×10−5), respectively. To explore the potential underlying mechanisms, we analyzed radiation sensitivity and eQTL relationships of the identified SNPs and their host genes in 277 ethnically defined human lymphoblastoid cell lines. Among the 24 host genes for the 26 identified SNPs, three genes (DDX58, GZMB, CDC2) showed significant association with radiation responses in these cell lines (P<0.05). Moreover, a significant eQTL relationship was identified between CDC2 expression and the genotype of the identified CDC2 SNP (P=0.022). Interestingly, this CDC2 SNP is predicted to create a new miRNA binding site. Luciferase reporter assays to test the influence of this SNP on miRNA regulation is currently ongoing. Our results provide evidence that inflammation-related genetic variants contribute to the development of radiation-induced pneumonitis and esophagitis. The results also suggest that gene expression changes through altered miRNA binding may be an underlying mechanism for these events. Citation Format: Xia Pu, Liewei Wang, Michelle AT Hildebrandt, Yuanqing Ye, Joe Y. Chang, Charles Lu, Heath D. Skinner, Nifang Niu, Gregory D. Jenkins, Ritsuko Komaki, John D. Minna, Jack A. Roth, Richard M. Weinshilboum, Xifeng Wu. Inflammation-related genetic variants predict radiation-induced toxicity following definitive radiotherapy for non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3626. doi:10.1158/1538-7445.AM2013-3626

Abstract Background: Peripheral T-cell lymphomas (PTCLs) represent a heterogeneous group of generally aggressive malignancies, with 5-year overall survival (OS) rates of ∼35%. Only ALK translocations, which define ALK-positive anaplastic large T-cell lymphoma (ALCL), have emerged as a genetic biomarker predicting favorable outcome following conventional chemotherapy (e.g. CHOP). Using next-generation sequencing, we discovered additional recurrent chromosomal translocations in PTCLs involving either the DUSP22 locus on 6p25.3 or TP63 on 3q28. The purpose of this study was to evaluate the prognostic utility of combined testing for both these events in PTCL patients. Methods: We examined the clinicopathologic features of 134 systemic PTCLs using WHO criteria, including 49 ALCLs, 23 angioimmunoblastic PTCLs, 50 PTCLs of “not otherwise specified” type, and 12 PTCLs of other subtypes. Immunohistochemistry was used to determine ALK expression, an established surrogate for ALK translocations in ALCL. Fluorescent in situ hybridization (FISH) was performed to detect translocations of DUSP22 or TP63 in all cases. OS was plotted using the Kaplan-Meier method. Comparisons were made using the log-rank test. Results: There were 83 males and 51 females, with a mean age of 58 years (range, 6 to 90 years). Median OS for all patients was 22 months (5-year OS, 36%) with a median follow-up of 24 months (range, 0.1 to 354 months). Translocations of DUSP22, TP63, and ALK were mutually exclusive. Patients with ALK-positive ALCL (n=17) had a median OS of 176 months (median follow-up, 68 months; 5-year OS, 69%). Despite being ALK-negative, cases with translocations of DUSP22 or TP63 shared pathologic features with ALCL. Median OS was not reached in patients with DUSP22 translocations (n=7; median follow-up, 88 months; 5-year OS, 100%). Patients with tumors harboring TP63 translocations (n=9) had a median OS of 13 months (all dead at 76 months; 5-year OS, 11%). Patients with none of these abnormalities (n=101) had a median OS of 17 months (median follow-up, 13 months; 5-year OS, 29%). Differences in OS among these groups were highly significant (p=0.0002). Conclusions: PTCLs with DUSP22 translocations had a favorable prognosis similar to ALK-positive ALCLs. In contrast, TP63 were associated with very poor prognosis. FISH for these biomarkers is a promising tool for risk stratification, particularly since both translocations occurred in cases with overlapping pathologic features. PTCLs with DUSP22 translocations may represent a genetically defined subset of ALK-negative ALCLs. Like patients with ALK-positive ALCLs, these patients may not derive additional benefit from intensified up-front strategies such as early transplantation. Patients with none of these abnormalities comprised 75% of patients studied and had an intermediate prognosis, indicating the need for additional biomarkers in this group to improve risk stratification. Citation Format: Edgardo R. Parrilla Castellar, George Vasmatzis, Ryan A. Knudson, Rhett P. Ketterling, Karen L. Grogg, William R. Macon, Mark E. Law, Stephen M. Ansell, Ahmet Dogan, Andrew L. Feldman. Genetic biomarkers for risk stratification of patients with peripheral T-cell lymphoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3538. doi:10.1158/1538-7445.AM2013-3538