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Loss of 18Q22.3 Involving the Carboxypeptidase of Glutamate-Like Gene Is Associated with Poor Prognosis in Resected Pancreatic Cancer

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Loss of 18Q22.3 Involving the Carboxypeptidase of Glutamate-Like Gene Is Associated with Poor Prognosis in Resected Pancreatic Cancer Published OnlineFirst November 29, 2011; DOI: 10.1158/1078-0432.CCR-11-1903 Clinical Cancer Imaging, Diagnosis, Prognosis Research Loss of 18q22.3 Involving the Carboxypeptidase of Glutamate-like Gene Is Associated with Poor Prognosis in Resected Pancreatic Cancer Jih-Hsiang Lee1, Elisa Giovannetti4, Jin-Hyeok Hwang1,5, Iacopo Petrini1, Qiuyan Wang1, Johannes Voortman1,4, Yonghong Wang2, Seth M. Steinberg3, Niccola Funel6, Paul S. Meltzer2, Yisong Wang1, and Giuseppe Giaccone1 Abstract Purposes: Pancreatic cancer is the fourth leading cause of cancer-related death, and studies on the clinical relevance of its genomic imbalances are warranted. Experimental Design: Recurrent copy number alterations of cytobands and genes were analyzed by array comparative genomic hybridization (aCGH) in 44 resected pancreatic cancer specimens. Prognostic markers identified by aCGH were validated by PCR gene copy number assay in an independent validation cohort of 61 resected pancreatic cancers. The functions of gene identified were evaluated by proliferation, cell cycle, and migration assays in pancreatic cancer cells. Results: We showed recurrent copy number gains and losses in the first cohort. Loss of 18q22.3 was significantly associated with short-term overall survival in the first cohort (P ¼ 0.019). This cytoband includes the carboxypeptidase of glutamate-like (CPGL) gene. CPGL gene deletion was associated with shorter overall survival in the validation cohort (P ¼ 0.003). CPGL deletion and mutations of TP53 or Kras seem to be independent events. A Cox model analysis of the two cohorts combined showed that loss of 18q22.3/deletion of the CPGL gene was an independent poor prognostic factor for overall survival (HR ¼ 2.72, P ¼ 0.0007). Reconstitution of CPGL or its splicing variant CPGL-B into CPGL-negative pancreatic cancer cells attenuated cell growth, migration, and induced G1 accumulation. Conclusion: Loss of 18q22.3/deletion of the CPGL gene is a poor prognostic marker in resected pancreatic cancer, and functional studies suggest the CPGL gene as growth suppressor gene in pancreatic cancer. Clin Cancer Res; 18(2); 524–33. Ó2011 AACR. Introduction stages (4); despite surgery, the median survival for resected pancreatic cancer patients is, however, only 12.6 months Pancreatic cancer is the thirteenth most common cancer (4). The annual age-adjusted cancer death rate due to worldwide (1) and is the fourth leading cause of cancer- pancreatic cancer has not improved in the past 4 decades related death in the United States (2). The prognosis of (2). Adjuvant chemotherapy is the standard treatment, even pancreatic cancer is very poor, with a 5-year survival rate if it is modestly effective and can cause substantial toxicities under 5% (3). Surgical resection is the treatment of choice (5, 6). The role of adjuvant chemoradiotherapy is, however, for resectable disease (3) but is only possible in less than controversial, and 5-FU–based adjuvant chemoradiother- 20% of cases because most tumors are detected at advanced apy alone may worsen survival (6, 7). Few clinicopathologic and biological factors are correlat- ed with prognosis in resected pancreatic cancer. For exam- 1 2 Authors' Affiliations: Medical Oncology Branch, Genetic Branch, and ple, neither expression of p53 nor mutation of the Kras gene 3Biostatistics and Data Management Section, National Cancer Institute, NIH, Bethesda, Maryland; 4Department of Medical Oncology, VU Univer- is a prognostic marker in resected pancreatic cancer patients sity, Amsterdam, the Netherlands; 5Department of Internal Medicine, Seoul who did not receive adjuvant chemotherapy (8, 9). Novel National University Bundang Hospital, Seoul, Republic of Korea; and 6Department of Oncology, University of Pisa, Pisa, Italy biomarkers to accurately predict survival or guide selection of patients for adjuvant treatment are urgently needed. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Given the heterogeneous and complex genetic nature of pancreatic cancer (10), many molecular alterations under- Corresponding Author: Giuseppe Giaccone, Medical Oncology Branch, National Cancer Institute, NIH, 9000 Rockville Pike, Building 10, Room lying progression and response to therapies are yet to be 12N226, Bethesda, MD 20892. Phone: 301-496-4916; Fax: 301-402-0172; identified. E-mail: [email protected] Array-based comparative genomic hybridization (aCGH) doi: 10.1158/1078-0432.CCR-11-1903 analysis has provided a powerful tool to study genomic Ó2011 American Association for Cancer Research. DNA copy number alterations in the cancer genome. aCGH 524 Clin Cancer Res; 18(2) January 15, 2012 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2012 American Association for Cancer Research. Published OnlineFirst November 29, 2011; DOI: 10.1158/1078-0432.CCR-11-1903 18q22.3 and Outcome of Pancreatic Cancer tion were included in the Korean cohort. Formalin-fixed, Translational Relevance paraffin-embedded samples were reviewed to confirm the diagnosis and determine tumor content at Seoul National Array comparative genomic hybridization assay has University Hospital and at National Cancer Institute, NIH, been used to identify genomic imbalance in pancreatic Bethesda, MD. Area with more than 50% of tumor cells was cancer cell lines and small cohorts of pancreatic cancer dissected for DNA extraction. patients, and the clinical relevance of genomic imbal- The Italian validation cohort was composed of frozen ance in pancreatic cancer has not yet been defined. We specimens, resected before chemotherapy from 61 pancre- comprehensively evaluated the association of genomic atic ductal adenocarcinoma Italian patients diagnosed imbalances and clinical outcome of resected pancreatic between 2001 and 2007 at the Regional Referral Center for cancer. We identified that loss of a small cytoband, Pancreatic Disease Treatment, University Hospital of Pisa, 18q22.3, which contains only 5 genes, including the Pisa, Italy. All patients underwent surgery, and adjuvant carboxypeptidase of glutamate-like (CPGL) gene, is asso- treatment consisted of gemcitabine 1,000 mg/m2/d on days ciated with worse prognosis in a testing cohort and an 1, 8, and 15 every 28 days for 2 cycles, followed by gemci- independent validation cohort of resected pancreatic tabine 300 mg/m2 weekly plus concomitant radiation ther- cancers. We showed that reconstitution of the CPGL apy to a total of 45 Gy. DNA was extracted from tumor cells gene, or its splicing variant CPGL-B, into CPGL-negative that were dissected using laser-captured microdissection as pancreatic cancer cells attenuated anchorage-indepen- described previously (31). The purity of tumor cells was dent cell growth and migration and induced G accu- 1 evaluated in 20 specimens by comparing the expression of mulation. These findings suggest that CPGL is a novel keration-7 in the microdissected samples versus in the growth suppressor for pancreatic cancer cells, and risk whole pancreas specimens as described previously (32), stratification based on the CPGL gene is warranted in and the purity was 96%. resected pancreatic cancer. Use of human samples was approved by Institutional Review Boards according to the legal regulations of the participating institutions. Written informed consent was obtained from all patients prior to inclusion in the study. analysis has been shown to be able to identify genetic Pancreatic cancer cell lines PANC-1, SU.86.86, AsPC-1, prognostic factors for several solid tumors, such as non– BxPC-3, and CFPAC-1 were obtained from American Type small cell lung cancer (11), colon cancer (12), breast cancer Culture Collection and were maintained in RPMI contain- (13), and neuroblastoma (14). Although aCGH studies ing 10% FBS. have revealed DNA copy number alterations of pancreatic cancer (15–28), the significance of these efforts were over- DNA and RNA extraction shadowed by small sample size, lack of functional valida- Genomic DNA from cancer cell lines and tumor speci- tion of emerging genes, and lack of clinical correlation. mens were extracted using DNeasy blood & tissue kit The aim of the present aCGH analysis was to identify (Qiagen) according to manufacturer’s protocol. RNA from genes whose copy number alterations might predict the pancreatic cancer cell lines was extracted by TRIzol (Invi- prognosis of resected pancreatic cancer. We employed high- trogen) according to manufacturer’s recommendation. resolution aCGH technology to a cohort of 44 paraffin embedded samples from Korean patients. This represents aCGH analysis the largest series of resected pancreatic carcinomas ever aCGH was done using the Human Genome CGH Micro- investigated by aCGH. In this series, we observed a signif- array 105A (Agilent Technologies Inc.) as described previ- icant association between shorter survival and loss of cyto- ously (33). In brief, genomic DNA was hybridized to a band 18q22.3. Deletion of the carboxypeptidase of gluta- reference male genomic DNA (Promega) using the Genomic mate-like (CPGL) gene, included in this cytoband, was DNA ULS labeling kit (Agilent Technologies Inc.). Slides related to shorter survival in an independent Italian cohort were scanned on an Agilent Microarray Scanner, followed of resected pancreatic cancers. In vitro studies indicated the by data extraction and normalization by Feature Extraction growth suppressor activity of this gene. v10.5 software (Agilent Technologies Inc.). Data analysis was
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