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Purposes: To determine whether the deregulation of genes relevant for normal thymus development can contribute to the biology of thymic epithelial tumors (TET).Experimental Design: Using array comparative genomic hybridization, we evaluated the copy number aberrations of genes regulating thymus development. The expression of genes most commonly involved in copy number aberrations was evaluated by immunohistochemistry and correlated with patients' outcome. Correlation between FOXC1 copy number loss and gene expression was determined in a confirmation cohort. Cell lines were used to test the role of FOXC1 in tumors.Results: Among 31 thymus development-related genes, PBX1 copy number gain and FOXC1 copy number loss were presented in 43.0% and 39.5% of the tumors, respectively. Immunohistochemistry on a series of 132 TETs, including those evaluated by comparative genomic hybridization, revealed a correlation between protein expression and copy number status only for FOXC1 but not for PBX1. Patients with FOXC1-negative tumors had a shorter time to progression and a trend for a shorter disease-related survival. The correlation between FOXC1 copy number loss and mRNA expression was confirmed in a separate cohort of 27 TETs. Ectopic FOXC1 expression attenuated anchorage-independent cell growth and cell migration in vitro.Conclusion: Our data support a tumor suppressor role of FOXC1 in TETs. Clin Cancer Res; 19(8); 1960–71. ©2013 AACR.

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 = 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 = 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 = 2.72, P = 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. ©2011 AACR.

PDF file - 3704K, Copy number aberrations of genes regulating normal thymus development in the confirmation cohort.

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PDF file - 2727K, Frequency of FOXC1 copy number loss and PBX1 copy number gain in the WHO histotypes overall in the 2 cohorts.

PDF file - 3599K, Copy number aberrations of genes regulating normal thymus development overall in the 2 cohorts.

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This study determined whether expression levels of a panel of biologically relevant microRNAs can be used as prognostic or predictive biomarkers in patients who participated in the International Adjuvant Lung Cancer Trial (IALT), the largest randomized study conducted to date of adjuvant chemotherapy in patients with radically resected non–small cell lung carcinoma (NSCLC). Expression of miR-21, miR-29b, miR-34a/b/c, miR-155, and let-7a was determined by quantitative real-time PCR in formalin-fixed paraffin-embedded tumor specimens from 639 IALT patients. The prognostic and predictive values of microRNA expression for survival were studied using a Cox model, which included every factor used in the stratified randomization, clinicopathologic prognostic factors, and other factors statistically related to microRNA expression. Investigation of the expression pattern of microRNAs in situ was performed. We also analyzed the association of TP53 mutation status and miR-34a/b/c expression, epidermal growth factor receptor and KRAS mutation status, and miR-21 and Let-7a expression. Finally, the association of p16 and miR-29b expression was assessed. Overall, no significant association was found between any of the tested microRNAs and survival, with the exception of miR-21 for which a deleterious prognostic effect of lowered expression was suggested. Otherwise, no single or combinatorial microRNA expression profile predicted response to adjuvant cisplatin-based chemotherapy. Together, our results indicate that the microRNA expression patterns examined were neither predictive nor prognostic in a large patient cohort with radically resected NSCLC, randomized to receive adjuvant cisplatin-based chemotherapy versus follow-up only. Cancer Res; 70(21); 8288–98. ©2010 AACR.

Supplementary Appendix 1 from MicroRNA Expression and Clinical Outcomes in Patients Treated with Adjuvant Chemotherapy after Complete Resection of Non–Small Cell Lung Carcinoma

Supplementary Figure 1 from MicroRNA Expression and Clinical Outcomes in Patients Treated with Adjuvant Chemotherapy after Complete Resection of Non–Small Cell Lung Carcinoma

Supplementary Tables 1-9 from MicroRNA Expression and Clinical Outcomes in Patients Treated with Adjuvant Chemotherapy after Complete Resection of Non–Small Cell Lung Carcinoma

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 = 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 = 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 = 2.72, P = 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. ©2011 AACR.

Background: Thymic epithelial tumors (TETs) are rare and the genomic aberrations relevant to TET biology are unknown. The goal of this study was to identify recurrent genomic aberrations in TETs. Materials and Methods: From a series of 132 TET resected patients we selected 59 formalin fixed paraffin embedded (FFPE) samples with more than 80% of cancer cells in order to perform high-resolution array-CGH. We used ULS labeling kit (Agilent) and 105A array (Agilent) for 20 and 180K array (Agilent) for 39 samples. For the immunohistochemistry we used a tissue micro-array built from FFPE samples of the 132 patients. The viability assay MTS (Promega) was used to evaluate cytotoxicity of Gx15–070 and ABT-263 (Selleck Chemicals) in T1889, TY82 and T1682 TET cell lines. Results: Chromosome arm level copy number (CN) aberrations were considered those chromosome arms with more than 80% of their length affected by either CN gain or loss. Rare non-recurrent chromosome arm-level CN aberrations were observed in type A thymomas, whereas types B3 and thymic carcinomas shared frequent gains of chromosomes 1q, 5 and 7, as well as losses of chromosomes 6 and 13q. In addition, thymic carcinomas presented frequent losses of chromosomes 16p and 17q. We applied the GISTIC algorithm to the whole set of CN aberrations in order to distinguish aberrations driving the cancer phenotype from the background level of random CN aberrations. 72 CN gain and 54 CN loss peaks were identified (q 0.3) containing BCL2 locus and one high-level CN loss (log2 ratio < −0.7) containing CDKN2A/B loci. None of the samples with CDKN2A CN loss (5/59) expressed the related proteins p16INK4 and p14ARF. Patients with CDKN2A-negative immunohistochemistry results (85/119) had a poorer disease related survival (LogRank p=0.041). TET cell lines did not have CDKN2A CN loss or BCL2 CN gain, none of them expressed CDKN2A proteins and T1682 and TY82 expressed BCL2. All TET cell lines expressed multiple BCL2 anti-apoptotic family members including MCL1, and were resistant to ABT-263, a BCL2, BCL-XL and BCL-W inhibitor, but sensitive to Gx15–070, a pan BCL2 anti-apoptotic family member (IC50: range 35.8–99.6 nM). Conclusion: Our data indicate that TET histotypes differ by distribution of chromosome arm level CN aberrations. Loss of CDKN2A is prognostic in TETs, whereas Bcl-2 family members may be valuable targets for treatment of this disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-314. doi:10.1158/1538-7445.AM2011-LB-314

The aim of our study was to assess whether expression levels of a panel of biologically relevant microRNAs can be used as prognostic and/or predictive biomarkers in patients who participated in the International Adjuvant Lung Cancer Trial (IALT), the largest randomized study conducted so far of adjuvant chemotherapy in patients with radically resected NSCLC stage I-III. Expression of miR-21, miR-29b, miR-34a/b/c, miR-155 and Let-7a was determined by quantitative real-time PCR in paraffin embedded formalin fixed tumor specimens from 639 IALT patients, using small nuclear RNA U66 as the endogenous normalization control. From 79 patients sufficient tumor adjacent normal tissue was available as well. The prognostic and predictive value of microRNA expression and chemotherapy for survival were studied using a Cox model, which included every factor used in the stratified randomization plus clinical and histological prognostic factors as well as other factors statistically related to microRNA expression. Association of p53 mutation status and miR-34a/b/c expression was analyzed, as well as association of EGFR and K-Ras mutation status with miR-21 and Let-7a expression, respectively. Finally association of p16 and miR-29b expression was assessed. In situ hybridization was performed for validation and to determine histological expression patterns. Overall, we found that there was no significant association between the expression profile of any of the tested microRNAs and survival. However, for miR-21, miR-34b and miR-34c, there is a suggested deleterious prognostic effect of lower values on survival. No single microRNA expression profile or a combination of microRNA expression profiles, as determined by cluster analysis, predicted response to adjuvant cisplatin-based chemotherapy. Concluding, expression levels of the tested microRNAs were neither predictive nor prognostic in this patient cohort. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2995.