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1.  Genomic and functional analysis identifies CRKL as an oncogene amplified in lung cancer 
Oncogene  2009;29(10):1421-1430.
DNA amplifications, leading to the overexpression of oncogenes, are a cardinal feature of lung cancer and directly contribute to its pathogenesis. To uncover novel such alterations, we performed an array-based comparative genomic hybridization survey of 128 non-small cell lung cancer cell lines and tumors. Prominent among our findings, we identified recurrent high-level amplification at cytoband 22q11.21 in 3% of lung cancer specimens, with another 11% of specimens exhibiting low-level gain spanning that locus. The 22q11.21 amplicon core contained eight named genes, only four of which were overexpressed (by transcript profiling) when amplified. Among these, CRKL encodes an adaptor protein functioning in signal transduction, best known as a substrate of the BCR-ABL kinase in chronic myelogenous leukemia. RNA interference-mediated knockdown of CRKL in lung cancer cell lines with (but not without) amplification led to significantly decreased cell proliferation, cell-cycle progression, cell survival, and cell motility and invasion. In addition, overexpression of CRKL in immortalized human bronchial epithelial cells led to EGF-independent cell growth. Our findings indicate that amplification and resultant overexpression of CRKL contributes to diverse oncogenic phenotypes in lung cancer, with implications for targeted therapy, and highlighting a role of adapter proteins as primary genetic drivers of tumorigenesis.
PMCID: PMC3320568  PMID: 19966867
CRKL; lung cancer; DNA amplification; genomic profiling; adapter protein
2.  Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer 
Cancer discovery  2011;1(1):78-89.
While genomically targeted therapies have improved outcomes for patients with lung adenocarcinoma, little is known about the genomic alterations which drive squamous cell lung cancer. Sanger sequencing of the tyrosine kinome identified mutations in the DDR2 kinase gene in 3.8% of squamous cell lung cancers and cell lines. Squamous lung cancer cell lines harboring DDR2 mutations were selectively killed by knock-down of DDR2 by RNAi or by treatment with the multi-targeted kinase inhibitor dasatinib. Tumors established from a DDR2 mutant cell line were sensitive to dasatinib in xenograft models. Expression of mutated DDR2 led to cellular transformation which was blocked by dasatinib. A squamous cell lung cancer patient with a response to dasatinib and erlotinib treatment harbored a DDR2 kinase domain mutation. These data suggest that gain-of-function mutations in DDR2 are important oncogenic events and are amenable to therapy with dasatinib. As dasatinib is already approved for use, these findings could be rapidly translated into clinical trials.
PMCID: PMC3274752  PMID: 22328973
Squamous cell lung cancer; DDR2; dasatinib; tyrosine kinase inhibitors; lung cancer genomics
3.  Gender and ploidy in cancer survival 
Cellular Oncology (Dordrecht)  2011;34(3):199-208.
Females carry a better prognosis than men for many cancer types. We hypothesized that chromosomal changes, in particular numerical alterations of the sex chromosomes or the presence of near-triploidy may contribute to these gender differences.
To characterize the influence of gender a literature search was performed for survival data of 27 tumor types. All entities were categorized by the strength of evidence for differences in survival between females and males. To test our hypothesis the Mitelman database of chromosomal alterations was evaluated for the major tumor types occurring in both women and men. Numerical gonosome alterations were documented and mean chromosome numbers were converted into histograms to provide insight into the ploidy level of 37 cancer types.
In general, a survival advantage of women could be shown for most, but not all cancer types. In addition, 36.859 karyograms were analyzed. Numerical gonosome alterations were more frequent in males than females indicating a potential link with gender differences in survival. Neartriploidy was a common phenomenon in many cancer types suggesting that it represents a metastable condition of the cancer genome. It was not related to gender differences in survival. However, the extent of triploidy and aneuploidy was associated with poor prognosis in carcinomas. There was no single case in the Mitelman database with normal chromosome number (n = 46) that did not carry at least one structural or numerical aberration.
Our study highlights the importance of chromosomal changes in tumor formation and progression. In addition, it suggests potential associations with gender specific differences in survival.
Electronic supplementary material
The online version of this article (doi:10.1007/s13402-011-0013-0) contains supplementary material, which is available to authorized users.
PMCID: PMC3149121  PMID: 21424817
Gender; Aneuploidy; Chromosomal chaos; Prognosis
4.  Immunoprofiles of 11 Biomarkers Using Tissue Microarrays Identify Prognostic Subgroups in Colorectal Cancer1 
Neoplasia (New York, N.Y.)  2005;7(8):741-747.
BACKGROUND AND AIMS: Genomewide expression profiling has identified a number of genes expressed at higher levels in colorectal cancer (CRC) than in normal tissues. Our objectives in this study were: 1) to test whether genes were also distinct on the protein level; 2) to evaluate these biomarkers in a series of well-characterized CRCs; and 3) to apply hierarchical cluster analysis to the immunohistochemical data. METHODS: Tissue microarrays (TMAs) comprising 351 CRC specimens from 270 patients were constructed to evaluate the genes Adam10, CyclinD1, AnnexinII, NFKB, Casein-kinase-2-beta (CK2B), YB-1, P32, Rad51, c-fos, IGFBP4, and Connexin26 (Cx26). In total, 3,797 samples were analyzed. RESULTS: Unsupervised hierarchical clustering discovered subgroups of CRC that differed by tumor stage and survival. Kaplan-Meier analysis showed that reduced Cx26 expression was significantly associated with shorter patient survival and higher tumor grade (G1/G2 vs G3, P = .02), and Adam10 expression with a higher tumor stage (pT1/2 vs pT3/4, P = .04). CONCLUSIONS: Our study highlights the potential of TMAs for a higher-dimensional analysis by evaluating serial sections of the same tissue core (three-dimensional TMA analysis). In addition, it endorses the use of immunohistochemistry supplemented by hierarchical clustering for the identification of tumor subgroups with diagnostic and prognostic signatures.
PMCID: PMC1501883  PMID: 16207476
Connexin26 (Cx26); Adam10; colorectal cancer (CRC); hierarchical clustering; tissue microarray (TMA)
5.  Microarray comparative genomic hybridization detection of chromosomal imbalances in uterine cervix carcinoma 
BMC Cancer  2005;5:77.
Chromosomal Comparative Genomic Hybridization (CGH) has been applied to all stages of cervical carcinoma progression, defining a specific pattern of chromosomal imbalances in this tumor. However, given its limited spatial resolution, chromosomal CGH has offered only general information regarding the possible genetic targets of DNA copy number changes.
In order to further define specific DNA copy number changes in cervical cancer, we analyzed 20 cervical samples (3 pre-malignant lesions, 10 invasive tumors, and 7 cell lines), using the GenoSensor microarray CGH system to define particular genetic targets that suffer copy number changes.
The most common DNA gains detected by array CGH in the invasive samples were located at the RBP1-RBP2 (3q21-q22) genes, the sub-telomeric clone C84C11/T3 (5ptel), D5S23 (5p15.2) and the DAB2 gene (5p13) in 58.8% of the samples. The most common losses were found at the FHIT gene (3p14.2) in 47% of the samples, followed by deletions at D8S504 (8p23.3), CTDP1-SHGC- 145820 (18qtel), KIT (4q11-q12), D1S427-FAF1 (1p32.3), D9S325 (9qtel), EIF4E (eukaryotic translation initiation factor 4E, 4q24), RB1 (13q14), and DXS7132 (Xq12) present in 5/17 (29.4%) of the samples.
Our results confirm the presence of a specific pattern of chromosomal imbalances in cervical carcinoma and define specific targets that are suffering DNA copy number changes in this neoplasm.
PMCID: PMC1186020  PMID: 16004614
6.  Chromosomal Alterations during Lymphatic and Liver Metastasis Formation of Colorectal Cancer1 
Neoplasia (New York, N.Y.)  2004;6(1):23-28.
Comparative genomic hybridization (CGH) was used to screen colorectal carcinomas for chromosomal aberrations that are associated with metastatic phenotype. In total, 63 tumor specimens from 40 patients were investigated, comprising 30 primary tumors, 22 systemic metastases (12 liver, 6 brain, and 4 abdominal wall metastases) and 11 lymph node tumors. Using statistical analysis and histograms to evaluate the chromosomal imbalances, overrepresentations were detected most frequently at 20q11.2–20q13.2, 7q11.1–7q12, 13q11.2–13q14, 16p12, 19p13, 9q34, and 19q13.1–19q13.2. Deletions were prominent at 18q12–18q23, 4q27–4q28, 4p14, 5q21, 1p21–1p22, 21q21, 6q16–6q21, 3p12, 8p22–8p23, 9p21, 11q22, and 14q13–14q21. Hematogenous metastases showed more alterations than lymph node tumors, particularly more deletions at 1p, 3, 4, 5q, 10q, 14, and 21q21 and gains at 1q, 7p, 12qter, 13, 16, and 22q. Comparing liver metastases with their corresponding primary tumors, particularly deletions at 2q, 5q, 8p, 9p, 10q, and 21q21 and gains at 1q, 11, 12qter, 17q12–q21, 19, and 22q were more often observed. The analysis suggested that the different pathways of tumor dissemination are reflected by a nonrandom accumulation of chromosomal alterations with specific changes being responsible for the different characteristics of the metastatic phenotype.
PMCID: PMC1508628  PMID: 15068668
CGH; colorectal cancer; metastasis; lymph node metastases; liver metastases

Results 1-6 (6)