Recurrent coamplification of cytoskeleton‐associated genes EMS1 and SHANK2 with CCND1 in oral squamous cell carcinoma

Freier, Kolja; Sticht, Carsten; Hofele, Christof; Flechtenmacher, Christa; Stange, Daniel E.; Puccio, Laura; Toedt, Grischa; Radlwimmer, Bernhard; Lichter, Peter; Joos, Stefan

doi:10.1002/gcc.20270

Cited by 61 publications

(68 citation statements)

References 34 publications

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“…The 11q13.3 amplicon is 1.7 Mb in size and contains 13 genes in almost all HNSCC cases with 11q13.3 amplification (Gibcus et al, 2007b). Therefore, multiple genes are enabled to increase their copy number and expression by 11q13.3 amplification (Freier et al, 2006;Gibcus et al, 2007a). Considering the different functions of cortactin, cyclin D1 and FADD it would be interesting to see whether these genes, coamplified in the same tumour, have a function at specific stages of tumorigenesis.…”

Section: Discussion Cortactin Predicts Poor Survival In Late Stage Lamentioning

confidence: 99%

“…Patients with laryngeal squamous cell carcinomas (LSCC) have not shown an increase in 5-year survival rates over the last 30 years (Almadori et al, 2005). Therefore, other parameters such as molecular markers that are able to more accurately predict the outcome of disease, are needed.A frequent molecular event in HNSCC is amplification of the 11q13 region (36%) (Schuuring, 1995;Freier et al, 2006). Amplification of this region in HNSCC has been associated with decreased survival (Akervall et al, 1995;Meredith et al, 1995), increased distant metastasis (Namazie et al, 2002) and lymph node metastasis (Chen et al, 2004;Hermsen et al, 2005;Xia et al, 2007).…”

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Cortactin expression predicts poor survival in laryngeal carcinoma

et al. 2008

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Amplification of the 11q13 region is one of the most frequent aberrations in squamous cell carcinomas of the head and neck region (HNSCC). Amplification of 11q13 has been shown to correlate with the presence of lymph node metastases and decreased survival. The 11q13.3 amplicon carries numerous genes including cyclin D1 and cortactin. Recently, we reported that FADD becomes overexpressed upon amplification and that FADD protein expression predicts for lymph node positivity and disease-specific mortality. However, the gene within the 11q13.3 amplicon responsible for this correlation is yet to be identified. In this paper, we compared, using immunohistochemical analysis for cyclin D1, FADD and cortactin in a series of 106 laryngeal carcinomas which gene correlates best with lymph node metastases and increased disease-specific mortality. Univariate Cox regression analysis revealed that high expression of cyclin D1 (P ¼ 0.016), FADD (P ¼ 0.003) and cortactin (P ¼ 0.0006) predict for increased risk to disease-specific mortality. Multivariate Cox analysis revealed that only high cortactin expression correlates with disease-specific mortality independent of cyclin D1 and/or FADD. Of genes located in the 11q13 amplicon, cortactin expression is the best predictor for shorter diseasespecific survival in late stage laryngeal carcinomas. Current methods to predict the outcome of head and neck squamous cell carcinoma (HNSCC) patients mainly involve clinicopathological parameters such as tumour size, differentiation grade and presence of lymph node metastasis. Patients with laryngeal squamous cell carcinomas (LSCC) have not shown an increase in 5-year survival rates over the last 30 years (Almadori et al, 2005). Therefore, other parameters such as molecular markers that are able to more accurately predict the outcome of disease, are needed.A frequent molecular event in HNSCC is amplification of the 11q13 region (36%) (Schuuring, 1995;Freier et al, 2006). Amplification of this region in HNSCC has been associated with decreased survival (Akervall et al, 1995;Meredith et al, 1995), increased distant metastasis (Namazie et al, 2002) and lymph node metastasis (Chen et al, 2004;Hermsen et al, 2005;Xia et al, 2007). It is believed that amplification increases gene dosage and expression of genes within the amplified region (amplicon) (Albertson, 2006). Recently, we reported that the commonly amplified region is located at 11q13.3 and contains at least six genes (cyclin D1, TAOS1, FGF19, FADD, PPFIA1 and cortactin) that are overexpressed when amplified (Gibcus et al, 2007b). We concluded that the selection for tumour cells with the 11q13.3 amplicon during tumorigenesis could be based on the increased doses of one or more of these genes. We proposed FADD as a possible candidate for this selection, since FADD showed the best correlation between DNA amplification and increased expression (Gibcus et al, 2007b). Furthermore, FADD protein expression correlated with disease specific mortality (DSM) in a series of late stage laryngeal carcinom...

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Section: Discussion Cortactin Predicts Poor Survival In Late Stage Lamentioning

confidence: 99%

mentioning

confidence: 99%

Cortactin expression predicts poor survival in laryngeal carcinoma

et al. 2008

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“…Amplification of the 11q13 locus, where CTTN resides, is the most frequent amplification event in HNSCC and may be driven by a set of genes that could cooperatively provide growth or metastatic advantage to cancer cells including CCND1, FGF4, FGF3, SHANK2, and PAK1 (see Huang et al, 2002and Gibcus et al, 2007. Indeed, recurrent coamplification of the cytoskeleton-associated genes CCTN and SHANK2 with the cellcycle control gene CCND1 has been observed in oral squamous cell carcinoma (Freier et al, 2006). Future studies are warranted to determine the possible involvement of other gene products of the 11q13 amplicon in HNSCC.…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of cortactin levels in head and neck squamous cell carcinoma: comparison with epidermal growth factor receptor status

et al. 2008

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Cortactin is an actin-binding Src substrate involved in cell motility and invasion. In this study, we sought to examine the prognostic importance of cortactin protein expression in head and neck squamous cell carcinoma (HNSCC). To do so, cortactin and EGF receptor (EGFR) expression was retrospectively evaluated by immunohistochemistry in a tissue microarray composed of 176 HNSCCs with a mean follow-up time of 5 years. Cortactin immunoreactivity was weak to absent in normal epithelial tissue. Overexpression of the protein in 77 out of 176 tumours (44%) was associated with more advanced tumour-node-metastasis stage and higher histologic grade. Cortactin overexpression was associated with significantly increased local recurrence rates (49 vs 28% for high and low expressing carcinomas, respectively), decreased disease-free survival (17 vs 61%), and decreased the 5-year overall survival of (21 vs 58%), independently of the EGFR status. In multivariate analysis, cortactin expression status remained an independent prognostic factor for local recurrence, disease-free survival, and overall survival. Importantly, we identified a subset of patients with cortactin-overexpressing tumours that displayed low EGFR levels and a survival rate that equalled that of patients with tumoral overexpression of both EGFR and cortactin. These findings identify cortactin as a relevant prognostic marker and may have implications for targeted therapies in patients with HNSCC.

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“…This is supported by the finding that the human 11q13 amplicon core is syntenic to mouse chromosomal band 7F5, which is frequently amplified in chemically-induced murine OSCC. Freier et al 90 proposed that coamplification of EMS1 and SHANK2 might have a cooperative effect on OSCC tumor cell motility and invasiveness. Thus, genetic alterations involving chromosome 11 appear to play a key role in OSCC.…”

Section: Gene Amplificationmentioning

confidence: 99%

Chromosomal imbalances in oral squamous cell carcinoma: Examination of 31 cell lines and review of the literature

et al. 2008

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Classical and molecular cytogenetic analysis, including fluorescence in situ hybridization (FISH) and chromosomal comparative genomic hybridization (CGH), were used to examine genetic changes involved in the development and/or progression of oral squamous cell carcinoma (OSCC). Of 31 OSCC cell lines studied, more than one-third expressed clonal structural abnormalities involving chromosomes 3, 7, 8, 9, and 11. Eleven OSCC cell lines were evaluated using CGH to identify novel genome-wide gains, losses, or amplifications. By CGH, more than half of the cell lines showed loss of 3p, gain of 3q, 8q, and 20q. Further, molecular cytogenetic analyses by FISH of primary tumors showed that the karyotypes of cell lines derived from those tumors correlated with specific gains and losses in the tumors from which they were derived. The most frequent nonrandom aberration identified by both karyotype and CGH analyses was amplification of chromosomal band 11q13 in the form of a homogeneously staining region. Our data suggest that loss of 9p and 11q13 amplification may be of prognostic benefit in the management of OSCC, which is consistent with the literature. The results of this study validate the relationship between these OSCC cell lines and the tumors from which they were derived. The results also emphasize the usefulness of these cell lines as in vitro experimental models and provide important genetic information on these OSCC cell lines that were recently reported in this journal.

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Recurrent coamplification of cytoskeleton‐associated genes EMS1 and SHANK2 with CCND1 in oral squamous cell carcinoma

Cited by 61 publications

References 34 publications

Cortactin expression predicts poor survival in laryngeal carcinoma

Cortactin expression predicts poor survival in laryngeal carcinoma

Prognostic significance of cortactin levels in head and neck squamous cell carcinoma: comparison with epidermal growth factor receptor status

Chromosomal imbalances in oral squamous cell carcinoma: Examination of 31 cell lines and review of the literature

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