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Sahi H.,University of Helsinki | Koljonen V.,University of Helsinki | Kavola H.,University of Helsinki | Haglund C.,University of Helsinki | And 3 more authors.
Virchows Archiv | Year: 2012

Merkel cell carcinoma (MCC) is an aggressive dermal tumour of neuroendocrine origin. The recently found Merkel cell polyomavirus (MCV) integrates clonally in the tumour genome, which suggests an important role in the pathogenesis of the disease. Previous small-scale studies have detected anti-apoptotic protein bcl-2 in 80% of MCC tumours, but its correlation to the prognosis of MCC remains controversial. Our aim was to clarify the correlation of immunohistochemical expression of bcl-2 to MCV presence and MCC prognosis. We analyzed 116 primary MCC specimens with corresponding clinical data by immunohistochemistry for bcl-2. The presence of MCV DNA had been analyzed by quantitative PCR for 108 tumours. The correlations were analyzed statistically. Of the primary MCC samples, 85% were bcl-2 positive. No significant differences in MCV DNA occurred between the bcl-2-positive and bcl-2-negative tumours. Local and systemic metastasis was more common in patients with bcl-2 negative tumours (33%) than in patients with bcl-2-positive tumours (12%; p=0.04) at the time of diagnosis. The mean overall survival was higher in patients with bcl-2-positive tumours than of those with negative tumours (mean survival 1,814 days (5.0 years) vs. 769 days (2.1 years), p=0.01). Bcl-2 positivity indicates better clinical stage at the time of diagnosis and a longer survival in MCC. © Springer-Verlag 2012.

Torino F.,University of Rome Tor Vergata | Bonmassar E.,University of Rome Tor Vergata | Bonmassar E.,National Research Council Italy | Bonmassar L.,Laboratory of Molecular Oncology | And 5 more authors.
Cancer Treatment Reviews | Year: 2013

The availability of sensitive methods has allowed the detailed study of circulating tumor cells only recently. Evolving evidence support the prognostic and predictive role of these cells in patients affected by several solid tumors, including colorectal cancer. Ongoing studies are aimed at confirming that the molecular characterization of circulating tumor cells in peripheral blood and in bone marrow of patients is a powerful tool to improve the patient risk-stratification, to monitor activity of the drugs, to develop more appropriate targeted therapies and tailored treatments. In parallel, results from these correlative studies promise to gain a better biological understanding of the metastatic process. The clinical utility of the detection of circulating tumor cells in patients affected by colorectal cancer is still hampered by a number of specific hurdles. Improvement in sensitivity and specificity of the available methods of detection, standardization of these methods and functional characterization of circulating tumor cells in well designed and statistically well powered studies are the key steps to reach these ambitious objectives in colorectal cancer patients as well. © 2013 Elsevier Ltd.

Sihto H.,Laboratory of Molecular Oncology | Sihto H.,University of Helsinki | Kukko H.,University of Helsinki | Koljonen V.,University of Helsinki | And 4 more authors.
Clinical Cancer Research | Year: 2011

Purpose: Merkel cell carcinoma (MCC) is rare skin cancer that is often associated with Merkel cell polyomavirus (MCPyV) infection. Polyomaviruses repress tumor suppressor proteins, thus influencing cell-cycle progression, but the effect of MCPyV on the key cell-cycle regulating proteins is poorly understood. Experimental Design: We evaluated expression of the MCPyV large T-antigen (LTA), Ki-67, and the key putative tumor suppressor proteins, the retinoblastoma protein (RB and phospho-RB) and p53, and their regulatory proteins (cyclin D1, cyclin E, p16, p21, p27, and MDM2) by using immunohistochemistry from tumors of 91 MCC patients identified from a population-based nationwide cohort. Tumor MCPyV DNA was measured by using quantitative PCR, and TP53 mutations were identified with sequencing. Results: MCPyV LTA expression was strongly associated with presence of MCPyV DNA in tumor, and it was almost invariably associated with tumor RB expression (P < 0.0001 for both comparisons). Both MCC LTA and RB expression were strongly associated with favorable MCC-specific and overall survival in univariable analyses (P ≤ 0.01 for all four analyses). Presence of MCPyV LTA was also associated with the female gender, the intermediate type of tumor histology, location of the tumor in a limb, cell proliferation rate, and absence of p53 expression. TP53 mutations were detected only in MCPyV DNA-negative tumors. Conclusions: MCPyV DNA-positive MCC has several clinical and molecular features that differ from MCPyV DNA-negative cancers. MCPyV-associated MCCs express RB, but may not harbor TP53 mutations. These findings provide further support that MCPyV causes the majority of MCCs. ©2011 AACR.

Yang J.,University of Oxford | Parsons J.,University of Oxford | Nicolay N.H.,University of Oxford | Caporali S.,Laboratory of Molecular Oncology | And 9 more authors.
Oncogene | Year: 2010

A significant proportion of human cancers overexpress DNA polymerase beta (Pol Β), the major DNA polymerase involved in base excision repair. The underlying mechanism and biological consequences of overexpression of this protein are unknown. We examined whether Pol Β, expressed at levels found in tumor cells, is involved in the repair of DNA damage induced by oxaliplatin treatment and whether the expression status of this protein alters the sensitivity of cells to oxaliplatin. DNA damage induced by oxaliplatin treatment of HCT116 and HT29 colon cancer cells was observed to be associated with the stabilization of Pol Β protein on chromatin. In comparison with HCT116 colon cancer cells, isogenic oxaliplatin-resistant (HCT-OR) cells were found to have higher constitutive levels of Pol Β protein, faster in vitro repair of a DNA substrate containing a single nucleotide gap and faster repair of 1,2-GG oxaliplatin adduct levels in cells. In HCT-OR cells, small interfering RNA knockdown of Pol Β delayed the repair of oxaliplatin-induced DNA damage. In a different model system, Pol Β-deficient fibroblasts were less able to repair 1,2-GG oxaliplatin adducts and were hypersensitive to oxaliplatin treatment compared with isogenic Pol Β-expressing cells. Consistent with previous studies, Pol Β-deficient mouse fibroblasts were not hypersensitive to cisplatin treatment. These data provide the first link between oxaliplatin sensitivity and DNA repair involving Pol Β. They demonstrate that Pol Β modulates the sensitivity of cells to oxaliplatin treatment. © 2010 Macmillan Publishers Limited All rights reserved.

Gajate P.,Hospital Clinico San Carlos | Sastre J.,Hospital Clinico San Carlos | Bando I.,Laboratory of Molecular Oncology | Alonso T.,Hospital Clinico San Carlos | And 4 more authors.
Clinical Colorectal Cancer | Year: 2012

Background: Patients with metastatic colorectal cancer (mCRC) with activating mutations at codon 12 or 13 of the KRAS gene are currently excluded from treatment with monoclonal antibodies against the epidermal growth factor receptor (EGFR), for example, cetuximab. Occasionally, some of these patients benefit from treatment with cetuximab, especially patients with a mutation at codon 13. We conducted an analysis to study the influence of the KRAS p.G13D mutation in patients with mCRC who were treated with cetuximab. Materials and Methods: We analyzed the KRAS mutation status of 110 patients who were treated with cetuximab between September 2003 and October 2008 at Hospital Clínico, San Carlos. We compared progression-free survival, overall survival, and response rate according to KRAS mutation status. Results: Patients with mutations at codon 13 compared with those with other KRAS mutations showed no statistically significant differences in progression-free survival (4.96 months [95% CI, 3.04-6.89 months] vs. 3.10 months [95% CI, 1.58-4.61 months]; hazard ratio [HR] 0.88 [95% CI, 44-1.75]; P =.72) and overall survival (8.2 months [95% CI, 4.2-12.1 months] vs. 14.6 months [95% CI, 8.0-21.2 months]; HR 0.50 [95% CI, 0.23-1.09]; P =.084). Patients with KRAS wild-type tumors have a longer progression-free survival (7.30 months [95% CI, 4.48-10.12 months]; HR 0.46 [95% CI, 0.23-0.91]; P =.025) and overall survival (19.0 months [95% CI, 10.2-27.8 months]; HR 0.32 [95% CI, 0.15-0.69]; P =.004) than patients with p.G13D-mutated tumors. Differences in the response rate were not observed between groups. Conclusion: Patients with mCRC and mutation at codon 13 of the KRAS gene do not appear to benefit from treatment with cetuximab. These results support the current clinical practice. © 2012 Elsevier Inc. All rights reserved.

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