Dimitri Korol

MAGE-C1/CT-7 expression in plasma cell myeloma: Sub-cellular localization impacts on clinical outcome

Plasma cell myelomas (PMs) have a poor prognosis. Cancer‐testis (CT) antigens are immunogenic proteins, representing potential targets for tumor vaccination strategies. The expression of the CT antigens GAGE, MAGE‐A4, MAGE‐C1/CT‐7, and NY‐ESO‐1 was investigated on paraffin‐embedded bone marrow biopsies from 219 PM and 8 monoclonal gammopathy of undetermined significance (MGUS) patients. The frequency and prognostic impact of these CT antigens were compared with known morphological prognostic markers (i.e. Mib1 labeling index) and the presence of the translocations t(4;14)(p16.3; q32) and t(11;14)(q13;q32). We show that MAGE‐C1/CT‐7 is the most prevalent CT antigen, expressed in 57% of PMs in a high percentage of tumor cells. While MAGE‐C1/CT‐7 was absent in non‐malignant plasma cells, plasma cells of patients with MGUS did express MAGE‐C1/CT‐7, but no other CT antigens. MAGE‐C1/CT‐7 was more frequently expressed in PMs with an elevated proliferation rate (Mib1 >10%) compared to PMs with a low proliferation rate (Mib1 ≤10%, 71%versus 29%, P < 0.001) and correlated with overall survival, depending on its subcellular distribution. PMs with pure cytoplasmic MAGE‐C1/CT‐7 expression showed a better prognosis (48 months versus 33 months, P < 0.05) than PMs with combined nuclear‐cytoplasmic or nuclear expression only. Thus, expression of MAGE‐C1/CT‐7 in patients with monoclonal gammopathies represents a predictor of outcome and overt malignant transformation. (Cancer Sci 2008; 99: 720–725)

IGFBP2 and IGFBP3 protein expressions in human breast cancer : association with hormonal factors and obesity

Purpose: The insulin-like growth factor (IGF) signaling system is involved in breast cancer initiation and progression. The prognostic relevance of tumor expression patterns of IGFI-related proteins remains poorly understood. This study associates the expression of selected IGF proteins with breast tumor and patient characteristics. Experimental Design: IGFI, IGFI receptor, IGF-binding protein (IGFBP)2, and IGFBP3 expression was measured in 855 primary breast carcinomas by immunohistochemistry using tissue microarrays. We investigated the association of tumor and nodal stage, grade, hormone receptor status, HER2 gene amplification, menopausal status, body mass index, and survival with IGF protein expression. Results: In contrast to IGFI, the expression of IGFI receptor, IGFBP2, and IGFBP3 was associated with estrogen receptor status. In addition, IGFBP3 was positively correlated with body mass index and premenopausal status. Importantly, IGFBP2 was an independent and positive predictor of overall survival (hazard ratio, 0.48; 95% confidence interval, 0.24-0.95; P = 0.04). There was a weak suggestion for IGFBP2 and overweight to modify each others effect on survival. Conclusions: According to these results, which need confirmation in larger patient series, the prognostic relevance of IGFBP2 and IGFBP3 protein expressions in breast cancer may depend on the hormonal context and body weight. Clin Cancer Res; 16(3); 1025–32

AID protein expression in chronic lymphocytic leukemia/small lymphocytic lymphoma is associated with poor prognosis and complex genetic alterations

The biological behavior of chronic lymphocytic leukemia and small lymphocytic lymphoma is unpredictable. Nonetheless, non-mutated IgVH gene rearrangement, ATM (11q22–23) and p53 (17p13) deletion are recognized as unfavorable prognosticators in chronic lymphocytic leukemia. The mRNA expression of activation-induced cytidine deaminase (AID), an enzyme indispensable for somatic hypermutation processes, was claimed to be predictive of non-mutated chronic lymphocytic leukemia cells in blood. Here, we evaluated AID protein expression compared with known molecular and immunohistochemical prognostic indicators in 71 chronic lymphocytic leukemia/small lymphocytic lymphoma patients using a tissue microarray approach. We found AID heterogeneously expressed in tumor cells as shown by colocalization analysis for CD5 and CD23. Ki-67 positive paraimmunoblasts of the proliferation centers displayed the highest expression. This observation is reflected by a significant association of AID positivity with a high proliferation rate (P=0.012). ATM deletion was detected in 10% (6/63) of patients and p53 deletion in 19% (13/67) of patients. Moreover, both ATM (P=0.002) and p53 deletion (P=0.004) were significantly associated with AID. IgVH gene mutation was seen in 45% (27/60) of patients. Twenty-five percent (17/69) of patients with AID-positive chronic lymphocytic leukemia/small lymphocytic lymphoma displayed a shorter survival than AID-negative chronic lymphocytic leukemia/small lymphocytic lymphoma patients (61 vs 130 months, P=0.001). Although there was a trend, we could not show an association with the IgVH gene mutation status. Taken together, our study shows that AID expression is an indicator of an unfavorable prognosis in chronic lymphocytic leukemia/small lymphocytic lymphoma patients, although it is not a surrogate marker for the IgVH status. Furthermore, the microenvironment of proliferation centers seems to influence AID regulation and might be an initiating factor in its transformation.

Glioblastoma in the Canton of Zurich, Switzerland revisited: 2005 to 2009.

A population‐based analysis of patients with glioma diagnosed between 1980 and 1994 in the Canton of Zurich in Switzerland confirmed the overall poor prognosis of glioblastoma. To explore changes in outcome, registry data were reevaluated for patients diagnosed between 2005 and 2009.

Chromosomal translocations t(4;14), t(11;14) and proliferation rate stratify patients with mature plasma cell myelomas into groups with different survival probabilities: a molecular epidemiologic study on tissue microarrays.

Plasma cell myelomas (PMs) exhibit clinical and molecular heterogeneity. To date, morphology and immunohistochemistry on bone marrow trephines are of limited value to stratify patients into different prognostic categories. However, some chromosomal translocations are of prognostic and/or of predictive importance in PMs. In this study, the prognostic significance of morphology, CyclinD1 expression, proliferation index (Mib1) and presence of the translocations FGFR3/IgH [t(4;14)] and CCND1/IgH [t(11;14)] are compared in 119 patients with PM. Immunohistochemistry and fluorescence in situ hybridization analysis were carried out on a tissue microarray containing bone marrow trephines. Hundred and one PMs showed a mature morphology whereas 10 were immature. All but one PM carrying a translocation showed a mature morphology. Patients with a t(4;14) (12%) had a statistically significant shorter 1-year survival (P=0.004), whereas those with a t(11;14) (21%) had a trend towards a better clinical outcome. CyclinD1 protein expression was not significantly associated with survival. Besides the t(4;14), an immature morphology (P<0.001) and a proliferation index (Mib1) of more than 10% (P=0.002) were associated with a significantly worse outcome. A high occurrence of strong CyclinD1 protein expression in the tumor cells was predictive of either a t(11;14) or of a low level amplification of the CCND1 gene, suggesting that different molecular mechanisms may have lead to an over-expression of the CyclinD1 protein in PMs. These findings demonstrate that a high proliferation rate and translocations involving the IgH locus can stratify mature PMs into groups with distinct survival probabilities.

Incidence of Second Malignancies for Prostate Cancer

Introduction There is a need to assess risk of second primary cancers in prostate cancer (PCa) patients, especially since PCa treatment may be associated with increased risk of second primary tumours. Methods We calculated standardized incidence ratios (SIRs) for second primary tumours comparing men diagnosed with PCa between 1980 and 2010 in the Canton of Zurich, Switzerland (n = 20,559), and the general male population in the Canton. Results A total of 1,718 men developed a second primary tumour after PCa diagnosis, with lung and colon cancer being the most common (15 and 13% respectively). The SIR for overall second primary cancer was 1.11 (95%CI: 1.06–1.17). Site-specific SIRs varied from 1.19 (1.05–1.34) to 2.89 (2.62–4.77) for lung and thyroid cancer, respectively. When stratified by treatment, the highest SIR was observed for thyroid cancer (3.57 (1.30–7.76)) when undergoing surgery, whereas liver cancer was common when treated with radiotherapy (3.21 (1.54–5.90)) and kidney bladder was most prevalent for those on hormonal treatment (3.15 (1.93–4.87)). Stratification by time since PCa diagnosis showed a lower risk of cancer for men with PCa compared to the general population for the first four years, but then a steep increase in risk was observed. Conclusion In the Canton of Zurich, there was an increased risk of second primary cancers among men with PCa compared to the general population. Increased diagnostic activity after PCa diagnosis may partly explain increased risks within the first years of diagnosis, but time-stratified analyses indicated that increased risks remained and even increased over time.

Intratumoral plasmacytoid dendritic cells associate with increased survival in patients with follicular lymphoma

Gene array studies on follicular lymphoma (FL) have associated non-malignant tumor-infiltrating immune cells with patient survival. We examined the role of such cells detectable by immunohistochemistry in a tissue microarray, focusing on plasmacytoid dendritic cells (pDCs). These cells physiologically produce interferon-α, which has been used in the therapy of FL. High numbers of pDCs are associated with increased survival, and so are high numbers of CD3+ T cells. The regular distribution of pDCs within T cell areas is reflected by a weak but significant correlation between pDCs and T cells. However, in multivariate Cox models, CD123 proved to be an independent prognostic factor. These findings support the hypothesis of an association of pDCs with better prognosis by producing interferon. Furthermore, due to a linear relationship between pDCs and survival shown by means of Kaplan–Meier plots, immunohistochemical staining of CD123 could serve as a prognostic tool for patients with FL.

IRF8 is associated with germinal center B-cell-like type of diffuse large B-cell lymphoma and exceptionally involved in translocation t(14;16)(q32.33;q24.1)

Abstract Chromosomal translocations involving the immunoglobulin loci represent frequent oncogenic events in B-cell lymphoma development. Although IRF8 (ICSBP-1) protein expression has been demonstrated in germinal center B-cells and related lymphomas in a single report, the IRF8 gene was not described as an immunoglobulin heavy chain (IGH) translocation partner. In a discovery-driven approach we searched for new translocation partners of IGH in diffuse large B-cell lymphoma (DLBCL) by long distance inverse polymerase chain reaction (LDI-PCR) and Sanger sequencing. A t(14;16)(q32.33;q24.1) IGH/IRF8 was detected in a CD5+de novo DLBCL, confirmed by translocation specific PCR and fluorescence in situ hybridization (FISH) analysis. No further IRF8 aberration could be identified either by LDI-PCR in an additional five CD5+DLBCLs or by FISH on 78 formalin-fixed paraffin-embedded biopsies. Subsequent screening for IRF8 by immunohistochemistry revealed IRF8 expression in 18/78 (23%), correlating with a germinal center B-cell-like (GCB) type of DLBCL. This hitherto unknown translocation t(14;16)(q32.33;q24.1) is likely to represent the initiator of a multistep lymphomagenesis in a CD5+de novo DLBCL.

Incidence trends and clinical-pathological characteristics of invasive cutaneous melanoma from 1980 to 2010 in the canton of Zurich, Switzerland.

The aims of this paper are to describe the incidence trends of invasive cutaneous melanoma in the Canton of Zurich and to evaluate clinical and pathological factors such as cancer subtype, localization, age and Breslow thickness. A retrospective analysis was carried out with data from the population-based Cancer Registry of Zurich and Zug located in Zurich. A total of 8469 cases in 8034 different patients of invasive cutaneous melanoma were registered for the period 1980–2010 in the Canton of Zurich. Incidence trends were age standardized to the European standard population. Joinpoint regression was used to compute changes in incidence and mortality rates, measured as the annual percent change (APC). The most common subtypes of cutaneous melanoma were superficial spreading melanoma (SSM, 41.1%), followed by nodular melanoma (16.5%), lentigo maligna melanoma (13.5%), acral-lentiginous melanoma (5.0%) and other types of melanoma (2.8%); 21.1% were melanoma not otherwise specified. The trunk was the most frequent location (30.8%), followed by the lower limb and hip (26.4%) and the upper limb and shoulder (22.8%). Statistically significantly increasing incidence trends were observed for both men (APC=3.0%) and women (APC=2.1%). Incidences of SSM and melanoma not otherwise specified were the histological subtypes for which a significant increase in incidence was observed (APC for the period 1980–2010=3.2% for both). In terms of Breslow thickness, thin melanomas (0.01–1.00 mm) showed an increasing incidence. The incidence of melanoma increased in both men and women between 1980 and 2010. In terms of the different subtypes and Breslow thickness, increasing incidences of the SSM and of thin melanomas (0.01–1.00 mm) were observed. These observations are in agreement with other studies from Southern and Western Switzerland as well as other European countries and the USA.

Recent trends in cancer incidence: impact of risk factors, diagnostic activities and data quality of registration

Aims and Background Cancer incidence variations are influenced by different factors including socioeconomic status, risk factors and use of screening. The purpose of this study was to examine trends in cancer incidence in two urban areas in Europe showing differences in influencing factors but also some common characteristics in the context of data quality of the corresponding cancer registries. Methods Age-standardized incidence rates (world standard – ASRW) for cases diagnosed in 2000–2009 for Sofia (Bulgaria) and the Canton of Zurich (Switzerland) were calculated using data from the corresponding cancer registries. Average annual percent change (AAPC) was estimated with Joinpoint regression analysis. Data quality was estimated in terms of proportions of microscopically verified (MV%) and deathcertificate-only (DCO%) cases. Results ASRWs for all sites were higher in Zurich for men (311 vs 262 per 100,000) and women (241 vs 231 per 100,000) than in Sofia. Colorectal (both sexes), lung (men), cervical and corpus uteri cancer had a higher incidence in Sofia. Prostate, breast and lung (women) cancer were more often diagnosed in Zurich. A significant increase in female lung cancer incidence was observed in both areas. Overall incidence decreased in Zurich, while it did not significantly change in Sofia. MV% was lower in Sofia than in the Canton of Zurich but increased steadily up to 85% in 2009, whereas in the Canton of Zurich MV% was more or less stable around 95%. The DCO% of Sofia was 19% in 2000 and steadily decreased to 8% in 2009. In the Canton of Zurich, the DCO% decreased from 5% in 2000 but increased again from 2006 onwards, up to 3% in 2009. Conclusions Cancer incidence rates differ between Sofia and Zurich. Differences concerning socioeconomic status, risk factors, use of cancer screening but also data quality may influence these results.