Expression and prognostic significance of cox-2 and p-53 in hodgkin lymphomas: a retrospective study

<p>Abstract</p> <p>Background</p> <p>Cyclooxygenase (cox) is the rate-limiting enzyme, which catalyzes the conversion of arachidonic acid into prostaglandins and contributes to the inflammatory process. Cyclooxygenase-2 (cox-2), which is one of the two isoforms, plays a role in tumor progression and carcinogenesis. p53 contributes to apoptosis, DNA renewal and cell cycle. Studies concerning the relationship of cox-2 and p53 expressions and carcinogenesis are available, but the association between cox-2 and p53 in Hodgkin lymphoma (HL) is not exactly known.</p> <p>In our study, we examined the association of cox-2 and p53 expression, with age, stage, histopathological subtype, and survival in HL. We also examined correlation between cox-2 and p53 expression.</p> <p>Methods</p> <p>Cox-2 and p53 expressions in Hodgkin-Reed Sternberg cells (HRS) were examined in 54 patients with HL depending on cox-2 expression, stained cases were classified as positive, and unstained cases as negative. Nuclear staining of HRS cells with p53 was evaluated as positive. The classifications of positivity were as follows: negative if<10%; (1+) if 10-25%; (2+) if 25-50%; (3+) if 50-75%, (4+) if >75%.</p> <p>Results</p> <p>Cox-2 and p53 expressions were found in 49 (80%) and 29 (46%) patients, respectively. There were differences between histological subtypes according to cox-2 expression (p = 0.012). Mixed cellular (MC) and nodular sclerosing (NS) subtypes were seen most of the patients and cox-2 expression was evaluated mostly in the mixed cellular subtype.</p> <p>There were no statistically significant relationships between p53 and the histopathological subtypes; or between p53, cox-2 and the factors including stage, age and survival; or between p53 and cox-2 expression (p > 0.05).</p> <p>Conclusion</p> <p>Considering the significant relationship between the cox-2 expression and the subtypes of HL, cox-2 expression is higher in MC and NS subtypes. However the difference between these two subtypes was not significant. This submission must be advocated by studies with large series</p

S100A7 (psoriasin) expression is associated with aggressive features and alteration of Jab1 in ductal carcinoma in situ of the breast

INTRODUCTION: The S100A7 (psoriasin) gene is highly expressed in ductal carcinoma in situ (DCIS) of the breast and can be downregulated in invasive carcinoma. Persistent S100A7 expression in invasive carcinoma is associated with a worse prognosis, and this effect may be mediated in part through interaction with the multifunctional cell signaling protein Jab1. METHODS: In order to investigate the relationship between S100A7 and progression from DCIS to invasive carcinoma, we studied S100A7 expression in 136 patients with DCIS (including 46 patients with associated invasive carcinoma) by immunohistochemistry. RESULTS: S100A7 expression was present in 63 out of 136 (46%) of DCIS lesions and was associated with estrogen receptor negative status (P = 0.0002), higher nuclear grade (P < 0.0001), necrosis (P < 0.0001) and inflammation (P < 0.0001). S100A7 status was no different between DCIS with and DCIS without an invasive component, but higher levels of S100A7 were present in DCIS associated with invasive carcinoma (P < 0.004). Analysis of a subset of cases showed that S100A7 expression was also associated with an increase in nuclear Jab1 (n = 43; P = 0.0019) and reduced p27(kip1 )(n = 47; P = 0.0168). In cases of DCIS associated with invasive carcinoma, there was also a significant reduction in S100A7 between in situ and invasive components (n = 46; P < 0.0001). In pure DCIS cases treated by local excision, there was no difference in frequency of S100A7 expression between patients with recurrence of DCIS (n = 9) and those without (n = 36). CONCLUSION: The findings reported here suggest that, although S100A7 may not be a marker for recurrence of DCIS, it is associated with poor prognostic markers in DCIS and may influence progression of breast carcinoma through its interaction with and influence on Jab1

Genome-Wide Local Ancestry Approach Identifies Genes and Variants Associated with Chemotherapeutic Susceptibility in African Americans

Chemotherapeutic agents are used in the treatment of many cancers, yet variable resistance and toxicities among individuals limit successful outcomes. Several studies have indicated outcome differences associated with ancestry among patients with various cancer types. Using both traditional SNP-based and newly developed gene-based genome-wide approaches, we investigated the genetics of chemotherapeutic susceptibility in lymphoblastoid cell lines derived from 83 African Americans, a population for which there is a disparity in the number of genome-wide studies performed. To account for population structure in this admixed population, we incorporated local ancestry information into our association model. We tested over 2 million SNPs and identified 325, 176, 240, and 190 SNPs that were suggestively associated with cytarabine-, 5′-deoxyfluorouridine (5′-DFUR)-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10−4). Importantly, some of these variants are found only in populations of African descent. We also show that cisplatin-susceptibility SNPs are enriched for carboplatin-susceptibility SNPs. Using a gene-based genome-wide association approach, we identified 26, 11, 20, and 41 suggestive candidate genes for association with cytarabine-, 5′-DFUR-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10−3). Fourteen of these genes showed evidence of association with their respective chemotherapeutic phenotypes in the Yoruba from Ibadan, Nigeria (p<0.05), including TP53I11, COPS5 and GAS8, which are known to be involved in tumorigenesis. Although our results require further study, we have identified variants and genes associated with chemotherapeutic susceptibility in African Americans by using an approach that incorporates local ancestry information

Immunohistochemical detection of BCL-3 in lymphoid neoplasms: a survey of 353 cases

The bcl-3 gene at chromosome 19q13 encodes a member of the lkappaB family involved in regulating the NFkappaB pathway. Originally identified by its involvement in the rare t(14:19)(q32;q13), BCL-3 expression has never been analyzed in a wide variety of lymphomas. We assessed BCL-3 expression in 353 cases of non-Hodgkin lymphoma and Hodgkin lymphoma using formalin-fixed, paraffin-embedded tissue specimens, a monoclonal antibody specific for BCL-3, and immunohistochemical methods. Of 172 B-cell lymphomas, 10 (6%) were positive for BCL-3, including six of 23 (26%) diffuse large B-cell lymphoma, one of 17 (6%) small lymphocytic lymphoma, one of 26 (40%) follicular lymphoma, and two of 49 (4%) mantle cell lymphoma. All other B-cell neoplasms were negative, including marginal zone lymphoma (n = 24, 11 extranodal, nine nodal, four splenic), Burkitt lymphoma (n=10), lymphoplasmacytic lymphoma (n=10), lymphoblastic lymphoma (n=8), and plasmacytoma (n=5). Of 111 T/NK-cell lymphomas, 25 (23%) were positive for BCL-3, including 13 of 40 (32%) anaplastic large-cell lymphoma, three of 10 (30%) angioimmunoblastic T-cell lymphoma, two of eight (25%) extranodal NK/T-cell lymphoma of nasal type, three of 12 (25%) mycosis fungoides, one of five (20%) enteropathy-type T-cell lymphoma, and two of 21 (10%) peripheral T-cell lymphoma unspecified. All other T-cell neoplasms were negative, including lymphoblastic lymphoma (n=6), prolymphocytic leukemia (n=6), and subcutaneous panniculitis-like T-cell lymphoma (n = 3). Of 70 Hodgkin lymphomas, of all types, 29 (41%) were positive for BCL-3. The relatively high frequency of BCL-3 expression in some non-Hodgkin and Hodgkin lymphoma types raises the possibility that BCL-3 is involved in the pathogenesis of these tumors, and may be a target of new therapies

Diagnosis and subclassification of follicle center and mantle cell lymphomas on fine-needle aspirates - A cytologic and immunocytochemical approach based on the revised European-American lymphoma (REAL) classification

BACKGROUND. Cytologic distinction between follicle center lymphoma (FCL) and mantle cell lymphoma (MCL) is difficult with cytomorphology alone and requires immunophenotyping. The current study describes the distinction between follicle center and mantle cell lymphoma made with fine-needle aspiration (FNA) material. METHODS. One hundred ten cases primarily diagnosed and classified on FNA material as centroblastic-centrocytic (CBCC) and centrocytic (CC) non-Hodgkin lymphomas (NHLs) (Kiel classification) were included in the study. An additional retrospective immunocytochemical analysis was performed on frozen cytospin preparations using the monoclonal antibodies Bcl-2, CD10, CD5, CD23, CD43, and immunoglobulin M. RESULTS. The initial diagnostic workup classified 106 cases as CBCC-NHL and 4 as CC-NHL. The immunophenotype Bcl-2(+), CD10(+/-), CD5(-), CD23(-/+), CD43(-) was observed in 93 of 106 previously reported CBCC NHLs. In 11 of 106 cytospin preparations, neoplastic B cells expressed the CD5 pan T marker and, as a group, showed the pattern Bcl (+/-), CD10(-/+), CD5(+), CD23(-), CD43(+), which is considered typical of MCL. Based on the additional immunocytochemical data, all but 2 of the tumors were reclassified as FCL (n = 93) and MCL (n = 15). The mean proliferation fraction measured by MIB-1 (Ki-67) immunoreactivity was 16.3% and 17.5% in FCL and MCL, respectively. The revised cytopathologic diagnosis correlated significantly (P &lt; 10(-9)) with the histology of 65 patients who underwent surgical excision biopsy. CONCLUSIONS. Subclassification of follicle-derived low grade NHL can be established with high accuracy on FNA material if cytomorphology is corroborated by a complete immunophenotypic analysis, which can be performed on both fresh and frozen stored cytospin material. The currently used criteria can be applied to aspirated cells for a conclusive cytopathologic diagnosis of MCL, which is of great clinical importance. (C) 1999 American Cancer Society

High expression levels of p27 correlate with lymph node status in a subset of advanced invasive breast carcinomas - Relation to E-cadherin alterations, proliferative activity, and ploidy of the tumors

BACKGROUND. The cyclin-dependent kinase inhibitor p27 plays a central role in cell cycle progression and is deregulated in breast carcinomas. Although its levels are inversely associated with tumor proliferation, overexpression of p27 has been reported in a subset of rapidly proliferating breast carcinoma cell lines. METHODS. p27 levels were determined by immunohistochemistry in a series of 52 sporadic invasive breast carcinomas consisting of 47 ductal, 2 lobular, and 3 mixed; most tumors were Grade 2 or 3 (46 of 52) and Tumor Node Metastasis (TNM) Stage II-IV (46 of 52). E-cadherin expression and its gene alterations at 16q22.1 were also studied, because in vitro evidence suggests a biologic association between p27 and E-cadherin-mediated growth suppression. RESULTS. The mean p27 labeling index (LI; percentage of p27 positive tumor cells) was 33.3% +/- 25.3% (range, 0.1-85%). High p27 levels (p27 LI, &gt; 50%) were observed in 14 (26.9%) of 52 carcinomas and were significantly associated with metastatic disease in axillary lymph nodes (14 of 33 vs. 0 of 19; P = 0.0007 by Fisher exact test). In addition, p27 LI was higher in the group of lymph node positive vs. lymph node negative tumors (mean p27 LI, 40.9% vs. 20.1%; P = 0.008 by Mann-Whitney test). Reduced or absent E-cadherin expression was found in 27 of 45 (60%) informative cases. Allelic imbalance of the 16q22.1 locus was found in 14 (27.5%) of 51 cases by using the microsatellite markets D16S503, D16S752, and D16S512. p27 LI and E-cadherin alterations were not statistically related. CONCLUSIONS. in summary, high p27 levels detected in a subset of advanced breast carcinomas correlate with lymph node metastasis, suggesting that other mechanisms may bypass the cell cycle inhibitory role or p27 and provide growth advantage in these tumors. (C) 2002 American Cancer Society

Effects of p53 mutants derived from lung carcinomas on the p53-responsive element (p53RE) of the MDM2 gene

The present study represents a continuation of previous works in which we observed that lung carcinomas co-expressing MDM2 protein and p53 mutants (mt p53) exhibited more aggressive behaviour. In the above studies, we suggested a ‘gain of function’ mechanism of mt p53 proteins based on the fact that the MDM2 gene possesses a p53-responsive element (MDM2-p53RE). In this study, to prove our hypothesis, we selected 12 cases from a series of 51 bronchogenic carcinomas. In these 12 cases, we examined the ability of the expressed mt p53 to bind the MDM2-p53RE and correlated the findings with MDM2 expression. Furthermore, we constructed four of these p53 mutants and studied their transactivation properties by co-transfecting them with a reporter plasmid carrying MDM2-p53RE in the p53 null non-small-cell lung carcinoma cell line (NSCLC) H1299. We observed mutant p53 protein DNA-binding activity, which depended on the nature and the position of the amino acid substitution. The fact that the cases with DNA-binding activity were accompanied with MDM2 protein isoforms’ overexpression is indicative of a ‘gain of function’ phenotype. This hypothesis was enforced by the findings of the transfection experiments, which revealed that certain p53 mutants enhanced the expression of the luciferase reporter gene either directly or indirectly via a dominant positive effect on the wild-type p53. In conclusion, this work is one first attempt to examine if the deregulation of the p53/MDM2 autoregulatory feedback loop is due to novel properties of certain p53 mutants in the specific environment of a subset of bronchogenic carcinomas