Skp2 expression is associated with high risk and elevated Ki67 expression in gastrointestinal stromal tumours

BACKGROUND: Gastrointestinal stromal tumors (GIST) exhibit an unpredictable clinical course and can rapidly progress to lethality. Predictions about the biological behavior of GIST are based on a number of canonical clinical and pathologic parameters whose validity in distinguishing between a benign and a malignant tumour is still imperfect. The aim of our study was to investigate the role of morphologic parameters and expression of cells cycle regulators as prognosticators in GIST. METHODS: We performed an immunohistochemical analysis for Ki67, p27Kip1, Jab1, and Skp2, on a Tissue Microarray (TMA) containing 94 GIST. Expression of the above proteins was correlated to classically used prognosticators, as well as to risk groups. Clinical significance of histologic and immunohistochemical features were evaluated in 59 patients for whom follow-up information was available. RESULTS: Overexpression of Ki67 and Skp2, and p27Kip1 loss directly correlated with the high risk group (p = 0.03 for Ki67 and Skp2, p = 0.05 for p27Kip1). Jab1 expression did not exhibit correlation with risk. In 59 cases provided with clinical follow-up, high cellularity, presence of necrosis, and Ki67 overexpression were predictive of a reduced overall survival in a univariate model. The same parameters, as well as mitotic rate, tumour size, and p27Kip1 loss were indicative of a shortened relapse free survival interval. High cellularity, and high mitotic rate retained their prognostic significance by multivariate analysis. CONCLUSION: Our data suggest that a number of histologic parameters in combination with immunohistochemical expression of cell cycle regulators can facilitate risk categorization and predict biologic behavior in GIST. Importantly this study demonstrates, for the first time, that Skp2 expression correlates with Ki67 expression and high risk in GIST

The prognostic role of WHO classification, urinary 5-hydroxyindoleacetic acid and liver function tests in metastatic neuroendocrine carcinomas of the gastroenteropancreatic tract

The World Health Organisation (WHO) classification (2000) is widely used to classify neuroendocrine carcinomas (NECs), yet its prognostic value needs to be confirmed. In this study, patients with metastatic NECs (n=119) were classified according to WHO guidelines into well differentiated and poorly differentiated (WDNECs and PDNECs). Histological differentiation based on WHO criteria had the highest impact on overall survival (OS) (PDNECs : WDNECs hazard ratio (HR)=4.02, P=0.02); however, PDNECs represented only a small percentage of patients (8%). In a WDNEC-restricted analysis, abnormal liver function tests (LFTs) and elevated urinary 5-hydroxyindoleacetic acid (u5HIAA) were independent prognostic factors for survival (HR=2.65, P=0.006 and HR=2.51, P=0.003, respectively) and were used to create a WDNEC-specific prognostic model (low risk=both normal, intermediate risk=one of them abnormal, high risk=both abnormal). Low-risk WDNECs had the most favourable prognosis (median OS, mOS 8.1 years), which was significantly better compared to both intermediate-risk and high-risk WDNECs (mOS 3.2 and 1.4 years, with P=0.01 and P<0.001, respectively). High-risk WDNECs displayed the shortest OS (1.3 years), which was similar to that of PDNECs (P=0.572). This analysis supports the prognostic value of WHO classification for metastatic NECs arising from the gastroenteropancreatic tract; however, risk stratification using readily available u5HIAA and LFTs may be necessary for the heterogeneous group of WDNECs

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