OMICS AND PROGNSTIC MARKERS

Abstract

Although histopathological diagnosis is essential in decision of therapeutic strategy for gliomas, sometimes the tumors diagnosed in one histological entity show thoroughly different clinical courses. This phenomenon is believed to be due primarily to the presence of the genetic subgroup. In fact, relationship between treatment response and certain genetic characteristics is indicated (e.g. better chemosensitivity in glioma with losses of 1p/19q (−1p/19q)). It is highly likely that genetic classification of glioma is useful to select the adjuvant treatment. Additionally, gain of 7q (+7q) and −1p/19q are early events in 2 distinct tumor lineages, astrocytic tumors and oligodendroglial tumors, respectively, and these tumors obtain additional genetic aberration (−9p, 10q) with tumor progression. On the other hand, concerning the tumors without +7q or −1p/19q, little is known about clinically important genetic aberration. Therefore the study on such tumors could provide useful information for the prognosis prediction and the determination of treatment strategy. METHODS: We selected 39 cases of gliomas without +7q or −1p/19q from 200 adult supratentorial glioma cases surgically treated and analyzed chromosomal DNA copy number aberrations (CNAs) by comparative genomic hybridization (CGH) from 2005 to 2012. We correlated clinical features of these tumors with histological characteristics, CNAs and IDH1 status. RESULTS: The clinical course of gliomas without +7q or −1p/19q was not correlated with additional genetic aberration of -9p or 10q, which have been known as genetic markers for poor prognosis, and absence of +7q or −1p/19q was maintained at the time of recurrence. The tumors without +7q or −1p/19q showed relatively favorable prognosis although mutation of IDH1 was infrequent in these tumors (35.8 %). CONCLUSION: The gliomas without +7q or −1p/19q have clinical features distinct from the +7q and −1p/19q gliomas. Prognostic markers for each subgroups could help establish therapeutic strategy against the tumor. OBJECTIVE: Glioblastoma is the most common type of primary brain tumor in adults and remains extremely lethal. Recently, the research efforts in identifying prognostic molecular biomarkers for glioblastoma have increased. Cysteine-rich protein 61(CYR61) is one of the CCN family of matricellular proteins which promotes proliferation and angiogenesis in cancers through its interaction with several integrins. In this study, we investigated the relations of CYR61 and other prognostic factors in glioblastoma. METHODS: We analyzed tissues excised from 33 glioblastoma patients in adults treated at Okayama University between 2006 and 2011 (male, 17 female, 16; mean age, 59.2 years; range, 19-81 years). All patients underwent surgical resection followed by adjuvant radiation therapy and chemotherapy with temozolomide. Extent of resection was classified as gross total resection (GTR, ≥ 95% by volume), subtotal resection (STR, ≥80, < 95% by volume) or partial resection and biopsy (PR/ biopsy, < 80% by volume) based on magnetic resonance imaging performed less than 48 hours after surgery. Tumor samples were examined by immunohistochemistry for CYR61 expressions. Multivariate Cox proportional hazard model was used to identify possible prognostic factors. RESULTS: GTR, STR, and PR/ biopsy were achieved in 17 (51%), 5 (15%), and 11 (33%) cases, respectively. CYR61 expression was positive in 22 glioblastoma (66%). Median progression-free survival (PFS) and overall survival (OS) of patients with strong CYR61 expression was significantly shorter than those of patients with weak CYR61 expression (PFS: 6 months and 18 months, OS: 12 months and 27 months, respectively, p < 0.005). In a multivariate Cox analysis, CYR61 proved to be an independent prognostic factor of patient survival (PFS: HR = 2.77 (1.08 - 7.09), p = 0.034, OS: HR = 2.92 (1.00 - 8.49), p = 0.049). CONCLUSION: CYR61 might emerge as a strong candidate for a significant association with prognosis of glioblastoma. Meningiomas constitute approximately one-third of primary CNS tumors. Most of them are classified as Meningioma (grade I) and are treated by surgical resection. However other different types of meningioma exist: atypical meningioma (grade II) and anaplastic meningioma (grade III), with poor outcome. Aim of this study was to investigate biomarkers implicated in tumorigenesis compared to clinical data, looking for prognostic factors suggestive of tendency to recur and potential therapeutic targets. We performed a retrospective study on 150 patients with 15-10 years follow up for meningiomas grade I-II. They were 50 meningiomas (grade I) without recurrence, 40 meningiomas (grade I) with recurrence, 40 atypical meningiomas and 20 anaplastic meningiomas. We investigated biomarkers implicated on different pathways: i) Angiogenesis (Vascular Endothelial Growth Factor (VEGF), angiogenesis promoter; Endoglin (CD105) marker of activated endothelial cells). ii) Receptor tyrosine kinases (Platelet-Derived Growth Factor Receptor a and b (PDGFR), implicated in tumorigenesis, related to expression of c-Kit; Fibroblast Growth Factor Receptor (FGFR)). iii) Invasion (Matrix-metalloproteinase (MMP9, 2, 3); cell adhesion molecules (β-catenin and E-cadherin). iiii) Proliferation (Cyclin-Dependent Kinases Regulatory Subunit 2 (CKS2) regulating metaphase/anaphase transition, down-regulating the gene codifying Leptin Receptor (LEPR2)). We analysed the expression of biomarkers using immunohistochemistry, Western Blot and RT-PCR. The results were correlated with clinical data. Our results suggest high frequency of recurrence on cases with high expression of PDGFR, c-Kit, MMP9, CKS2. In particular, increasing expression of PDGFR was observed related to the grade. c-Kit immunohistochemical expression was present on about 20% of cases with worse prognosis. MMP9 seems to be a negative prognostic factor independently to the grade. CKS2 expression was related to recurrences. In atypical meningiomas β-catenin seems related to better prognosis. In conclusion, the different expression profiles of biomarkers in meningiomas related to clinical data, may have a role as new prognostic markers and potential therapeutic targets.