BACKGROUND: Epigenetic silencing of O 6 -methylguanine-DNA-methyltransferase (MGMT) by promoter methylation is associated with improved survival in glioblastomas treated with alkylating agents. In this study, we investigated MGMT promoter methylation in glioblastomas treated with temozolomide and radiotherapy in a single UK treatment centre. METHODS: Quantitative methylation data at individual CpG sites were obtained by pyrosequencing for 109 glioblastomas. RESULTS: Median overall survival (OS) was 12.4 months with 2-year survival of 17.9%. Pyrosequencing data were reproducible with archival samples yielding data for all glioblastomas. Variation in methylation patterns of discrete CpG sites and intratumoral methylation heterogeneity were observed. A total of 58 out of 109 glioblastomas showed average methylation 4non-neoplastic brain in at least one clinical sample; 86% had homogeneous methylation status in multiple samples. Methylation was an independent prognostic factor associated with prolonged progression-free survival (PFS) and OS. Cases with methylation more than 35% had the longest survival (median PFS 19.2; OS 26.2 months, 2-year survival of 59.7%). Significant differences in PFS were seen between those with intermediate or high methylation and unmethylated cases, whereas cases with low, intermediate or high methylation all showed significantly different OS. CONCLUSIONS: These data indicate that MGMT methylation is prognostically significant in glioblastomas given chemoradiotherapy in the routine clinic; furthermore, the extent of methylation may be used to provide additional prognostic stratification.
X-box binding protein 1 (XBP-1) is stimulated by endoplasmic reticulum stress as part of the unfolded protein response (UPR), which can promote apoptosis or cell survival. Non-conventional splicing, stimulated during the UPR, converts mRNA for ''unspliced'' XBP-1U to ''spliced'' XBP-1S mRNA. XBP-1 mRNA is oestrogen-responsive, but XBP-1S confers oestrogen independence and anti-oestrogen resistance to breast cancer cell lines. We therefore evaluated XBP-1 mRNA splicing as a factor in response of breast cancer patients to endocrine treatment. XBP-1 isoforms were measured by quantitative RT-PCR in 100 primary breast cancer patients treated with adjuvant tamoxifen (including 30 ERa-negative cases). In ERa-positive cases, levels of XBP-1U mRNA correlated with ERa mRNA levels and were lower in grade 3 tumors. Higher levels of XBP-1U mRNA were significantly associated with breast cancer survival (Log-rank p 5 0.002; Cox hazard ratio (HR) 0.2, p 5 0.005), independent of grade, size, nodal status and progesterone receptor status. However, in the full cohort, higher ratios of XBP-1S/XBP-1U mRNA (indicating enhanced splicing) were associated with poor survival (Log-rank p 5 0.03; Cox HR 2.3, p 5 0.03) and related factors: ERa-negative status, progesterone receptor negative status, grade 3 tumors and greater proliferation. Significant associations with poor outcome were also seen for XBP-1 splicing in ERa-positive cases. Our findings, that XBP-1 isoforms are differently associated with outcome of endocrine therapy for patients, can be explained by higher levels of dominant-negative XBP-1U favouring apoptosis of tumor cells and higher levels of XBP-1S increasing tumor survival.
Oligodendroglial neoplasms with the -1p/-19q genotype are more indolent with longer survival and increased therapeutic responsiveness than those with intact 1p/19q, but the biological basis for these clinical differences is unclear. Recent research suggests that oligodendrogliomas with and without the -1p/-19q genotype may be distinguished by their magnetic resonance imaging (MRI) appearance, suggesting possible differences in growth characteristics. This study examined the relationship between genotype and histological growth patterns of oligodendroglial neoplasms in association with MR imaging characteristics. Tumour imaging features assessed on MRI included sharp-versus-indistinct border, smooth-versus-irregular contour, homogeneous-versus-heterogeneous signal, contrast enhancement and paramagnetic susceptibility effect. Growth patterns (solid : mixed : infiltrative), tumour-margin transitions in cellularity and calcification were determined histopathologically. Allelic imbalance in chromosomes 1p36 and 19q13 was determined. Thirty-three oligodendrogliomas (25 with 1p/19q loss) and 53 oligoastrocytomas (18 with 1p/19q loss) were investigated. Solid, mixed or infiltrative growth patterns were seen in grade II and grade III tumours with or without 1p/19q loss, but infiltrative growth was more common in tumours with intact 1p/19q (chi2: P = 0.029). Grade III tumours were more likely to have a solid growth pattern (chi2: P = 0.046) associated with contrast enhancement (chi2: P = 0.011). Transition in cellularity at the radiological margin did not differ according to genotype. All cases with T1 or T2 signal homogeneity had intact 1p/19q. Tumours with sharp/smooth borders were more likely to have intact 1p/19q than those with indistinct/irregular borders (chi2: P < 0.001), but this was not related to histological growth characteristics. This study identified a group of oligodendroglial tumours with intact 1p/19q displaying distinctive MR imaging features that were unrelated to the histopathology characteristics.
Introduction The biological factors responsible for differential chemoresponsiveness in oligodendroglial tumours with or without the −1p/−19q genotype are unknown, but tumour vascularity may contribute. We aimed to determine whether dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) could distinguish molecular subtypes of oligodendroglial tumour, and examined the relationship between relative cerebral blood volume (rCBV) and outcome following procarbazine, lomustine and vincristine (PCV) chemotherapy. Methods Pretherapy rCBV was calculated and inter-and intraobserver variability assessed. Allelic imbalance in 1p36, 19q13, 17p13, 10p12-15, and 10q22-26 and p53 mutation (exons 5-8) were determined. rCBV was compared with genotype and clinicopathological characteristics (n=37) and outcome following PCV chemotherapy (n=33). Results 1p/19q loss was seen in 6/9 grade II oligodendrogliomas, 6/14 grade II oligoastrocytomas, 4/4 grade III oligodendrogliomas, and 3/10 grade III oligoastrocytomas. rCBV measurements had good inter-and intraobserver variability, but did not distinguish histology subtype or grade. Tumours with 1p/19q loss had higher rCBV values (Student's t-test P=0.001). Receiver operating characteristic analysis revealed a cut-off of 1.59 for identifying genotype (sensitivity 92%, specificity 76%). Tumours with high and low rCBV showed response to chemotherapy. The −1p/ −19q genotype, but not rCBV, was strongly associated with response, progression-free and overall survival following PCV chemotherapy. Tumours with high rCBV and intact 1p/19q were associated with shorter progression-free and overall patient survival than those with intact 1p/19q and low rCBV or high rCBV and 1p/19q loss. Conclusion rCBV identifies oligodendroglial tumours with 1p/19q loss, but does not predict chemosensitivity. The prognostic significance of rCBV may differ in oligodendroglial tumours with or without the −1p/−19q genotype.
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