在新一期的PLoS ONE上刊登的一項(xiàng)新研究確定出可預(yù)測(cè)腦瘤患者預(yù)后的一號(hào)染色體上的一個(gè)基因座,。這項(xiàng)研究可能為研發(fā)更有效抵抗腦癌的藥物奠定了基礎(chǔ)。
瑞士Hospital basel大學(xué),、德國(guó)heinrich Heine大學(xué)和美國(guó)Emory大學(xué)的臨床和基礎(chǔ)研究人員確定出Notch2基因是腦瘤形成的候選基因。
Notch2基因座能很精確地預(yù)測(cè)腦瘤患者亞群的存活率,。這個(gè)基因是發(fā)育過(guò)程的一個(gè)重要調(diào)節(jié)因子,。
利用一種包含了Notch2基因的復(fù)雜DNA拷貝，研究人員發(fā)明出一種精確區(qū)別預(yù)后良好與預(yù)后不良的腦瘤病例的分子分析方法,。
在正在進(jìn)行的研究中,，Basel的研究人員發(fā)現(xiàn)Notch2上調(diào)了tenascin-C基因——一種在腦瘤形成過(guò)程中起到關(guān)鍵作用的基因。這個(gè)新的腦瘤途徑不但能提供精確的診斷信息,，而且還能有助于找到分子干預(yù)新靶標(biāo)以促進(jìn)開(kāi)發(fā)出治療這種嚴(yán)重人類(lèi)疾病的藥物,。
原始出處:
PLoS ONE
Received: April 17, 2007; Accepted: June 1, 2007; Published: June 27, 2007
Loss of NOTCH2 Positively Predicts Survival in Subgroups of Human Glial Brain Tumors
Jean-Louis Boulay1, André R. Miserez2, Christian Zweifel1,3, Balasubramanian Sivasankaran1, Veronika Kana1, Anthony Ghaffari1,3, Cordelia Luyken4, Michael Sabel4, Abdessamad Zerrouqi5, Morten Wasner3, Erwin Van Meir5, Markus Tolnay6, Guido Reifenberger4, Adrian Merlo1,3*
1 Laboratory of Molecular Neuro-Oncology, Department of Research, University Hospital, Basel, Switzerland, 2 Research Laboratories, Diagene Inc., Reinach, Switzerland, 3 Neurosurgical Clinic, University Hospital, Basel, Switzerland, 4 Departments of Neuropathology, and Neurosurgery, Heinrich-Heine-University, Düsseldorf, Germany, 5 Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, Emory University, Atlanta, Georgia, United States of America, 6 Institute of Pathology, University Hospital, Basel, Switzerland
The structural complexity of chromosome 1p centromeric region has been an obstacle for fine mapping of tumor suppressor genes in this area. Loss of heterozygosity (LOH) on chromosome 1p is associated with the longer survival of oligodendroglioma (OD) patients. To test the clinical relevance of 1p loss in glioblastomas (GBM) patients and identifiy the underlying tumor suppressor locus, we constructed a somatic deletion map on chromosome 1p in 26 OG and 118 GBM. Deletion hotspots at 4 microsatellite markers located at 1p36.3, 1p36.1, 1p22 and 1p11 defined 10 distinct haplotypes that were related to patient survival. We found that loss of 1p centromeric marker D1S2696 within NOTCH2 intron 12 was associated with favorable prognosis in OD (P = 0.0007) as well as in GBM (P = 0.0175), while 19q loss, concomitant with 1p LOH in OD, had no influence on GBM survival (P = 0.918). Assessment of the intra-chromosomal ratio between NOTCH2 and its 1q21 pericentric duplication N2N (N2/N2N-test) allowed delineation of a consistent centromeric breakpoint in OD that also contained a minimally lost area in GBM. OD and GBM showed distinct deletion patterns that converged to the NOTCH2 gene in both glioma subtypes. Moreover, the N2/N2N-test disclosed homozygous deletions of NOTCH2 in primary OD. The N2/N2N test distinguished OD from GBM with a specificity of 100% and a sensitivity of 97%. Combined assessment of NOTCH2 genetic markers D1S2696 and N2/N2N predicted 24-month survival with an accuracy (0.925) that is equivalent to histological classification combined with the D1S2696 status (0.954) and higher than current genetic evaluation by 1p/19q LOH (0.762). Our data propose NOTCH2 as a powerful new molecular test to detect prognostically favorable gliomas.
Figure 1. Glioma patients with centromeric 1p allelic loss show better survival.
(A) Deletion patterns on chromosome 1p in GBM and OD. Somatic deletion mapping in 118 GBM and 26 OD WHO grades II and III was performed using 43 microsatellite markers. Four markers at deletion hotspots (D1S2845 at 1p36.3, D1S507 at 1p36.1, D1S216 at 1p22 and D1S2696 at 1p11) were selected to define chromosome 1p haplotypes. In GBM, 10 haplotypes were grouped into tumors with centromeric (H8–H10), interstitial (H5–H7) and telomeric (H2–H4) deletion patterns. In OD, only haplotypes H1 and H10 were observed. Chromosomal positions of 1p markers are shown on the left and areas of allelic loss are shown in grey. (B) Kaplan-Meier cumulative survival curve of the haplotype groups.
