Abstract
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.
Highlights
Histological classification and the WHO grading of glial brain tumors represents the gold standard to estimate prognosis and guide therapy [1,2]
OD differ from GBM by frequent loss of heterozygosity (LOH) on the entire chromosome 1p, combined with LOH on 19q [7,8], which is a result from an unbalanced translocation t(1;19)(q10;p10) [9,10]
We found that NOTCH2 is a common deletion target in OD as well as in GBM, raising the hypothesis of a possible causal relationship between NOTCH2 status and tumor behavior
Summary
Histological classification and the WHO grading of glial brain tumors represents the gold standard to estimate prognosis and guide therapy [1,2]. Even within one histological glioma subtype, the course of the disease can be highly variable, depending of the genetic background of the tumor For these reasons, molecular markers are expected to improve diagnostic and prognostic accuracy and guide therapy. OD differ from GBM by frequent loss of heterozygosity (LOH) on the entire chromosome 1p, combined with LOH on 19q [7,8], which is a result from an unbalanced translocation t(1;19)(q10;p10) [9,10]. This genetic alteration is associated with favorable prognosis and response to radio- and chemotherapy in OD grade III [11,12]. The reference sequence of human chromosome 1 only recently unraveled the structural complexity of intrachromosomal duplications, at the centromeric region [18]
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