Numerical and structural aberrations in advanced neuroblastoma tumours by CGH analysis; survival correlates with chromosome 17 status

Rapid tumour progression in neuroblastoma is associated with MYCN amplification, deletion of the short arm of chromosome 1 and gain of 17q. However, patients with advanced disease without MYCN amplification and/or 1p deletion have a very poor outcome too, which suggests other genetic defects may predict an unfavourable prognosis. We employed CGH to study 22 tumours of patients at stages 3 and 4 over one year of age (6 and 16 cases respectively). Patients were divided in groups (A) long-term survivors and (B) short-term survivors. CGH showed a total of 226 chromosome imbalances (110 in group A and 116 in group B). The neuroblastoma cells of long-term survivors showed a preponderance of numerical aberrations (54%vs 43%); particularly gains of entire chromosomes 1 (P< 0.03), 7 (P< 0.04) and 19 (P< 0.05). An extra copy of 17 was detected in 6/8 (75%) samples of group A and only 1/14 (7%) samples of group B (P< 0.002). Conversely, tumours of patients who died from disease progression displayed a higher frequency of structural abnormalities (43%vs 35%), including loss of 1p, 9p, 11q, 15q and 18q and gain of 12q, although the difference was not significant (P= 0.24). Unbalanced gain of 17q was detected in 8/14 (57%) tumours of group B and only 1/8 (13%) tumours of group A (P< 0.05). The peculiar genetic difference observed in the tumours of long and short-term survivors may have prognostic relevance. © 2000 Cancer Research Campaig

A NOVEL FUSION 5'AFF3/3'BCL2 ORIGINATED FROM A t(2;18)(Q11.2-Q21.33) TRANSLOCATION IN FOLLICULAR LYMPHOMA

Follicular lymphoma is the second most frequent type of non-Hodgkin's lymphoma in adults. The basic molecular defect consists of the t(14;18)(q32;q21) translocation, juxtaposing the B-cell lymphoma protein 2 gene BCL2 to the immunoglobulin heavy chain locus IGH@, and leading to the antiapoptotic BCL2 protein overproduction. Variations in the t(14;18) are rare and can be classified into two categories: (i) simple variants, involving chromosomes 18 and 2, or 22, in which the fusion partner of BCL2 is the light-chain IGK@ or IGL@; (ii) complex variant translocations occurring among chromosomes 14, 18 and other chromosomes. We report a follicular lymphoma case showing BCL2 overexpression, detected by immunohistochemistry and real-time quantitative PCR, consequently to the formation of a novel fusion gene between the 5' of the lymphoid nuclear transcriptional activator gene AFF3 at 2q11.2, and the 3' of BCL2. This case shows evidence, for the first time, of BCL2 overexpression consequently to the fusion of BCL2 to a non-IG partner locus

Structural and functional analysis of cyclin-dependent kinase inhibitor genes (CDKN2A, CDKN2B, and CDKN2C) in neuroblastoma

The status of the CDKN2A gene family, including CDKN2A, CDKN2B, and CDKN2C, was investigated in 24 cases of neuroblastoma. These genes were selected on the basis of 1) high incidence of their inactivation in several human cancers and 2) their localization on chromosomal regions (9p and 1p) frequently rearranged in neuroblastomas. Detailed molecular analyses indicated the absence of homozygous deletions and point mutations involving these genes in all investigated tumor samples. However, when loss of heterozygostity for chromosome 9p21 (the region where CDKN2A and CDKN2B are localized) was investigated, 16% of cases showed abnormalities in an area telomeric to the CDKN2A locus. To study transcriptional silencing of the CDKN2A gene, the methylation status of exon 1 was examined. In about 35% of cases, a partial methylation was evidenced. Analysis of the CDKN2A mRNA expression, however, did not show any relationship between methylation status and gene transcription. Finally, expression of the CDKN2B gene was demonstrated in all stage IV neuroblastomas, whereas none of stage I tumors expressed this gene. This finding suggests the occurrence of a correlation between CDKN2B transcription and tumor phenotype