DMBT1, a new member of the SRCR superfamily, on chromosome 10q25.3–26.1 is deleted in malignant brain tumours

Abstract

Loss of sequences from human chromosome 10q has been associated with the progression of human cancer. Medulloblastoma and glioblastoma multiforme are the most common malignant brain tumours in children and adults, respectively. In glioblastoma multiforme, the most aggressive form, 80% of the tumours show loss of 10q. We have used representational difference analysis to identify a homozygous deletion at 10q25.3-26.1 in a medulloblastoma cell line and have cloned a novel gene, DMBT1, spanning this deletion. DMBT1 shows homology to the scavenger receptor cysteine-rich (SRCR) superfamily. Intragenic homozygous deletions has been detected in 2/20 medulloblastomas and in 9/39 glioblastomas multiformes. Lack of DMBT1 expression has been demonstrated in 4/5 brain-tumour cell lines. We suggest that DMBT1 is a putative tumour-suppressor gene implicated in the carcinogenesis of medulloblastoma and glibolastoma multiforme.

Comparative molecular genetic profiles of anaplastic astrocytomas/ glioblastomas multiforme and their subsequent recurrences

“…The molecular parameters analysed on matched pairs of primary and malignant glioblastomas included (1) multiple restriction fragment length polymorphism (RFLP) markers on chromosome 17p (D17S34, D17S28, D17S5, D17S31, p53, and D17S71) spanning the p53 locus as well as the region where another putative tumor suppressor gene implicated in glioblastoma resides , (2) multiple RFLP (D10S1, D10S4, D10S25, D10S19 and D10S28) and microsatellite markers (D10S215, D10S541, AFM086, AFM280, D10S169, D10S209, D10S216, D10S217) on chromosome 10, spanning the recently cloned PTEN/ MMAC1 (Li et al, 1997;Steck et al, 1997) and DMBT1 genes (Mollenhauer et al, 1997), (3) sequencing of the exons 5 ± 9 of the p53 gene, (4) SSCP analysis of all nine exons of the PTEN/MMAC1 gene, (5) duplex PCR to determine the homozygous deletion of the DMBT1 gene, (6) ampli®cation and/or overexpression of the EGFR and PDGFRa genes, and (7) expression of gelatinase A (gelA) and its inhibitor, tissue inhibitor of metalloproteinase-2 (TIMP-2) by Northern blotting.…”

“…The same Taq 1 digested blot stripped and probed with D10S4 marker is shown as a control for DNA loading. (b) Patient 53: homozygous deletion of the marker g14ext located within the DMBT1 gene ampli®ed in a duplex PCR reaction using the c12 marker on chromosome 8 as an internal control as described (Mollenhauer et al, 1997). Patient 102: allelic deletion at D17S5 (integrated densities: L, 100%; P, 115%; R, 49%) and homozygous deletion at markers 36k and g14ext located within the DMBT1 gene in the recurrent tumor DNA.…”

“…Overexpression of both a and b forms of PDGFR at the protein level (Fleming et al, 1992) and amplification of the CDK4 gene (Saxena et al, 1996) were also detected in the recurrent tumor of patient 16. Figure 1b demonstrates homozygous deletion of the DMBT1 gene, located on 10q25.3-26.1 (Mollenhauer et al, 1997), in the recurrent tumor of patient 53. In the duplex PCR, the marker g14ext, located within the DMBT1 gene, was ampli®ed in the lymphocyte and the primary tumor, but was absent from the recurrent tumor.…”

Molecular analysis of two putative tumour suppressor genes, PTEN and DMBT, which have been implicated in glioblastoma multiforme disease progression

“…The DMBT (Deleted in Malignant Brain Tumours) gene was isolated by representational di erential analysis and mapped to a region spanning 10q25.3-26.1 (Mollenhauer et al, 1997). At the amino acid level, this gene has homology to members of the scavenger receptor cystein rich family (SCRC).…”

“…In the initial study of 39 patients with glioblastoma multiforme, intragenic homozygous deletions were detected in 23% of cases. To determine whether any of the GBMs in our series showed DMBT deletions, all 21 tumours that had been examined for PTEN mutations, were screened for homozygous deletions by PCR using the primers described by Mollenhauer et al (1997). Homozygous, intragenic deletions were detected in eight of the 21 (38%) tumours screened (Figure 2).…”