Expression of the DMBT1 Gene Is Frequently Suppressed in Human Lung Cancer

Abstract

DMBT1 (deleted in malignant brain tumors) is a candidate tumor suppressor gene that has been mapped to chromosome 10q25.3-q26.1, a region in which frequent loss of heterozygosity (LOH) has been observed in several human tumors. Since DMBT1 is highly expressed in the lung, we analyzed LOH at the DMBT1 locus and expression of this gene in lung cancer. Thirty-five (53%) of 66 primary lung cancers showed LOH, and diminished expression of DMBT1 was observed in 20 (91%) of 22 lung cancer cell lines: three (14%) of them showed loss of expression. We further determined the primary structure of DMBT1 and analyzed genetic alterations in this gene using 23 lung cancer cell lines. Two (9%) of them had homozygous deletion within the gene, and two cell lines had genetic aberrations: one was a rearrangement involving exons 5 and 6, and the other was a missense mutation at codon 52. These results suggest that inactivation of the DMBT1 gene plays an important role in human lung carcinogenesis.

Rare mutations of the DMBT1 gene in human astrocytic gliomas

“…It is a glycoprotein containing multiple scavenger receptor cysteine-rich (SRCR) domains separated by SRCR-interspersed domains (SID) (Mollenhauer et al, 1997. Somatic alterations in genome structure affecting the DMBT1 gene region and loss of DMBT1 gene expression have been observed in glioblastomas, medulloblastomas (Mollenhauer et al, 1997) and in non-CNS tumors such as lung cancers (Takeshita et al, 1999;Wu et al, 1999) and GI tumors (Mori et al, 1999). In malignant astrocytic tumors further studies confirmed either hemizygous or homozygous alterations (Fujisawa et al, 1999;Sasaki et al, 2001;Somerville et al, 1998;Steck et al, 1999).…”

“…In malignant astrocytic tumors further studies confirmed either hemizygous or homozygous alterations (Fujisawa et al, 1999;Sasaki et al, 2001;Somerville et al, 1998;Steck et al, 1999). So far, systematic analysis of the entire coding region of DMBT1 in tumors has not yet been performed since either distinct regions could not be amplified (Petersen et al, 2000), major portions of the gene were not included (Takeshita et al, 1999) or the primer design allowed simultaneous amplification of multiple amplicons in the highly repetitive regions of DMBT1 (Wu et al, 1999). Those alterations reported as a potential point mutation in codon 52 by two studies (Takeshita et al, 1999;Wu et al, 1999) turned out to be a single nucleotide polymorphism (SNP) in our analysis.…”

“…So far, systematic analysis of the entire coding region of DMBT1 in tumors has not yet been performed since either distinct regions could not be amplified (Petersen et al, 2000), major portions of the gene were not included (Takeshita et al, 1999) or the primer design allowed simultaneous amplification of multiple amplicons in the highly repetitive regions of DMBT1 (Wu et al, 1999). Those alterations reported as a potential point mutation in codon 52 by two studies (Takeshita et al, 1999;Wu et al, 1999) turned out to be a single nucleotide polymorphism (SNP) in our analysis. The prior failure to detect mutations may, therefore, be due to some mutations residing in regions not sufficiently covered by previous analyses.…”

The Conserved Scavenger Receptor Cysteine-Rich Superfamily in Therapy and Diagnosis

“…Furthermore, certain subpopulations of glioblastoma multiforme were actually shown to overexpress the protein (Mollenhauer et al, 2000). However, most cancer types that have been analyzed displayed a down-regulation of DMBT1/gp340/SAG expression levels, so that this might represent a more common mechanism of inactivation (Mori et al, 1999;Takeshita et al, 1999;Wu et al, 1999;Mollenhauer et al, 2000Mollenhauer et al, , 2001. A clearer role for DMBT1/gp340/SAG in the development, regeneration, and homeostasis of epithelia is now emerging thanks to recent reports.…”

“…Indeed, deregulation of DMBT1 expression has been reported for a number of tumors, including gliomas (Lin et al, 1998), small-and non-small-cell lung cancer cell lines and tumors (Takeshita et al, 1999;Wu et al, 1999;Mollenhauer et al, 2002), carcinoma of the esophagus (Mori et al, 1999;Mollenhauer et al, 2001), epithelial skin cancer , intrahepatic cholangiocarcinoma (Sasaki et al, 2003), breast cancer (Braidotti et al, 2004;Mollenhauer et al, 2004;Blackburn et al, 2007), salivary gland tumors (Bikker et al, 2004b), pancreatic ductal adenocarcinomas (Hustinx et al, 2004;Cheung et al, 2008), oral squamous cell carcinoma (Imai et al, 2005), gastric cancer (Conde et al, 2007), and cutaneous melanoma . In many cases, expression of DMBT1/gp340/SAG was deregulated not only at the tumor site but also in flanking tissue, which could arise as a consequence of the proinflammatory environment generated by the tumor.…”