The presence of multiple regions of homozygous deletion at the CSMD1 locus in oral squamous cell carcinoma question the role of CSMD1 in head and neck carcinogenesis

Abstract

We and others previously identified a region of hemizygous or homozygous deletion at chromosome band 8p23 in oral and oropharyngeal squamous cell carcinomas (OSCCs) and many other cancer types, suggesting the presence of a tumor-suppressor gene (TSG) in this region. Recently, based on a single region of homozygous deletion in head and neck squamous cell carcinomas (HNSCC), a putative TSG, CUB and sushi multiple domains-1 (CSMD1), has been identified. In the present study, we mapped three OSCC cell lines with previously described homozygous deletions at a high resolution onto a detailed physical map. Critically, this map covered a wider region than that used in previous studies, and in contrast to these studies, our results revealed multiple regions of homozygous deletion within a small interval on 8p23. To investigate this deletion pattern further, we generated a panel of 34 sequence tagged site (STS) markers spanning the region and tested these three cell lines and an additional 34 OSCC cell lines, identifying homozygous deletions in a further four. Combining the results from all seven deleted cell lines identified three non-overlapping regions of homozygous deletion. This complex pattern could be consistent with the presence of multiple TSGs or one very large TSG in this region, and/or specific chromosomal instability. CSMD1 spans two of the three deleted regions and, therefore, would appear to be an excellent candidate for a TSG. However, deletion mapping with STSs corresponding to the exons of CSMD1 shows that some of the deletions do not interrupt its coding region, and in other cell lines the coding region is interrupted by two discontinuous homozygous deletions, suggesting the presence of redundant deletions. These results call into question whether the CSMD1 gene is the 8p23 TSG or whether this or any other genes at this locus are involved in the development of OSCC.

High-resolution analysis of chromosome rearrangements on 8p in breast, colon and pancreatic cancer reveals a complex pattern of loss, gain and translocation

“…Most of the candidates proposed previously -none of which are particularly convincing -are in the region 3-24 Mb (e.g. DLC1, DBC2, FEZ1/LZTS1 and TUSC3; for references see Birnbaum et al, 2003;Toomes et al, 2003;Asatiani et al, 2005) and our array CGH (Figure 2) gives no obvious support to this region as it is substantially distal to the breaks we have detected. However, if breaks are concentrated in regions of relative fragility, this argument would not hold.…”

Mapping DNA structural variation in dogs

“…Deletion and reduced expression of CSMD1 are associated with poor prognosis in prostate and squamous cell cancers (Scholnick et al 1996;Henshall et al 2003;Paris et al 2004). Both somatic point mutations and allele loss of CSMD1 are associated with cancer (Toomes et al 2003;Richter et al 2005;Farrell et al 2008). We found a microduplication within CSMD1 in 14 of 22 Rottweilers (64%), but not in any of 29 non-Rottweilers (including 11 dogs in the broadly defined Mastiff breed class) (Wilcox and Walkowicz 1995).…”

Prognostic implications of loss of heterozygosity at 8p21 and 9p21 in head and neck squamous cell carcinoma

“…At 8p23.2, the CSMD1 gene spans from 2.78 cM to 4.84 cm from the p-terminus and encodes a transmembrane protein of unknown function. Recently, however, Toomes et al 17 were unable to confirm independently a role for CSMD1 in HNSCC. The authors performed deletion mapping using 34 sequence-tagged site (STS) markers in a total of 37 cell lines and identified 3 nonoverlapping regions of homozygous deletion, 2 of which reside within the span of the CSMD1 gene.…”