The SRCR/SID region of DMBT1 defines a complex multi-allele system representing the major basis for its variability in cancer

Deleted in malignant brain tumors I (DMBTI) at 10q25.3-q26.1 has been proposed as a candidate tumor-suppressor gene for brain and epithelial cancer. DMBTI encodes a multifunctional mucin-like protein presumably involved in epithelial differentiation and protection. The gene consists of highly homologous and repeating exon and intron sequences. This specifically applies to the region coding for the repetitive scavenger receptor cysteine-rich (SRCR) domains and SRCR-interspersed domains (SIDs) that constitutes the major part of the gene. This particular structure may previously have interfered with the delineation of DMBTI alterations in cancer. Uncovering these, however, is of mechanistic importance. By a combined approach, we conducted a detailed mutational analysis, starting from a panel of 51 tumors, including 46 tumor cell lines and five primary tumors. Alterations in the repetitive region were present in 22/31 (71%) tumors that were investigated in detail. Six tumors showed presumably de novo mutations, among these three with point mutations in combination with a loss of heterozygosity. However, none of the alterations unambiguously would be predicted to lead to an inactivation of DMBTI. We define seven distinct DMBTI alleles based on variable numbers of tandem repeats (VNTRs). At least II tumors exclusively harbored these VNTRs. The data suggest that the SRCR/SID region defines a complex multi-allele system that has escaped previous analyses and that represents the major basis for the variability of DMBTI in cancer. DMBTI thus compares to mucins rather than to conventional tumor suppressors. © 2002 Wiley-Liss, Inc.