Analysis of 11q21–24 loss of heterozygosity candidate target genes in breast cancer: Indications of TSLC1 promoter hypermethylation

Abstract

Loss of heterozygosity (LOH) at the distal half of chromosome arm 11q is frequent in a variety of human tumors, including breast cancer, and is often associated with poor prognosis. In an ongoing attempt to locate and characterize the main target genes within this chromosome region, we first looked for aberrations in known genes either suggested to be involved in tumorigenesis or shown to suppress tumor formation. We examined 31 primary breast tumors showing LOH in 11q21-24 for mutations in the MRE11A, CHK1, PPP2R1B, and TSLC1 genes. The absence of intragenic alterations related to cancer led us next to evaluate possible gene silencing resulting from promoter region CpG hypermethylation, using the bisulfite sequencing technique. In addition to the four genes mentioned above, we also analyzed the ATM gene, which had been investigated for certain germline mutations in an earlier study. Only the TSLC1 promoter region exhibited aberrant methylation patterns, and altogether 33% (10/30) of the successfully analyzed tumors showed evidence of elevated levels of TSLC1 CpG methylation. Ten percent (3/30) of the tumors showed significantly increased methylation. Thus, as has been shown in lung and some other forms of cancer, hypermethylation of the TSLC1 promoter region is also frequently a second hit along with LOH in breast cancer.

Association of a lung tumor suppressor TSLC1 with MPP3, a human homologue of Drosophila tumor suppressor Dlg

“…We have previously identified the tumor suppressor in lung cancer 1 (TSLC1) gene on chromosome 11q23.2 by functional complementation through suppression of tumorigenicity of the human lung cancer cell line, A549 . Two-hit inactivation by loss of one allele and promoter methylation or truncating mutations in the other allele are observed in approximately 40% of primary NSCLC tumors as well as in 20-30% of tumors from the liver, pancreas, prostate, breast, and stomach Allinen et al, 2002;Fukuhara et al, 2002;Honda et al, 2002;Jansen et al, 2002;Murakami, 2002). An extracellular domain of TSLC1 contains three immunoglubulin-like C2-type loops showing significant homology with NCAM.…”

Atypical 11q deletions identified by array CGH may be missed by FISH panels for prognostic markers in chronic lymphocytic leukemia

“…Deregulation of the TSLC1 tumor suppressor gene has been described in a number of human malignancies, including neuroblastoma, nasopharyngeal carcinoma, breast cancer, lung adenocarcinoma, high-grade gliomas, pancreatic adenocarcinoma, esophageal squamous cell carcinoma, some forms of primary gastric cancer and prostate cancer. [23][24][25][26][27][28][29][30][31][32] The altered expression of TSLC1 has been associated with both promoter hypermethylation, as well as loss of heterozygosity. 25,29,[30][31][32] Each of these three putative deletion target genes is located clearly within the minimally deleted region on 11q as determined by both BAC and oligonucleotide array CGH, in all four of the CLL cases with atypical 11q deletions included in this study.…”

Overexpression of a cell adhesion molecule, TSLC1, as a possible molecular marker for acute-type adult T-cell leukemia

“…22,[28][29][30][31][32] Therefore, we examined the state of the TSLC1 gene promoter in the cell lines using a bisulfite-SSCP analysis coupled with sequencing of the 6 cytosine-phosphorothioate-guanine (CpG) sites within the promoter. Among the HTLV-1-infected T-cell or ATL cell lines, 3 lines (ED, SO-4, and HUT-102) expressing no or very little TSLC1 showed hypermethylation or partial methylation of the promoter.…”