Analysis of 11q21-24 loss of heterozygosity candidate target genes in breast cancer: indications of TSLC1 promoter hypermethylation.
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.
Allinen
Minna
M
Department of Clinical Genetics, University Hospital, University of Oulu, FIN-90029 OYS, Oulu, Finland.
Peri
Liisa
L
Kujala
Sonja
S
Lahti-Domenici
Jaana
J
Outila
Kati
K
Karppinen
Sanna-Maria
SM
Launonen
Virpi
V
Winqvist
Robert
R
D064007:Ataxia Telangiectasia Mutated Proteins; D001943:Breast Neoplasms / Q000235:genetics*; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D000071877:Checkpoint Kinase 1; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D004252:DNA Mutational Analysis / Q000379:methods; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D007136:Immunoglobulins; D019656:Loss of Heterozygosity / Q000235:genetics*; D000076228:MRE11 Homologue Protein; D008565:Membrane Proteins; D009363:Neoplasm Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011494:Protein Kinases / Q000235:genetics; D054648:Protein Phosphatase 2; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011506:Proteins / Q000235:genetics*; D025521:Tumor Suppressor Proteins
C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D007136:Immunoglobulins; C121766:MRE11 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C432785:PPP2R1B protein, human; D011506:Proteins; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases; D000076228:MRE11 Homologue Protein; D054648:Protein Phosphatase 2