Candidate tumour suppressor genes at 11q23-q24 in breast cancer: evidence of alterations in PIG8, a gene involved in p53-induced apoptosis.
One of the most consistently deleted chromosomal regions in solid tumours is 11q23-q25, which consequently has been postulated to harbour one or more tumour suppressor loci. Despite large efforts to identify the responsible genes, the goal remains elusive, but as knowledge accumulates new candidates are emerging. The present study was undertaken in an attempt to assess the possible implication of four genes residing at 11q23-q24, in a population of early onset breast cancer (n=41). The coding sequence of PIG8, CHK1, LOH11CR2A and PPP2R1B were screened for mutations using the protein truncation test or single-strand conformational polymorphism, in combination with direct DNA sequencing. Varying proportions of alterations were detected, ranging from 6% in PPP2R1B to 39% in PIG8. Many of these changes were deletions, in some cases corresponding to complete exons, thus likely to represent splice variants, while others were presumed to arise from aberrant splicing, since they occurred at sites with resemblance to exon/intron borders. Considering only bona fide mutations, the highest alteration frequency (17%) was again found in PIG8. Most of these alterations were likely to have an adverse impact on the translated protein as they either altered the reading frame or affected phylogenetically conserved residues. Our data represent the first evidence of alterations in the PIG8 gene in human malignancies, a finding that substantiates its role as a potential tumour suppressor gene as suggested by its involvement in p53-induced apoptosis.
Gentile
M
M
Department of Biomedicine and Surgery, Division of Oncology, University Hospital, S-581 85 Linköping, Sweden.
Ahnström
M
M
Schön
F
F
Wingren
S
S
D000328:Adult; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms / Q000235:genetics*; D000071877:Checkpoint Kinase 1; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics*; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics*; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011494:Protein Kinases / Q000235:genetics; D054648:Protein Phosphatase 2; D011506:Proteins / Q000737:chemistry / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C402592:EI24 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C432785:PPP2R1B protein, human; D010750:Phosphoproteins; D011506:Proteins; D016159:Tumor Suppressor Protein p53; C109969:VWA5A protein, human; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D054648:Protein Phosphatase 2