Stress-induced aberrant splicing of TSG101: association to high tumor grade and p53 status in breast cancers

The TSG101 gene, identified through insertional mutagenesis, is localized i n a region that exhibits LOH in human cancers, suggesting that TSG101 might be a tumor suppressor gene. Numerous studies have then shown the presence of abnormal transcripts in various tumors which appear to result from aberr ant splicing of the gene, rather than from intragenic deletions. Moreover, many studies demonstrated that these aberrantly spliced transcripts mere no t found in matched normal tissues, We have analysed TSG101 transcripts in 8 5 breast cancer samples and found that abnormal splicing of the gene is tig htly correlated with tumor grade and p53 mutation. In addition, stress indu ced the appearance of these abnormal transcripts in primary lymphocytes. He nce, TSG101 splicing defects, while unrelated to the oncogenic process per se, could reflect the cellular environment of the tumor cells. The proposed role of stress and hypoxia to select p53 mutant cells could account for th e tight association with p53 status.