Analysis of genetic abnormalities in locally advanced breast carcinomas determined by microsatellite alterations and p53 gene mutations

SF Picard, ST, N Franco, ST, L Hahnel, MS, M Arnal, MS, and S Lizard, PhD

Laboratory of Molecular Genetic, Centre Georges Francois Leclerc, INSERM U517, Dijon 21034, France

AIM: Several studies have shown that genetic alterations could be a prognosis factor of clinical response and/or survival in many human cancers. In this study we determined the role of microsatellite instability and p53 gene mutations in breast cancer. METHODS: Microsatellite instability (LOH for Loss of Heterozygosity and MIN for Microsatellite Instability) was determined at 11 loci by fragment analysis (ABI310, PE Applied Biosystem), and p53 mutations were assessed by SSCP and direct sequencing (ABI310) on 47 patients with locally advanced breast cancer. RESULTS: Our results show that the most altered loci are the D3S1244 (22%), D3S1612 (19%), Tp53 (17%), AR (16%), D17S855 (15%) and D3S1514 (13%) for LOH, and D8S256 (4%), D3S1612 (2%) and D6S264 (2%) for MIN. Statistical analysis revealed strong associations between p53 (p=0.0003), D3S1514 (p=0.0006), D3S1244 (p=0.0016), and D17S855 (p=0.022) alterations with the LOH of the remaining loci. In contrast, positive relations were found with disease-free survival (p=0.031, and p=0.045), and with death (p=0.014, and p=0.026) at 3 years only for p53 and D3S1514, respectively. CONCLUSIONS: Our study confirms the role of p53 gene for the poor indicative prognosis in breast cancer, but also show the importance of D3S1514 (hMLH1 locus) and D17S855 (BRCA1 locus) link with genomic instability, disease-free survival, and death. Furthers studies are needed to clarify the prognostic value of these gene alterations in breast carcinomas.

KEY WORDS: Breast cancer, Loss of heterozygosity, Microsatellite instability, Fragment analysis.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Prognostic Markers.