Laetitia Huiart

Perforin gene (PRF1) mutations have been identified in some patients diagnosed with the familial form of hemophagocytic lymphohistiocytosis (HLH) and in patients with lymphoma. The aim of the present study was to determine whether patients with a familial aggregation of hematological malignancies harbor germline perforin gene mutations. For this purpose, 81 unrelated families from Tunisia and France with aggregated hematological malignancies were investigated. The variants detected in thePRF1coding region amounted to 3.7% (3/81). Two of the three variants identified were previously described: the p.Ala91Val pathogenic mutation and the p.Asn252Ser polymorphism. A new p.Ala 211Val missense substitution was identified in two related Tunisian patients. In order to assess the pathogenicity of this new variation, bioinformatic tools were used to predict its effects on the perforin protein structure and at the mRNA level. The segregation of the mutant allele was studied in the family of interest and a control population was screened. The fact that this variant was not found to occur in 200 control chromosomes suggests that it may be pathogenic. However, overexpression of mutatedPRF1in rat basophilic leukemia cells did not affect the lytic function of perforin differently from the wild type protein.

Background: Methods: Results: Conclusion:

To evaluate improvement in breast cancer management between 1975 and 2003, we constituted a cohort of 5722 women with an invasive non-metastatic breast cancer. An active follow-up was carried out and completed using administrative databases. Survival rates were computed using a classical person-time and a period analyses. Relative survival rates were also presented. Advanced cancers at diagnosis decreased from 70.7% to 45.5% between 1975 and 2003. Person-time analysis showed a 48.8% reduction in death rates over 30 years. Survival at 10 years ranged from 50% (CI95% = 45-55) for women diagnosed in 1975-1979 to 66% (CI95% = 63-69) for those diagnosed in 1990-1994. Using period analysis, we estimated the 10 year survival of women diagnosed in 2000-2003 to be 68% (CI95% = 64-72). Overall relative survival was 76% (CI95% = 71-80) at 10 years. Taking into account known prognosis factors, survival was significantly improved for recent diagnosis periods (p<0.00001). Observed improvement in survival confirmed 'in real life' data from clinical trials.