Two novel variants in the 3′UTR of the BRCA1 gene in familial breast and/or ovarian cancer

For the majority of breast and/or ovarian cancer patients tested for BRCA1/2 genes, mutation screening of the coding regions remains negative. MicroRNAs which negatively regulate mRNA translation by binding to 3′ untranslated region (3′UTR) are implicated in cancer. Genetic changes in the 3′UTR of several genes were reported to be associated with higher susceptibility to particular tumor types. The aim of this study was to analyze the BRCA1 3′UTR in patients tested negative for BRCA1/2 deleterious mutations, in order to find variants implicated in the decrease of BRCA1 expression through modification of miRNA binding. Genotyping analyses were performed on genomic DNA of 70 BRCA negatives index cases, selected among patients with breast or ovarian cancer, less than 50 years old, with a strong family history. The co-occurrence of the identified variants with deleterious BRCA1 mutations was then determined in a control population of 210 patients. A luciferase gene reporter assay was used to investigate the impact of the variants on the BRCA1 gene expression. Two novel variants, c.*750A>G and c.*1286C>A, were identified in the 3′UTR of BRCA1 gene, in two patients. The former was found three times in the control population, whereas the latter was absent. The used functional assay did not reveal any effect on the luciferase expression. This study reveals a weak genomic variability in the 3′UTR of the BRCA1 gene. All together, the results led us to classify the variant c.*750A>G as probably neutral, the variant c.*1286C>A remaining unclassified.     

Myeloid cell differentiation arrest by miR-125b-1 in myelodysplastic syndrome and acute myeloid leukemia with the t(2;11)(p21;q23) translocation

Most chromosomal translocations in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) involve oncogenes that are either up-regulated or form part of new chimeric genes. The t(2;11)(p21;q23) translocation has been cloned in 19 cases of MDS and AML. In addition to this, we have shown that this translocation is associated with a strong up-regulation of miR-125b (from 6- to 90-fold). In vitro experiments revealed that miR-125b was able to interfere with primary human CD34⁺ cell differentiation, and also inhibited terminal (monocytic and granulocytic) differentiation in HL60 and NB4 leukemic cell lines. Therefore, miR-125b up-regulation may represent a new mechanism of myeloid cell transformation, and myeloid neoplasms carrying the t(2;11) translocation define a new clinicopathological entity.     

High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation for adult histiocytic disorders with central nervous system involvement

We postulated that high-dose chemotherapy (HDC) followed by peripheral autologous hematopoietic stem cell transplantation might help to control refractory central nervous system (CNS) histiocytic disorders. Six patients with histiocytic CNS involvement were treated in this way. Two patients achieved non-active disease status, although one relapsed at 84 months. Two patients had regressive disease, one of whom progressed at 21 months. One patient had progressive disease at 14 months. One patient had extra-CNS progression but CNS regression. After a median follow-up of 22.4 months, only one of the six patients still has non-active disease. Treatment was effective on craniofacial and space-occupying brainstem lesions, and was ineffective on neurodegenerative lesions.