[Haplotype of the BRCA2 6857delAA mutation in 4 families with breast/ovarian cancer]. / Análisis del haplotipo en portadores de la mutación 6857delAA en el gen BRCA2 en 4 familias con cáncer de mama u ovario hereditario.

BACKGROUND AND OBJECTIVE: It is estimated that 5-10% of all breast cancers are hereditary, mainly are due to germline mutations in the BRCA1 and BRCA2 genes. PATIENTS AND METHOD: A BRCA2 screening was carried out in familial breast/ovarian cancer at two centres in Spain and Chile. The 6857delAA mutation was identified in 3 Spanish families and one Chilean, all of them with Spanish ancestors. The BRCA2 haplotype of the 6857delAA carriers was analyzed using five microsatellite markers flanking the BRCA2 gene, spanning a region of 6 cM: cen-D13S260, D13S1698, (BRCA2), D13S171, D13S310 and D13S267-tel. RESULTS: Two families shared the allelic variants of the 5 microsatellites studied. Markers D13S260 and D13S267 differed in one allele in two families, respectively. The defined haplotype was absent in non-carriers from these families, and was not detected in 100 control chromosomes without the mutation. CONCLUSIONS: Our results suggest the existence of a common ancestry with the mutation originating in the Northeast of Spain. Given the migratory movements from Spain to Latin America, the screening of recurrent Spanish mutations can be useful in establishing a more rational and cost-effective analysis in such populations.

Interstitial deletions at the long arm of chromosome 13 may be as common as monosomies in multiple myeloma. A genotypic study.

BACKGROUND AND OBJECTIVES: Deletions at the long arm of chromosome 13, mostly at the q14, and monosomy of chromosome 13 are described to be common in multiple myeloma (MM). 13q- has been associated with an adverse outcome and it has been proposed as one of the most important prognostic factors for MM patients. Deletions of 13q14 are rare in monoclonal gammopathy of undetermined significance (MGUS) and are thus believed to be associated with the development of the full myeloma phenotype. DESIGN AND METHODS: A genotyping analysis on purified neoplastic plasma cells was performed on 14 consecutive MM cases to determine the minimally deleted region at chromosome 13. Freshly obtained bone marrow was analyzed by flow cytometry in order to establish the percentage of plasma cell infiltration (CD38+BB4+CD56+/-CD19-). Neoplastic enrichment was carried out using BB4 coated immunomagnetic beads. This method allowed us to monitor the enrichment process. DNA obtained from the enriched neoplastic population and DNA from the clean fraction was amplified using combination sets of chromosomes 12 and 13. Amplimers were run on acrylamide gels, analyzed by automatic fluorescence quantification, and their size determined using the software programs Genescan and Genotyper. RESULTS: In 11 patients electropherograms were suggestive of loss of heterozygosity (LOH) for polymorphic markers located at the long arm of chromosome 13. Four patients showed monosomy and 7 had interstitial deletions in the telomeric region. LOH was not evidenced at chromosome 12 in any sample. The minimal region with deletion was defined by the markers D13S159 (13q32.2, centromeric) and D13S1267 (13q32.3, telomeric). A gene with a potentially pathogenic role may be located in this very small region. Three patients did not show LOH at chromosome 13 by genotypic analysis; however, in one of these, proximal deletion at the long arm of chromosome 13 (13q2.1-2.2) was demonstrated by comparative genomic hybridization (CGH). INTERPRETATION AND CONCLUSIONS: These findings suggest that interstitial deletions of the long arm of chromosome 13 may be more common than previously recognized. The methodologic approach reported in this work may simplify LOH analysis in MM patients. The potential uses of genotyping analysis in risk stratification remain to be investigated.