ABSTRACT
We report the analysis of altogether 1050 suspected hereditary breast/ovarian cancer (HBOC) families, 524 fully screened for BRCA1/BRCA2 mutations and 526 tested only for the most common mutations. Of the 119 families with pathogenic mutations, 40 (33.6%) had the BRCA2 c.156_157insAlu rearrangement and 15 (12.6%) the BRCA1 c.3331_3334del mutation, the former being specific of Portuguese ancestry and the latter showing a founder effect in Portugal. Interestingly, the two most common mutations were found in a significant proportion of the HBOC families with an a priori BRCAPRO mutation probability <10%. We recommend that all suspected HBOC families from Portugal or with Portuguese ancestry, even those fulfilling moderately stringent clinical-criteria for genetic testing, should be specifically analyzed for the two most common BRCA1/BRCA2 founder mutations, and we here present a simple method for this first tier test. Screening of the entire coding regions of BRCA1 and BRCA2 should subsequently be offered to those families with a mutation probability ≥10% if none of those founder mutations are found.
Subject(s)
Genes, BRCA1 , Genes, BRCA2 , Genetic Testing , Hereditary Breast and Ovarian Cancer Syndrome/genetics , Mutation , Adult , Female , Founder Effect , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Portugal , White People/geneticsABSTRACT
We have identified a new mixed lineage leukemia (MLL) gene fusion partner in a patient with treatment-related acute myeloid leukemia (AML) presenting a t(2;11)(q37;q23) as the only cytogenetic abnormality. Fluorescence in situ hybridization demonstrated a rearrangement of the MLL gene and molecular genetic analyses identified a septin family gene, SEPT2, located on chromosome 2q37, as the fusion partner of MLL. RNA and DNA analyses showed the existence of an in-frame fusion of MLL exon 7 with SEPT2 exon 3, with the genomic breakpoints located in intron 7 and 2 of MLL and SEPT2, respectively. Search for DNA sequence motifs revealed the existence of two sequences with 94.4% homology with the topoisomerase II consensus cleavage site in MLL intron 7 and SEPT2 intron 2. SEPT2 is the fifth septin family gene fused with MLL, making this gene family the most frequently involved in MLL-related AML (about 10% of all known fusion partners). The protein encoded by SEPT2 is highly homologous to septins 1, 4 and 5 and is involved in the coordination of several key steps of mitosis. Further studies are warranted to understand why the septin protein family is particularly involved in the pathogenesis of MLL-associated leukemia.
Subject(s)
Chromosomes, Human, Pair 11 , Chromosomes, Human, Pair 2 , Leukemia, Myeloid/genetics , Myeloid-Lymphoid Leukemia Protein/genetics , Phosphoric Monoester Hydrolases/genetics , Translocation, Genetic , Amino Acid Sequence , Base Sequence , DNA, Neoplasm , Exons , Female , Histone-Lysine N-Methyltransferase , Humans , In Situ Hybridization, Fluorescence , Karyotyping , Leukemia, Myeloid/chemically induced , Middle Aged , Molecular Sequence Data , Reverse Transcriptase Polymerase Chain Reaction , Sequence Homology, Nucleic AcidSubject(s)
Chromosomes, Human, Pair 11 , Chromosomes, Human, Pair 5 , Leukemia, Myeloid/genetics , Nuclear Pore Complex Proteins/genetics , Oncogene Proteins, Fusion/genetics , Transcription, Genetic , Translocation, Genetic , Acute Disease , Child , Humans , In Situ Hybridization, Fluorescence , Karyotyping , RNA, Neoplasm/genetics , RNA, Neoplasm/isolation & purification , Sequence DeletionABSTRACT
Hereditary non-polyposis colorectal cancer (HNPCC) is considered to be determined by germline mutations in the mismatch repair (MMR) genes, especially MSH2 and MLH1. While screening for mutations in these two genes in HNPCC portuguese families, 3 previously unreported MSH2 and 1 MLH1 mutations have been identified in families meeting strict Amsterdam criteria. Hum Mutat 15:116, 2000.
Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , DNA-Binding Proteins , Neoplasm Proteins/genetics , Proto-Oncogene Proteins/genetics , Adaptor Proteins, Signal Transducing , Base Pair Mismatch , Base Sequence , Carrier Proteins , Humans , Molecular Sequence Data , MutL Protein Homolog 1 , MutS Homolog 2 Protein , Mutation, Missense , Nuclear Proteins , Polymerase Chain Reaction , Polymorphism, Single-Stranded Conformational , PortugalABSTRACT
In mammalian epidermis a population of ATPase-positive dendritic cells, identified as Langerhans cells, has been found. Such cells are bone marrow-derived and participate in the immunological functions of the skin. We demonstrate the existence of ATPase-positive dendritic cells in separated epidermal sheets of chicken skin, by means of light and electron microscopy. They have a mean distribution of 688 +/- 265 cells/mm2 and showed several features in common with Langerhans cells. Since chickens can develop contact dermatitis, the finding is taken as the first formal demonstration of the presence of Langerhans cells in this group of vertebrates.
