RESUMO
Heterozygous APC germline alteration is responsible for familial adenomatous polyposis, a colon cancer predisposition with almost complete penetrance. Point mutations generally lead to truncated proteins or no protein at all. They mainly involve exon 3 to codon 1700 (exon 15). The work presented here delineates precisely the APC mutation spectrum from 15 years of systematic molecular screening which identified 863 independent alterations in the French population.
Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/genética , Análise Mutacional de DNA/métodos , Mutação em Linhagem Germinativa , Hibridização Genômica Comparativa , França , Genes APC , Predisposição Genética para Doença , Testes Genéticos , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Mutação Puntual , Análise de Sequência de DNARESUMO
BACKGROUND: Chronic myelomonocytic leukemia (CMML) is a hematological disease close to, but separate from both myeloproliferative disorders (MPD) and myelodysplastic syndromes and may show either myeloproliferative (MP-CMML) or myelodysplastic (MD-CMML) features. Not much is known about the molecular biology of this disease. METHODS: We studied a series of 30 CMML samples (13 MP- and 11 MD-CMMLs, and 6 acutely transformed cases) from 29 patients by using Agilent high density array-comparative genomic hybridization (aCGH) and sequencing of 12 candidate genes. RESULTS: Two-thirds of samples did not show any obvious alteration of aCGH profiles. In one-third we observed chromosome abnormalities (e.g. trisomy 8, del20q) and gain or loss of genes (e.g. NF1, RB1 and CDK6). RAS mutations were detected in 4 cases (including an uncommon codon 146 mutation in KRAS) and PTPN11 mutations in 3 cases. We detected 11 RUNX1 alterations (9 mutations and 2 rearrangements). The rearrangements were a new, cryptic inversion of chromosomal region 21q21-22 leading to break and fusion of RUNX1 to USP16. RAS and RUNX1 alterations were not mutually exclusive. RAS pathway mutations occurred in MP-CMMLs (approximately 46%) but not in MD-CMMLs. RUNX1 alterations (mutations and cryptic rearrangement) occurred in both MP and MD classes (~38%). CONCLUSION: We detected RAS pathway mutations and RUNX1 alterations. The latter included a new cryptic USP16-RUNX1 fusion. In some samples, two alterations coexisted already at this early chronic stage.
Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Perfilação da Expressão Gênica , Genes ras/genética , Leucemia Mielomonocítica Crônica/genética , Cromossomos Humanos Par 21 , Hibridização Genômica Comparativa , Humanos , Leucemia Mielomonocítica Crônica/patologia , Mutação , Proteínas de Fusão Oncogênica/genética , Análise de Sequência de DNA , Transdução de Sinais/genética , Ubiquitina Tiolesterase/genéticaRESUMO
The t(8;16)(p11;p13) translocation, associated with poor prognosis acute monocytic leukemia, fuses MYST3 on chromosome region 8p11 to CBP on chromosome region 16p13. Two types of MYST3-CBP and CBP-MYST3 fusion transcripts have been identified in patients. We describe two new types of MYST3-CBP transcripts and a new primer set.
Assuntos
Proteínas de Transporte/genética , Cromossomos Humanos Par 16 , Cromossomos Humanos Par 8 , Histona Acetiltransferases/genética , Leucemia Mieloide Aguda/genética , Proteínas de Fusão Oncogênica/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Translocação Genética , Idoso , Corticosterona , Primers do DNA/química , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/biossíntese , PrognósticoRESUMO
We report two cases of translocation associated with deletion on derivative chromosomes in atypical myeloproliferative disorder (MPD). In a MPD with t(3;12)(q29;q14), the rearrangement targeted the HMGA2 locus at 12q14 and deleted a region of about 1.5 megabases (Mb) at 3q29. In an MPD with t(9;12)(q13 approximately q21;q22) and JAK2 V617F mutation, array comparative genomic hybridization delineated a deletion of about 3 Mb at 9q13 approximately q21 and a deletion of about 2 Mb at 12q22 containing SOCS2. These results show that close examination of translocations in hematopoietic diseases may reveal associated microdeletions. The role of these deletions is discussed.