Assuntos
Vacinas Bacterianas/provisão & distribuição , Medicina Baseada em Evidências , Modelos Organizacionais , Organização Pan-Americana da Saúde , Formulação de Políticas , Infecções por Rotavirus/imunologia , Streptococcus pneumoniae/imunologia , Vacinas Virais/provisão & distribuição , América , Vacinas Bacterianas/uso terapêutico , Humanos , Estudos de Casos Organizacionais , Vacinas Virais/uso terapêuticoRESUMO
The CDKN2A gene, which encodes the proteins p16(INK4a) and p14(ARF), is located on chromosome 9p21. Germline mutations at this locus increase susceptibility to cutaneous malignant melanoma (CMM). In general, missense and nonsense mutations are primarily responsible for defective p16(INK4a) and possibly p14(ARF) protein function and account for approximately 20% of inherited CMM cases. We report a G>T transversion mutation in the last nucleotide of exon 2, affecting the aspartic acid residue at position 153 of CDKN2A-p16(INK4a) in a proband with melanoma. If splicing were unaffected, this mutation would change Asp to Tyr. RT-PCR analysis, however, revealed that this mutation, which we have termed D153spl(c.457G>T), and a previously described mutation at the next nucleotide, IVS2+1G>T, result in identical aberrant splicing affecting both p16(INK4a) and p14(ARF). The two main alternate splice products for each of the two normal transcripts includes a 74 bp deletion in exon 2, revealing a cryptic splice site, and the complete skipping of exon 2. The dual inactivation of p16(INK4a) and p14(ARF) may contribute to the CMM in these families.
Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Genes p16 , Melanoma/genética , Mutação Puntual , Neoplasias Cutâneas/genética , Proteína Supressora de Tumor p14ARF/genética , Regiões 3' não Traduzidas , Sequência de Aminoácidos , Sequência de Bases , Humanos , Dados de Sequência Molecular , Splicing de RNARESUMO
Two potential breast cancer susceptibility genes, encoding the BRCA1-interacting proteins ZNF350 (or ZBRK1) and BRIP1 (or BACH1), have been identified in yeast two-hybrid screens. We sequenced these genes in probands from 21 families with potentially inherited breast/ovarian cancer, all of which were negative for BRCA1/BRCA2 mutations. Families had at least one case of male breast cancer, two cases of ovarian cancer, or three or more cases of breast and ovarian cancer. In addition, 58 early-onset (before age 35) breast cancer cases and 30 reference individuals were analyzed. Of 17 variants detected in ZBRK1, a missense mutation Val524Ile was identified in the proband of one high-risk family, but no other family members were available for testing. Of 25 variants identified in BRIP1, in addition to four common silent or missense mutations, we identified Gln540Leu, a non-conservative amino acid change, in a single familial proband with inflammatory breast cancer, but this mutation was not present in her three relatives with breast cancer. Haplotype analysis suggests that all ZBRK1 SNPs fall within a single block with two SNPs capturing 92% of the haplotype diversity, while the BRIP1 SNPs fall in two blocks, with five SNPs capturing 89% of the haplotype diversity. Based on sequencing of ZBRK1 and BRIP1 in 21 BRCA1/2-negative probands from inherited breast/ovarian cancer families, it appears unlikely that mutations in these genes account for a significant fraction of inherited breast cancer. Further analysis in unselected cases will be required to know whether the identified variants play a role in genetic predisposition to breast cancer in the general population. Hum Mutat 22:121-128, 2003. Published 2003 Wiley-Liss, Inc.
