RESUMO
Melanoma is the most deadly form of skin cancer and DiGeorge syndrome (DGS) is the most frequent interstitial deletion syndrome. We characterized a novel balanced t(9;22)(p21;q11.2) translocation in a patient with melanoma, DNA repair deficiency, and features of DGS including deafness and malformed inner ears. Using chromosome sorting, we located the 9p21 breakpoint in CDKN2A intron 1. This resulted in underexpression of the tumor suppressor p14 alternate reading frame (p14ARF); the reduced DNA repair was corrected by transfection with p14ARF. Ultraviolet radiation-type p14ARF mutations in his melanoma implicated p14ARF in its pathogenesis. The 22q11.2 breakpoint was located in a palindromic AT-rich repeat (PATRR22). We identified a new gene, FAM230A, that contains PATRR22 within an intron. The 22q11.2 breakpoint was located 800 kb centromeric to TBX1, which is required for inner ear development. TBX1 expression was greatly reduced. The translocation resulted in a chimeric transcript encoding portions of p14ARF and FAM230A. Inhibition of chimeric p14ARF-FAM230A expression increased p14ARF and TBX1 expression and improved DNA repair. Expression of the chimera in normal cells produced dominant negative inhibition of p14ARF. Similar chimeric mRNAs may mediate haploinsufficiency in DGS or dominant negative inhibition of other genes such as those involved in melanoma.
Assuntos
Distúrbios no Reparo do DNA/genética , Surdez/genética , Fusão Gênica , Melanoma/genética , Proteínas com Domínio T/genética , Translocação Genética , Proteína Supressora de Tumor p14ARF/genética , Sequência de Bases , Proteínas de Transporte , Cromossomos Humanos Par 22 , Cromossomos Humanos Par 9 , Distúrbios no Reparo do DNA/metabolismo , Surdez/metabolismo , Genes p16 , Humanos , Masculino , Melanoma/metabolismo , Dados de Sequência Molecular , RNA Longo não Codificante , Análise de Sequência de DNA , Proteínas com Domínio T/metabolismo , Proteína Supressora de Tumor p14ARF/metabolismo , Adulto JovemRESUMO
Advances in technology have accelerated the translation of genetics and genomics into the arena of cancer prevention. This provides unique opportunities to individualize cancer risk prediction so early intervention can either modify risk or allow for early diagnosis thereby potentially decreasing the morbidity and mortality of cancer and containing costs. While the full potential of these genetic/genomic discoveries have yet to be realized, many have clear clinical relevance such as the value of family history and/or tumor profiling to identify those who may harbor a mutation in a cancer susceptibility gene and are therefore candidates for genetic testing. Here, we provide an overview of the scope of genetic and genomic influences on cancer risk assessment and the entire spectrum of cancer prevention.
Assuntos
Anticarcinógenos/uso terapêutico , Proteínas de Neoplasias/genética , Neoplasias/genética , Neoplasias/prevenção & controle , Farmacogenética , Humanos , Neoplasias/patologiaRESUMO
To complement the 2005 Annual Clinical Focus on medical genomics, AFP is publishing a series of short reviews on genetic syndromes. This series was designed to increase awareness of these diseases so that family physicians can recognize and diagnose children with these disorders and understand the kind of care they might require in the future. This review discusses Klinefelter syndrome.
Assuntos
Síndrome de Klinefelter/diagnóstico , Humanos , Síndrome de Klinefelter/tratamento farmacológico , Síndrome de Klinefelter/genética , MasculinoRESUMO
To complement the 2005 Annual Clinical Focus on medical genomics, AFP is publishing a series of short reviews on genetic syndromes. This series was designed to increase awareness of these diseases so that family physicians can recognize and diagnose children with these disorders and understand the type of care they might require in the future. This review discusses Prader-Willi syndrome.
Assuntos
Síndrome de Prader-Willi/diagnóstico , Criança , Cromossomos Humanos Par 15/genética , Humanos , Síndrome de Prader-Willi/epidemiologia , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/terapiaRESUMO
The collection of a family history ranges from simply asking patients if family members have the same presenting illness to diagramming complex medical and psychosocial relationships as part of a family genogram. The three-generation pedigree provides a pictorial representation of diseases within a family and is the most efficient way to assess hereditary influences on disease. Two recent events have made family history assessment more important than ever: the completion of the Human Genome Project with resultant identification of the inherited causes of many diseases, and the establishment of national clinical practice guidelines based on systematic reviews of preventive interventions. The family history is useful in stratifying a patient's risk for rare single-gene disorders and more common diseases with multiple genetic and environmental contributions. Major organizations have endorsed using standardized symbols in pedigrees to identify inherited contributions to disease.
Assuntos
Anamnese , Linhagem , Predisposição Genética para Doença , Testes Genéticos , HumanosRESUMO
To complement the 2005 Annual Clinical Focus on medical genomics, AFP will be publishing a series of short reviews on genetic syndromes. This series was designed to increase awareness of these diseases so that family physicians can recognize and diagnose children with these disorders and understand the kind of care they might require in the future. The second review in this series discusses fetal alcohol syndrome and fetal alcohol spectrum disorders.
Assuntos
Transtornos do Espectro Alcoólico Fetal , Adulto , Face , Feminino , Transtornos do Espectro Alcoólico Fetal/complicações , Transtornos do Espectro Alcoólico Fetal/diagnóstico , Transtornos do Espectro Alcoólico Fetal/etiologia , Humanos , Recém-Nascido , Idade Materna , GravidezRESUMO
To complement the 2005 Annual Clinical Focus on medical genomics, AFP will be publishing a series of short reviews on genetic syndromes. This series was designed to increase awareness of these diseases so that family physicians can recognize and diagnose children with these disorders and understand the kind of care they might require in the future. The first review in this series discusses fragile X syndrome.
