RESUMO
The breast cancer risk of women already under family history surveillance was accurately assessed according to national guidelines in an attempt to rationalize the service. Women attending two breast units in Glasgow between November 2003 and February 2005 were included. One thousand and five women under annual surveillance were assessed and had their relatives diagnoses verified. Four hundred and ninety-seven women were at significantly increased risk and eligible for follow-up. Five hundred and eight (50%) women attending were not eligible for family history surveillance, and 498 (98%) of these women accepted discharge. In conclusion, national guidelines have helped to more clearly define women who should undergo surveillance. This avoids unnecessary and potentially harmful routine investigations, and the service has been improved.
Assuntos
Neoplasias da Mama/diagnóstico , Detecção Precoce de Câncer , Fidelidade a Diretrizes/estatística & dados numéricos , Guias de Prática Clínica como Assunto , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Feminino , Humanos , Mamografia , Anamnese , Pessoa de Meia-Idade , Medição de Risco , Escócia , Procedimentos Desnecessários/estatística & dados numéricosRESUMO
Mutations in mtDNA-encoded components of the mitochondrial translational apparatus are associated with diverse pathological states in humans, notably sensorineural deafness. To develop animal models of such disorders, we have manipulated the nuclear gene for mitochondrial ribosomal protein S12 in Drosophila (technical knockout, tko). The prototypic mutant tko(25t) exhibits developmental delay, bang sensitivity, impaired male courtship, and defective response to sound. On the basis of a transgenic reversion test, these phenotypes are attributable to a single substitution (L85H) at a conserved residue of the tko protein. The mutant is hypersensitive to doxycyclin, an antibiotic that selectively inhibits mitochondrial protein synthesis, and mutant larvae have greatly diminished activities of mitochondrial redox enzymes and decreased levels of mitochondrial small-subunit rRNA. A second mutation in the tko gene, Q116K, which is predicted to impair the accuracy of mitochondrial translation, results in the completely different phenotype of recessive female sterility, based on three independent transgenic insertions. We infer that the tko(25t) mutant provides a model of mitochondrial hearing impairment resulting from a quantitative deficiency of mitochondrial translational capacity.
Assuntos
DNA Mitocondrial/genética , Surdez/genética , Drosophila/genética , Mitocôndrias/metabolismo , Mutação , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/fisiologia , Animais , Animais Geneticamente Modificados , Antibacterianos/farmacologia , Northern Blotting , Southern Blotting , Núcleo Celular/genética , Clonagem Molecular , Cruzamentos Genéticos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Doxiciclina/farmacologia , Drosophila/fisiologia , Feminino , Humanos , Infertilidade Feminina/genética , Masculino , Modelos Genéticos , Oligonucleotídeos/metabolismo , Oxirredução , Fenótipo , Reação em Cadeia da Polimerase , Biossíntese de Proteínas , RNA Ribossômico/metabolismo , Análise de Sequência de DNA , Som , Fatores de Tempo , TransgenesRESUMO
It is not uncommon for cancer geneticists to be referred families with apparently Mendelian co-inheritance of breast and bowel cancer. Such families present a particular problem as regards the intensity of their screening for these diseases and the utility of genetic testing. Many 'breast-colon' cancer families probably result from chance clustering of two common cancers. Other 'breast-colon' cancer families may result from known cancer syndromes, such as hereditary breast-ovarian cancer or hereditary non-polyposis colon cancer, either by conferring a high risk of one cancer type and a slightly increased risk of the other, or through a predisposition to one of the two cancers and chance occurrence of the other. Anecdotally, however, many geneticists wonder about the existence of a distinct 'breast-colon cancer syndrome', since some families present good a priori evidence of genetic disease and yet cannot readily be accounted for by known genes or chance. The identification of unknown 'breast-colon cancer' genes is likely to be difficult, relying primarily on candidate gene analysis, including loci separately implicated in breast or colorectal cancer, or in other multiple cancer syndromes. Studies such as those on APC I1307K and CHEK2 1100delC may suggest the way forward for the identification of 'breast-colon cancer' genes.
Assuntos
Neoplasias da Mama/genética , Neoplasias Colorretais/genética , Heterogeneidade Genética , Predisposição Genética para Doença , Adulto , Quinase do Ponto de Checagem 2 , Feminino , Frequência do Gene , Genes APC , Humanos , Masculino , Mutação , Linhagem , Fenótipo , Proteínas Serina-Treonina Quinases/genéticaRESUMO
To evaluate current guidelines criteria for inclusion of women in special 'breast cancer family history' surveillance programmes, records were reviewed of women referred to Scottish breast cancer family clinics between January 1994 and December 2003 but discharged as at 'less than 'moderate' familial risk'. The Scottish Cancer Registry was then interrogated to determine subsequent age-specific incidence of breast cancer in this cohort and corresponding Scottish population figures. Among 2074 women, with an average follow-up of 4.0 years, 28 invasive breast cancers were recorded up to December 2003, where 14.4 were expected, a relative risk (RR) of 1.94. Eleven further breast cancers were recorded between January 2004 and February 2006 (ascertainment incomplete for this period). The overall RR for women in the study cohort exceeded the accepted 'cutoff' level (RR=1.7) for provision of special counselling and surveillance. The highest RR was found for the age group 45-59 years and this group also generated the majority of breast cancers. The National Institute for Clinical Excellence ('NICE') guidelines appear to be more accurate than those of the Scottish Intercollegiate Guidelines Network ('SIGN') in defining 'moderate' familial risk, and longer follow-up of this cohort could generate an evidence base for further modification of familial breast cancer services.