RESUMO
The detection of germline mutations in BRCA1 and BRCA2 is essential to the formulation of clinical management strategies, and in Brazil, there is limited access to these services, mainly due to the costs/availability of genetic testing. Aiming at the identification of recurrent mutations that could be included in a low-cost mutation panel, used as a first screening approach, we compiled the testing reports of 649 probands with pathogenic/likely pathogenic variants referred to 28 public and private health care centers distributed across 11 Brazilian States. Overall, 126 and 103 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-six novel variants were reported from both genes, and BRCA2 showed higher mutational heterogeneity. Some recurrent mutations were reported exclusively in certain geographic regions, suggesting a founder effect. Our findings confirm that there is significant molecular heterogeneity in these genes among Brazilian carriers, while also suggesting that this heterogeneity precludes the use of screening protocols that include recurrent mutation testing only. This is the first study to show that profiles of recurrent mutations may be unique to different Brazilian regions. These data should be explored in larger regional cohorts to determine if screening with a panel of recurrent mutations would be effective.
Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Mutação em Linhagem Germinativa , Adulto , Brasil , Feminino , Humanos , MasculinoRESUMO
Introdução: A síndrome de Li-Fraumeni é uma síndrome de predisposição hereditária ao câncer de caráter autossômico dominante que leva a um alto risco para o desenvolvimento de neoplasias. Objetivos: Nesse estudo avaliamos a efetividade do F18-FDG-PET-CT na detecção de câncer em portadores da mutação germinativa no gene TP53, um defeito genético que leva à Síndrome de Li-Fraumeni e Li-Fraumeni like (LFS/LFL) que predispõe a vários tipos de câncer no decorrer da vida. Pacientes e Métodos: Um total de 30 pacientes adultos procedentes de seis famílias com mutação germinativa no gene TP53 foram recrutados. Esses pacientes não apresentavam diagnóstico de câncer nos 24 meses que precederam o estudo. Concentração anômala do 18F-FDG no corpo inteiro foi avaliada por dois especialistas independentemente. Lesões suspeitas foram retiradas cirurgicamente e analisadas por histopatologia. Resultados: Um total de 6/30 pacientes mostraram concentração anômala do 18F-FDG. Estudos confirmatórios revelaram três casos de câncer em estádio avançado, incluindo um caso de adenocarcinoma de pulmão (estádio IIIB, um de ovário (estádio IV) e um carcinoma ductal de mama disseminado. Dois anos após a realização do 18F-FDG-PET-CT, três pacientes que eram negativos para câncer no primeiro PET-CT, evoluíram com câncer (próstata, tireóide e mama). Três outros pacientes apresentaram lesões não neoplásicas (cisto de Bartholin e dois casos de linfonodos reacionais). Conclusões: 18F-FDG-PET-CT é eficaz na detecção de câncer em indivíduos assintomáticos de acordo com as diretrizes atuais de rastreamento. No entanto, as lesões malignas foram detectadas em estádio avançado e pacientes que eram inicialmente negativos no 18F-FDG-PET-CT desenvolveram câncer em dois anos após o primeiro exame. Esses resultados sugerem que o 18F-FDG-PET-CT pode ser uma estratégia apropriada para a vigilância do risco de câncer em portadores da mutação no geneTP53.
Introduction: Li-Fraumeni syndrome is an autosomal dominant inherited cancer syndrome that predisposes individuals for a high risk of developing cancer. Objectives: In this study we will evaluate the effectiveness of 18F-FDG-PET-CT for detecting cancer in carriers of germline TP53 mutations, the genetic defect underlying Li-Fraumeni and Li-Fraumeni like syndromes (LFS/LFL) which predispose to many forms of cancer throughout life. Patients and Methods: A total of 30 adult patients from 6 families with germline TP53 mutations were recruited. These patients did not have a diagnosis of cancer in the 24 months preceding the study. Anomalous concentration from whole-body 18F-FDGwas assessed by two independent experts. Suspicious lesions were excised and analyzed by histopathology. Results: A total of 6/30 patients showed anomalous 18F-FDG concentrations. Confirmation studies revealed three cases of advanced stage cancer, including one adenocarcinoma of the lung (stage IIIB), one ovarian cancer (stage IV) and one disseminated invasive ductal breast cancer. Within two years after 18F-FDGPET-CT, three patients who were negative in this examination developed cancer (prostate, thyroid and breast cancers). Three other patients had non-cancer lesions (a Bartholin's cyst and two cases of non-malignant lymph nodes). Conclusions: 18FFDG-PET-CT is effective in detecting cancer in subjects who are asymptomatic using current screening guidelines. However, the lesions detected were detected at an advanced stage and patients who were negative in 18F-FDG-PET-CT developed a cancer within 2 years after examination. These results further suggest that 18F-FDGPET-CT may be an appropriate strategy for surveillance of cancer risk in TP53 mutation carriers.