RESUMO
PURPOSE: Screening multiple genes for inherited cancer predisposition expands opportunities for cancer prevention; however, reports of variants of uncertain significance (VUS) may limit clinical usefulness. We used an expert-driven approach, exploiting all available information, to evaluate multigene panels for inherited cancer predisposition in a clinical series that included multiple cancer types and complex family histories. METHODS: For 1,462 sequential patients referred for testing by BROCA or ColoSeq multigene panels, genomic DNA was sequenced and variants were interpreted by multiple experts using International Agency for Research on Cancer guidelines and incorporating evolutionary conservation, known and predicted variant consequences, and personal and family cancer history. Diagnostic yield was evaluated for various presenting conditions and family-history profiles. RESULTS: Of 1,462 patients, 12% carried damaging mutations in established cancer genes. Diagnostic yield varied by clinical presentation. Actionable results were identified for 13% of breast and colorectal cancer patients and for 4% of cancer-free subjects, based on their family histories of cancer. Incidental findings explaining cancer in neither the patient nor the family were present in 1.7% of subjects. Less than 1% of patients carried VUS in BRCA1 or BRCA2. For all genes combined, initial reports contained VUS for 10.5% of patients, which declined to 7.5% of patients after reclassification based on additional information. CONCLUSIONS: Individualized interpretation of gene panels is a complex medical activity. Interpretation by multiple experts in the context of personal and family histories maximizes actionable results and minimizes reports of VUS.Genet Med 18 10, 974-981.
Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias Colorretais/diagnóstico , Predisposição Genética para Doença , Proteínas de Neoplasias/genética , Adulto , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pessoa de Meia-Idade , Mutação , Fatores de RiscoRESUMO
OBJECTIVES: To discuss how understanding and manipulation of tumor genetics information and technology shapes cancer care today and what changes might be expected in the near future. DATA SOURCES: Published articles, web resources, clinical practice. CONCLUSIONS: Advances in our understanding of genes and their regulation provide a promise of more personalized cancer care, allowing selection of the most safe and effective therapy in an individual situation. IMPLICATIONS FOR NURSING PRACTICE: Rapid progress in the technology of tumor profiling and targeted cancer therapies challenges nurses to keep up-to-date to provide quality patient education and care.