RESUMO
The remarkable advances in next-generation sequencing technology have enabled the wide usage of sequencing as a clinical tool. To promote the advance of precision oncology for breast cancer in China, here we report a large-scale prospective clinical sequencing program using the Fudan-BC panel, and comprehensively analyze the clinical and genomic characteristics of Chinese breast cancer. The mutational landscape of 1,134 breast cancers reveals that the most significant differences between Chinese and Western patients occurred in the hormone receptor positive, human epidermal growth factor receptor 2 negative breast cancer subtype. Mutations in p53 and Hippo signaling pathways are more prevalent, and 2 mutually exclusive and 9 co-occurring patterns exist among 9 oncogenic pathways in our cohort. Further preclinical investigation partially suggests that NF2 loss-of-function mutations can be sensitive to a Hippo-targeted strategy. We establish a public database (Fudan Portal) and a precision medicine knowledge base for data exchange and interpretation. Collectively, our study presents a leading approach to Chinese precision oncology treatment and reveals potentially actionable mutations in breast cancer.
Assuntos
Povo Asiático/genética , Neoplasias da Mama , Terapia de Alvo Molecular , Mutação , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , China , Gerenciamento de Dados , Feminino , Marcadores Genéticos , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neurofibromina 2/genética , Oncogenes , Medicina de Precisão , Estudos Prospectivos , Transdução de Sinais/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
BACKGROUND: Variation within the C1QTNF6 gene at 22q12.3, the RAC2 gene at 22q13.1, and an intergenic region at 14q32.2 were found to be associated with risk to Graves' disease (GD) in a recent study. We aimed to validate these associations with GD in an independent sample set of Han Chinese population. METHODS: We investigated these associations by genotyping the most significantly associated single nucleotide polymorphisms (SNPs) located in these three regions. Rs1456988 within the intergenic region at 14q32.2, rs229527 within C1QTNF6 at 22q12.3, and rs2284038 within RAC2 at 22q13.1 were selected for genotyping. These three SNPs were genotyped using a case-control study that included 2382 GD patients and 3092 unrelated healthy controls from Northern Han Chinese ancestry. The genotyping was performed using TaqMan assays on the ABI7900 platform. RESULTS: We found both the rs229527 allele within C1QTNF6 (odds ratio [OR] = 1.23, confidence interval [95% CI]: 1.12-1.33, pAllelic = 4.60 × 10-6) and the rs2284038 allele within RAC2 (OR = 1.10, 95% CI: 1.01-0.19, pAllelic = 3.00 × 10-2) showed significant associations with GD susceptibility. However, rs1456988 located in 14q32.2 (OR = 1.08, 95% CI: 0.99-1.16, pAllelic = 7.01 × 10-2) showed no association. Analysis of models of inheritance suggested that both the dominant and recessive models showed significant associations for rs229527 (OR = 1.24, 95% CI: 1.13-1.38, pDominant = 9.90 × 10-5; OR = 1.49, 95% CI: 1.19-1.86, pRecessive = 3.90 × 10-4), with the dominant model being preferred. For rs2284038, the recessive model was preferred (OR = 1.18, 95% CI: 1.00-1.40, pRecessive = 4.76 × 10-2), whereas analysis of dominant model showed no association (OR = 1.10, 95% CI: 0.98-1.22, pDominant = 0.10). CONCLUSIONS: Our findings confirmed that chromosome 22q12.3 and 22q13.1 variants are associated with GD in an independent Han Chinese population; however, 14q32.2 showed no association with GD.