ABSTRACT
Mutation in BRCA1/BRCA2 genes accounts for 20% of familial breast cancers, 5% to 10% of which may be due to other less penetrant genes which are still incompletely studied. Herein, a four-gene panel was used to examine the prevalence of BRCA1, BRCA2, TP53, and PTEN in hereditary breast and ovarian cancers in Southern Chinese population. In this cohort, 948 high-risk breast and/or ovarian patients were recruited for genetic screening by next-generation sequencing (NGS). The performance of our NGS pipeline was evaluated with 80 Sanger-validated known mutations and eight negative cases. With appropriate bioinformatics analysis pipeline, the detection sensitivity of NGS is comparable with Sanger sequencing. The prevalence of BRCA1/BRCA2 germline mutations was 9.4% in our Chinese cohort, of which 48.8% of the mutations arose from hotspot mutations. With the use of a tailor-made algorithm, HomopolymerQZ, more mutations were detected compared with single mutation detection algorithm. The frequencies of PTEN and TP53 were 0.21% and 0.53%, respectively, in the Southern Chinese patients with breast and/or ovarian cancers. High-throughput NGS approach allows the incorporation of control cohort that provides an ethnicity-specific data for polymorphic variants. Our data suggest that hotspot mutations screening such as SNaPshot could be an effective preliminary screening alternative adopted in a standard clinical laboratory without NGS setup.
Subject(s)
Genetic Predisposition to Disease , Germ-Line Mutation , Hereditary Breast and Ovarian Cancer Syndrome/diagnosis , Hereditary Breast and Ovarian Cancer Syndrome/genetics , High-Throughput Nucleotide Sequencing , Adult , Algorithms , Alleles , Female , Gene Frequency , Genes, BRCA1 , Genes, BRCA2 , Genes, p53 , High-Throughput Nucleotide Sequencing/methods , Humans , Middle Aged , PTEN Phosphohydrolase/genetics , Reproducibility of Results , WorkflowABSTRACT
OBJECTIVE: Age is a known risk factor for breast cancer behaviour. We studied the relationship of age with clinical characteristics, tumour pathology, therapeutic options and outcome in an affluent Asian population. METHODS: From 2003 to 2008, data on newly diagnosed breast carcinoma patients under the care of the multidisciplinary breast cancer team based at a private hospital in Hong Kong were collected prospectively. Patients were divided into three groups: age < 40 years (group I), 41-69 years (group II), and ≥ 70 years (group III). RESULTS: There were 2,079 patients: 334 in group I, 1,538 in group II and 148 in group III. The clinical presentation and tumour stages were similar. Younger patients had higher tumour grading (p = 0.000) and more lymphovascular permeation (p = 0.011). For older patients, combination therapy was employed less frequently (p < 0.0005), and more radical resection with less reconstructive procedures were performed (p = 0.000). The 3-year disease-free survival was 97.8% and there was no difference between the three groups. CONCLUSION: Although breast cancer in younger Chinese patients was more aggressive pathologically, the differences between clinical presentation, tumour staging and survival were similar. Treatment strategies should follow the clinical condition of the patient rather than age alone.
