Multiple gene sequencing for risk assessment in patients with early-onset or familial breast cancer

// Po-Han Lin 1, 2 , Wen-Hung Kuo 3 , Ai-Chu Huang 2 , Yen-Shen Lu 4 , Ching-Hung Lin 4 , Sung-Hsin Kuo 4 , Ming-Yang Wang 3 , Chun-Yu Liu 6 , Fiona Tsui-Fen Cheng 7 , Ming-Hsin Yeh 8 , Huei-Ying Li 2 , Yu-Hsuan Yang 2 , Yu-Hua Hsu 2 , Sheng-Chih Fan 2 , Long-Yuan Li 9 , Sung-Liang Yu 10 , King-Jen Chang 11 , Pei-Lung Chen 2 , Yen-Hsuan Ni 2, 5 , Chiun-Sheng Huang 3 1 Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan 2 Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan 3 Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan 4 Department of Medical Oncology, National Taiwan University Hospital, Taipei, Taiwan 5 Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan 6 Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan 7 Department of Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan 8 Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan 9 Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan 10 Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan 11 Department of Surgery, Cheng Ching Hospital, Taichung, Taiwan Correspondence to: Chiun-Sheng Huang, e-mail: huangcs@ntu.edu.tw Yen-Hsuan Ni, e-mail: yhni@ntu.edu.tw Keywords: multiple gene sequencing, hereditary breast cancer, BRCA, variant of uncertain significance, genetic counseling Received: July 02, 2015      Accepted: January 01, 2016      Published: January 27, 2016 ABSTRACT Since BRCA mutations are only responsible for 10–20% of cases of breast cancer in patients with early-onset or a family history and since next-generation sequencing technology allows the simultaneous sequencing of a large number of target genes, testing for multiple cancer-predisposing genes is now being considered, but its significance in clinical practice remains unclear. We then developed a sequencing panel containing 68 genes that had cancer risk association for patients with early-onset or familial breast cancer. A total of 133 patients were enrolled and 30 (22.6%) were found to carry germline deleterious mutations, 9 in BRCA1 , 11 in BRCA2 , 2 in RAD50 , 2 in TP53 and one each in ATM, BRIP1, FANCI, MSH2, MUTYH , and RAD51C . Triple-negative breast cancer (TNBC) was associated with the highest mutation rate (45.5%, p = 0.025). Seven of the 9 BRCA1 mutations and the single FANCI mutation were in the TNBC group; 9 of the 11 BRCA2 , 1 of the 2 RAD50 as well as BRIP1 , MSH2, MUTYH , and RAD51C mutations were in the hormone receptor (HR)(+)Her2(−) group, and the other RAD50, ATM , and TP53 mutations were in the HR(+)Her2(+) group. Mutation carriers were considered as high-risk to develop malignancy and advised to receive cancer screening. Screening protocols of non- BRCA genes were based on their biologic functions; for example, patients carrying RAD51C mutation received a screening protocol similar to that for BRCA , since BRCA and RAD51C are both involved in homologous recombination. In conclusion, we consider that multiple gene sequencing in cancer risk assessment is clinically valuable.