title: Multiple gene sequencing for risk assessment in patients with early-onset or familial breast cancer.
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.
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.|Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Po-Han
authors.initials: PH
authors.lastname: Lin
authors.affiliation: Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Wen-Hung
authors.initials: WH
authors.lastname: Kuo
authors.affiliation: Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Ai-Chu
authors.initials: AC
authors.lastname: Huang
authors.affiliation: Department of Medical Oncology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Yen-Shen
authors.initials: YS
authors.lastname: Lu
authors.affiliation: Department of Medical Oncology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Ching-Hung
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Department of Medical Oncology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Sung-Hsin
authors.initials: SH
authors.lastname: Kuo
authors.affiliation: Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Ming-Yang
authors.initials: MY
authors.lastname: Wang
authors.affiliation: Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Liu
authors.affiliation: Department of Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
authors.forename: Fiona Tsui-Fen
authors.initials: FT
authors.lastname: Cheng
authors.affiliation: Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Ming-Hsin
authors.initials: MH
authors.lastname: Yeh
authors.affiliation: Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Huei-Ying
authors.initials: HY
authors.lastname: Li
authors.affiliation: Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Yu-Hsuan
authors.initials: YH
authors.lastname: Yang
authors.affiliation: Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Hsu
authors.affiliation: Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Sheng-Chih
authors.initials: SC
authors.lastname: Fan
authors.affiliation: Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan.
authors.forename: Long-Yuan
authors.initials: LY
authors.lastname: Li
authors.affiliation: Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Sung-Liang
authors.initials: SL
authors.lastname: Yu
authors.affiliation: Department of Surgery, Cheng Ching Hospital, Taichung, Taiwan.
authors.forename: King-Jen
authors.initials: KJ
authors.lastname: Chang
authors.affiliation: Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Pei-Lung
authors.initials: PL
authors.lastname: Chen
authors.affiliation: Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.|Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Yen-Hsuan
authors.initials: YH
authors.lastname: Ni
authors.affiliation: Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chiun-Sheng
authors.initials: CS
authors.lastname: Huang
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000145:classification / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D018095:Germ-Line Mutation / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018570:Risk Assessment
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger
keywords: BRCA; genetic counseling; hereditary breast cancer; multiple gene sequencing; variant of uncertain significance
references.citation: EMBO J. 2001 Oct 1;20(19):5521-31
references.pmid: 11574484
references.citation: DNA Cell Biol. 2013 Jun;32(6):329-35
references.pmid: 23713947
references.citation: Oncologist. 2013;18(10 ):1083-90
references.pmid: 24037976
references.citation: Cancer. 2012 Mar 1;118(5):1362-70
references.pmid: 21932393
references.citation: Bioinformatics. 2006 Jan 15;22(2):195-201
references.pmid: 16301204
references.citation: Twin Res. 2004 Apr;7(2):182-91
references.pmid: 15169603
references.citation: Hum Mutat. 2008 Nov;29(11):1282-91
references.pmid: 18951446
references.citation: J Natl Compr Canc Netw. 2014 Sep;12(9):1326-38
references.pmid: 25190698
references.citation: J Hum Genet. 2012 Feb;57(2):130-8
references.pmid: 22277901
references.citation: Cancer Res. 2008 May 1;68(9):3523-31
references.pmid: 18451181
references.citation: J Clin Oncol. 2012 Dec 10;30(35):4409-15
references.pmid: 23091106
references.citation: N Engl J Med. 2014 Aug 7;371(6):497-506
references.pmid: 25099575
references.citation: Genome Res. 2010 Sep;20(9):1297-303
references.pmid: 20644199
references.citation: Cancer. 2009 May 15;115(10):2222-33
references.pmid: 19241424
references.citation: Oncogene. 2007 Apr 2;26(15):2157-65
references.pmid: 17401424
references.citation: J Comput Chem. 2004 Oct;25(13):1605-12
references.pmid: 15264254
references.citation: Bioinformatics. 2009 Aug 15;25(16):2078-9
references.pmid: 19505943
references.citation: Am J Med Genet. 2002 Jul 22;111(1):96-102
references.pmid: 12124744
references.citation: Ann Surg Oncol. 2014 Oct;21(10):3209-15
references.pmid: 25029991
references.citation: Int J Cancer. 2006 Aug 15;119(4):964-7
references.pmid: 16550608
references.citation: Nucleic Acids Res. 2006 Mar 06;34(5):1317-25
references.pmid: 16522644
references.citation: Nat Methods. 2010 Apr;7(4):248-9
references.pmid: 20354512
references.citation: Carcinogenesis. 2011 Sep;32(9):1354-60
references.pmid: 21700777
references.citation: Breast Cancer Res Treat. 2007 Aug;104(2):121-8
references.pmid: 17061036
references.citation: Gynecol Oncol. 2012 Feb;124(2):347-53
references.pmid: 22264603
references.citation: Science. 2011 Jul 15;333(6040):312-6
references.pmid: 21764741
references.citation: Fam Cancer. 2013 Jun;12(2):159-68
references.pmid: 23572416
references.citation: Nat Protoc. 2009;4(7):1073-81
references.pmid: 19561590
references.citation: J Clin Oncol. 2014 Jul 1;32(19):2001-9
references.pmid: 24733792
references.citation: BMC Syst Biol. 2013;7 Suppl 6:S8
references.pmid: 24564972
references.citation: CA Cancer J Clin. 2013 May;63(3):151-66
references.pmid: 23386565
references.citation: Bioinformatics. 2009 Jul 15;25(14):1754-60
references.pmid: 19451168
references.citation: Hum Genet. 1999 Mar;104(3):201-4
references.pmid: 10323242
references.citation: Mutagenesis. 2013 Mar;28(2):187-95
references.pmid: 23328489
references.citation: Nucleic Acids Res. 2010 Sep;38(16):e164
references.pmid: 20601685
references.citation: Mutat Res. 2013 Mar-Apr;743-744:53-66
references.pmid: 23391514
references.citation: Clin Cancer Res. 2011 Nov 15;17(22):6973-84
references.pmid: 21908578
references.citation: J Clin Oncol. 2015 Feb 1;33(4):304-11
references.pmid: 25452441