Identification of a comprehensive spectrum of genetic factors for hereditary breast cancer in a Chinese population by next-generation sequencing.
The genetic etiology of hereditary breast cancer has not been fully elucidated. Although germline mutations of high-penetrance genes such as BRCA1/2 are implicated in development of hereditary breast cancers, at least half of all breast cancer families are not linked to these genes. To identify a comprehensive spectrum of genetic factors for hereditary breast cancer in a Chinese population, we performed an analysis of germline mutations in 2,165 coding exons of 152 genes associated with hereditary cancer using next-generation sequencing (NGS) in 99 breast cancer patients from families of cancer patients regardless of cancer types. Forty-two deleterious germline mutations were identified in 21 genes of 34 patients, including 18 (18.2%) BRCA1 or BRCA2 mutations, 3 (3%) TP53 mutations, 5 (5.1%) DNA mismatch repair gene mutations, 1 (1%) CDH1 mutation, 6 (6.1%) Fanconi anemia pathway gene mutations, and 9 (9.1%) mutations in other genes. Of seven patients who carried mutations in more than one gene, 4 were BRCA1/2 mutation carriers, and their average onset age was much younger than patients with only BRCA1/2 mutations. Almost all identified high-penetrance gene mutations in those families fulfill the typical phenotypes of hereditary cancer syndromes listed in the National Comprehensive Cancer Network (NCCN) guidelines, except two TP53 and three mismatch repair gene mutations. Furthermore, functional studies of MSH3 germline mutations confirmed the association between MSH3 mutation and tumorigenesis, and segregation analysis suggested antagonism between BRCA1 and MSH3. We also identified a lot of low-penetrance gene mutations. Although the clinical significance of those newly identified low-penetrance gene mutations has not been fully appreciated yet, these new findings do provide valuable epidemiological information for the future studies. Together, these findings highlight the importance of genetic testing based on NCCN guidelines and a multi-gene analysis using NGS may be a supplement to traditional genetic counseling.
Department of Breast Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Xiaochen
X
Yang
Department of Breast Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Jiong
J
Wu
Department of Breast Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Jingsong
J
Lu
Department of Breast Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Guangyu
G
Liu
Department of Breast Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Genhong
G
Di
Department of Breast Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Canming
C
Chen
Department of Breast Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Yifeng
Y
Hou
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Tissue Bank, Department of Pathology, Shanghai Cancer Center, Fudan University, Shanghai, China.
Menghong
M
Sun
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Department of Pathology, Shanghai Cancer Center, Fudan University, Shanghai, China.
Wentao
W
Yang
Laboratory of molecular biology, National Engineering Center for Biochip at Shanghai, Shanghai, China.
Xiaojing
X
Xu
Laboratory of molecular biology, National Engineering Center for Biochip at Shanghai, Shanghai, China.
Ying
Y
Zhao
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Key Laboratory of Breast Cancer in Shanghai, Shanghai Cancer Center, Fudan University, Shanghai, China.
Xin
X
Hu
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Key Laboratory of Breast Cancer in Shanghai, Shanghai Cancer Center, Fudan University, Shanghai, China.
Daqiang
D
Li
Department of Breast Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Zhigang
Z
Cao
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Department of Pathology, Shanghai Cancer Center, Fudan University, Shanghai, China; Institute of Pathology, Fudan University, Shanghai, China.
Xiaoyan
X
Zhou
Department of Breast Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Xiaoyan
X
Huang
Department of Breast Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Zhebin
Z
Liu
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Tissue Bank, Department of Pathology, Shanghai Cancer Center, Fudan University, Shanghai, China.
Huan
H
Chen
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Tissue Bank, Department of Pathology, Shanghai Cancer Center, Fudan University, Shanghai, China.
Yanzi
Y
Gu
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Key Laboratory of Breast Cancer in Shanghai, Shanghai Cancer Center, Fudan University, Shanghai, China.
Yayun
Y
Chi
Department of Breast Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Xia
X
Yan
Department of Breast Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Qixia
Q
Han
Department of Breast Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Zhenzhou
Z
Shen
Department of Breast Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Key Laboratory of Breast Cancer in Shanghai, Shanghai Cancer Center, Fudan University, Shanghai, China.
Zhimin
Z
Shao
Department of Breast Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Zhen
Z
Hu
D000328:Adult; D017668:Age of Onset; D044466:Asian People / Q000235:genetics*; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics; D002681:China; D019295:Computational Biology; D004268:DNA-Binding Proteins / Q000235:genetics; D004843:Epistasis, Genetic; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D000074081:MutS Homolog 3 Protein; D010375:Pedigree; D011159:Population Surveillance; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D004268:DNA-Binding Proteins; C078444:MSH3 protein, human; D000074081:MutS Homolog 3 Protein; D016159:Tumor Suppressor Protein p53