Prevalence and Prognostic Role of BRCA1/2 Variants in Unselected Chinese Breast Cancer Patients.
BACKGROUND
The prevalence of BRCA1/2 variants in Chinese breast cancer patients varies among studies. Germline or somatic BRCA1/2 mutations are associated with sensitivity to poly(ADP-ribose) polymerase-1 inhibitors and DNA-damaging agents. We aimed to investigate the distribution of both somatic and germline BRCA1/2 variants in unselected Chinese breast cancer patients, and explore their roles in tumor phenotype and disease prognosis.


METHODS
507 breast cancer patients, unselected for family history of breast cancer or age at diagnosis, were prospectively enrolled from West China Hospital between Feb. 2008 and Feb. 2014. BRCA1/2 variants in the exons/flanking regions were detected in fresh-frozen tumors using next-generation sequencing and confirmed by independent methods. Germline/somatic status was validated by Sanger sequencing in paired blood/normal tissue.


RESULTS
BRCA1/2 pathogenic or likely pathogenic (P/LP) variants were detected in 50 patients (9.9%), including 40 germline carriers (18 in BRCA1, 22 in BRCA2), 9 patients with somatic variants (3 in BRCA1, 6 in BRCA2), and 1 patient with concurrent germline/somatic variants in BRCA2. The triple-negative (21.4%) and Luminal B (9.7%) subtypes had higher rates of BRCA1/2 variants. In patients with disease stage 0~II, presence of a germline or somatic BRCA1 P/LP variant increased the risk of relapse as compared to non-carriers [univariate hazard ratio (HR): 3.70, P = 0.04]. Germline BRCA1 P/LP variants, which were associated with aggressive tumor phenotypes, predicted worse disease-free survival in the subgroup of stage 0~II (HR: 4.52, P = 0.02) and N0 (HR: 5.4, P = 0.04) compared to non-carriers.


CONCLUSIONS
A high frequency of germline and somatic BRCA1/2 P/LP variants was detected in unselected Chinese breast cancer patients. Luminal B subtype should be considered as a high-risk population of BRCA1/2 mutation, in addition to triple-negative breast cancer. BRCA1 status was associated with aggressive tumor phenotype and worse disease progression in early stage breast cancer patients.
Laboratory of Molecular Diagnosis of Cancer, State Key Laboratory of Biotherapy, National Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu Sichuan, P. R. China.
Xiaorong
X
Zhong
Asia and Emerging Markets iMed, AstraZeneca, Shanghai, P. R. China.
Zhengwei
Z
Dong
Asia and Emerging Markets iMed, AstraZeneca, Shanghai, P. R. China.
Hua
H
Dong
Department of Epidemiology and Bio-Statistics, West China School of Public Health, Sichuan University, Chengdu, Sichuan, P.R. China.
Jiayuan
J
Li
Laboratory of Molecular Diagnosis of Cancer, State Key Laboratory of Biotherapy, National Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu Sichuan, P. R. China.|Department of Thyroid and Breast Surgery, West China Hospital, Sichuan University, Chengdu Sichuan, P. R. China.
Zuxiang
Z
Peng
Laboratory of Molecular Diagnosis of Cancer, State Key Laboratory of Biotherapy, National Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu Sichuan, P. R. China.
Ling
L
Deng
Asia and Emerging Markets iMed, AstraZeneca, Shanghai, P. R. China.
Xuehua
X
Zhu
Asia and Emerging Markets iMed, AstraZeneca, Shanghai, P. R. China.
Yun
Y
Sun
Asia and Emerging Markets iMed, AstraZeneca, Shanghai, P. R. China.
Xuesong
X
Lu
Asia and Emerging Markets iMed, AstraZeneca, Shanghai, P. R. China.
Fuxiao
F
Shen
Asia and Emerging Markets iMed, AstraZeneca, Shanghai, P. R. China.
Xinying
X
Su
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America.
Liying
L
Zhang
Asia and Emerging Markets iMed, AstraZeneca, Shanghai, P. R. China.
Yi
Y
Gu
Laboratory of Molecular Diagnosis of Cancer, State Key Laboratory of Biotherapy, National Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu Sichuan, P. R. China.|Cancer center, West China Hospital, Sichuan University, Chengdu, Sichuan, P. R. China.
Hong
H
Zheng
D000328:Adult; D044466:Asian People; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D002681:China; D018572:Disease-Free Survival; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology; D015995:Prevalence; D011379:Prognosis; D011446:Prospective Studies; D064726:Triple Negative Breast Neoplasms / Q000235:genetics
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human