Multicenter cross‑sectional screening of the BRCA gene for Chinese high hereditary risk breast cancer populations
- Authors:
- Published online on: April 18, 2018 https://doi.org/10.3892/ol.2018.8538
- Pages: 9420-9428
Abstract
Introduction
Even though, the incidence of breast cancer (BC) in China is lower compered to Western countries, since the 1990s it has increased twice as fast as the global rate (1) with very early onset (2,3). In China, BC patients <50 years old account for 46% of the total cases (4), with the peak prevalence observed in the 45 to 55 years old age (5–8). Meanwhile, the highest mortality is observed in even younger age i.e. in the 30 to 44 years old age (5). Therefore, in order to reduce the number of BC patients, and the growing burden of this disease, it is urgent to promote BC prevention in China.
BRCA (Breast Cancer Susceptibility Gene) is associated with the majority of hereditary BC, which accounts for about 5 to 10% of all cases of breast cancers (9). Meanwhile, the resemblance in clinical and pathologic features between sporadic triple-negative BC (TNBC) and BRCA1 mutant BC implies that mechanism behind BRCA germline mutant tumors is strongly associated with somatic mutation of sporadic BC (10). However, a lack of basic information about the prevalence and spectrum of BRCA mutations hinders research progress on the etiology (6) and risk evaluation of model of breast cancer prevention in China. Additionally, because of the large presence of ethnic-specific contexts (11–14), the Western risk evaluation models do not apply well to China. Therefore, the following paper assembled a wide-range clinic-based cross-sectional study of hereditary risk among BC patients, who were representative for BRCA mutations study. The patients were from different parts of mainland China, which was important for determining the prevalence and types of BRCA mutations, as well as to provide basic information for further studies of BRCA and BC prevention models in China.
Materials and methods
Study population
The present study has been approved by center medical ethics committee (Ethics Committee of the First Affiliated Hospital of Third Military Medical University, PLA), and was successfully registered with Chinese Clinical Trial Registry (ChiCTR), which is the international clinical trial registration platform.
In the time period from October 2015 to February 2016, 445 patients diagnosed with BC were recruited from 18 tertiary general clinics located in North, South and Northwest China, which account for 3/4 of Chinese national territory (Fig. 1). Among these patients, three refused to participate in the study, while for other five the recruitment criteria couldn't be confirmed. Pathological examination was used to confirm the cancer diagnoses and breast cancer subtype. Furthermore, twenty-seven participants were additionally excluded from the clinical data analysis due to incomplete or illegible clinical information. Where it was possible, family members of probands with confirmed BC were recruited to participate.
After reading and signing the informed consent, participants were interviewed in order to provide medical details including past medical history, present BC diagnosis age, tumor size, states of axillary lymph nodes and metastasis, and details of family cancer history. Consequently, fresh peripheral venous blood (5 ml) was collected from each participant, and transferred into a coded Ethylene Diamine Tetraacetie Acid (EDTA) tube at 4°C. During the same day, blood samples were sent to Annoroad Gene Technology (Beijing) Co., Ltd, for further analyses (BRCA genetic testing). Each participant received a sealed file filled with BRCA test result (excluding their clinical records). Genetic consultation was provided in order to better explain the BRCA test results. The participants did not encounter any financial costs (including genetic consultation) for their participation in the present study.
Recruitment criteria
The recruitment criteria adhered to the breast cancer diagnosis and treatment guidelines and specifications (Chinese Cancer Society, V2015). Participants who met one of the following criteria were included in the study: i) BC with onset age ≤35 years old (early-onset BC group), ii) ≥1 relativea (either sex) from the same side of the family as BC patient and (or) ovarian cancer (BC/OC) diagnosed at any age (BC/OC family history group), iii) two primary BC cancersb [bilateral BC (BBC) group], iv) male BC patients (MBC group), v) BC with OC (BC&OC group) and vi) meeting ≥2 criteria above simultaneously (mixed group). aIncluding first, second and third degree relative with no age limitation. bTwo primary BC, bilateral BC excluding metastatic contralateral BC or unilateral BC including two or more different types of cancers.
In case the patients failed to sign the informant consent, they were excluded from the present study.
BRCA gene analysis
BRCA1 (MIM:113705) and BRCA2 (MIM:600185) testing was performed using Annoroad Gene Technology (Beijing, China) on an Illumina HiSeq 2500 platform (Illumina, San Diego, CA, USA). Genomic DNA was first extracted from peripheral blood white cells using the QIAGEN DNeasy Blood and Tissue Kit (Qiagen, Shanghai, China). The genomic DNA was then fragmented by a bioruptor sonication device (Diagenode, Leige, Belgium). The construction and capture of the DNA library followed the standard protocols from Illumina (Illumina, San Diego, CA, USA) and Roche (Roche, Shanghai, China). A Qubit 3.0 Fluorometer (Invitrogen, San Francisco, CA, USA) and Bioanalyzer (Agilent, Santa Clara, CA, USA) were used to determine the quantity of the library. Finally, the library was sequenced on one lane using 100 paired-end (2x100 bp) strategies.
Variant nomenclature
Reference sequences used for BRCA1 and BRCA2 analyses were GenBank NM_007294.2 (BRCA1) and NM_000059.3 (BRCA2). Mutation nomenclature was described according to Human Genome Variation Society (v2.0) (15).
Statistical analysis
Medians were used with interquartile ranges of abnormally distributed data for continuous variables (diagnosed ages of patients) and rank test for analyses. Proportions were shown for categorical variables. Comparisons of mutation rates and proportions were analyzed by Chi-square test of unordered categorical variable. Univariate and multivariate logistic analysis were used to examine the relationships between hormone receptors (HRs, including estrogen receptor ER, progesterone receptor PR) and human epidermal growth factor receptor 2 (HER2) and BRCA mutation states with odd ratios (OR) and 95% confidence intervals (95% CI).
All P-values were two-sided. P<0.05 was considered to indicate a statistically significant difference. All data were analyzed using PASW Statistics 22.0 (SPSS, Inc., Chicago, IL, USA).
Results
Study population
From a total of 437 BC patients enrolled in the study, almost half came from north China (Table I). Forty percent of early-onset BCs (173/437) and 30% of patients with BC/OC family history (163/437) were observed in more than half of the participants (Table II). The median age of 437 BC patients was 35.0 (31.0, 46.0) years. The median age of mutation carriers was higher compared to non-carriers [41.0 (34.0, 47.0) vs. 35.0 (30.0, 46.0), P=0.002].
Mutation frequency
Seventy-six (17.4%) BRCA mutation carriers were identified, 31 (15.4%) of which were from patients from North China, 30 (19.9%) from patients from South China, and 15 (17.6%) from patients from Northwest China. No significant difference in gene mutation rates was found between different region areas (Table I). Furthermore, the early-onset patient rate (9.2%) was significantly different in relation to remaining 5 groups (P=0.007) (Table II); while no significant difference was found between the 5 groups (P>0.05).
BRCA mutation status
According to the American College of Medical Genetics and Genomics (ACMG) (16), a total of 61 deleterious mutation points (29 in BRCA1, 32 in BRCA2) were observed in 76 carriers (Table III), and consequently classified into the already ‘known’ (Table IV) and the ‘novel’ (Table V) mutations. Briefly, 72% of novel variations were found in BRCA2 (Tables IV and V). Moreover, five mutations of 61 were observed in more than one unrelated patients from different areas (Fig. 2 and Table IV).
Thirty-four points (55.7%) were frame shift, followed by 17 (27.9%) nonsenses, 7 splices (11.5%), 2 pathogenic missenses (3.3%), and 1 synonymous mutation (1.6%). Extra 10 missenses were found as variants of uncertain significance (VUS) (Table VI), accounting for 14.1% of all the variants including 61 deleterious mutation.
Eleven different mutations in 10 families were related to hereditary breast and ovarian cancer syndrome (HBOC), four in BRCA2 were novel (Table VII). Moreover, none of the identified mutations were shared between the families. BRCA1 c.190T>C&BRCA2 c.9090dup were found in one same family, and were carried by a proband from maternal and paternal line respectively. The proband's BC was inherited from maternal HBOC (Fig. 3A). In BRCA1 c.5431C>T hereditary family, all the middle-age females had BC/OC, but all the male carriers of four general relatives were healthy (Fig. 3B).
Clinical analysis
410 precise tumor node metastasis TNM results were obtained. No significant difference was found among wild type BRCA (BRCA−), BRCA1 and BRCA2 mutation patients (Table VIII).
Univariate analysis demonstrated higher expression of ER negative (ER−) and PR negative (PR−) in BRCA1 group compared to BRCA− group (72.6% vs. 35.1%, P<0.0001; 82.4% vs. 40.6%, P<0.0001). Conversely, higher expression of ER positive (ER+) and PR positive (PR+) were found in BRCA2 group compered to BRCA− group patients (93.5% vs. 64.9%, P=0.001; 87.1% vs. 59.4%, P=0.002). Moreover, BRCA1 and BRCA2 groups were both more frequently HER2 negative (HER2−) compared to BRCA− group (97.1, 96.8% vs. 74.3%, P=0.003 and 0.005 respectively). Based on the multivariate analysis, PR− and HER2− were the independent risk factors for BRCA1 mutation, HER2− alone for BRCA2 (Tables IX and X). Then, compared with BRCA−, BRCA1 mutation tended to be TNBC (68.6% vs. 24.8%, P<0.0001), while BRCA2 mutation had higher proportion of HRs positive (HRs+) BC (93.5% vs. 75.2%, P=0.002) (Table XI).
Discussion
The results from the present study, which is to our knowledge, the largest screening study ever performed in China, reveal that the total BRCA mutation rate is 17.4% for breast cancer patients at risk of hereditary BRCA mutation across China with no observed geographical differences.
One of the main components of the present study has to do with 21.7% of mutation rate which lies in BC/OC family history subgroup. This finding is in line with a Korean study conducted across 36-centers (22.3%) (17). The mutation rate appears generally lower compared to Western countries (23~35.3%) (18–22), but higher compared to Peking or Shanghai regions (10.5~18.2%) (23–25). Lower prevalence of BRCA mutation is in line with comparisons of BC incidence with the Western countries. It clearly suggests essential distinction in BRCA mutation between Asian and Euromerican people that goes well beyond different study design biases. Furthermore, thus far observed domestic inconsistencies may be caused by the limitations related to areas and criteria. The present study covers most of the Chinese regions, i.e. areas with huge concentrations of Chinese populations. Moreover, the present study does not impose the BC onset age limitation for family cancer history, which allows for wider screening rang. However, some families with late-onset hereditary BC/OC that are really in need of BRCA testing may be excluded from testing due to young cutoff diagnose age established by BRCA testing guideline. Most of all, our results are representative of the real data on hereditary risk for breast cancer patients in China.
The sporadic early-onset (≤35 years) BC mutation rates (9.2%) are nearly twice higher compared to those obtained by the recent studies from China (5%, ≤40 years) (24) and from Western countries (5.9%, <36 years) (26), but lower compared to other 5 risk factor groups in this study. The observed discrepancy may come from different sample sizes and study populations. Moreover, different age limitations for early-onset suggest that cutoff age may impact the mutation rates in younger patients. Currently, the age of 45 is set as upper limitation of young BC for BRCA testing according to Chinese BC Treatment Guideline (27). Nevertheless, increasing trend of breast cancer incidence in younger patients in China (6) may imply more patients with sporadic early-onset from the whole population. Ten years interval, between the ages 35 and 45, may actually double the difference on sensitivity and specificity for BRCA screening in Chinese patients with breast cancer. Additionally, besides onset age, family history, bilateral BC, with OC and similar should also be considered in the early-onset BC to improve BRCA test indications (24). Consequently, we suggest re-evaluation of the early-onset age for BRCA test to increase sensitivity of BRCA mutation screening and to fit current BC epidemiology in China.
BRCA mutation sites in our study suggest special features of BRCA mutation in China. Four sites are hereditary, and nearly half are novel. Also, 14.1% VUS were slightly higher than Asian data (13.6%) obtained from a study conducted by Hall et al. Interestingly, their data were already more than 2.5 times higher compared to European VUS (28). Then, BRCA1 c.2572C>T reappeared twice in two unrelated patients from Chongqing and Shanxi Provinces, respectively. Up to now, it has been found in unrelated patients from five different provinces in China (29). Nevertheless, it has not been frequently reported in international studies, meaning it might be one of founder mutation candidates among Chinese populations. BRCA1 c.5470_5477del is another highly repeated site found three times in our study. Internationally, the site has been previously identified in Korean sample (30), while nationally it has been reported in Shanghai (31), Beijing (32), Zhejiang, and Liaoning (33). Thus far, it has been found in 12 unrelated carriers from six different areas of China, including HBOC patients (33.3%) (32), sporadic BC patients (33.3%) (31,33) and early-onset BC (33) or BBCpatients (33.3%) (the present study). Also, three of the patients (from Zhejiang, Shanghai, and Liaoning) share the same haplotype (33). To our knowledge, it has only once been reported in native Asian patient (34), therefore, it is strongly associated with Asian founder mutation. However, Kwong et al have recognized BRCA2 c.3109C>T as a founder mutation in southern Chinese population in Hong Kong (35,36). 81.5% of probands in the study were immigrants from Guangdong. It was repeated in two unrelated patients from Chongqing, southwest of China, but it did not appear in our population sample from southern China. Further large scale unselected population epidemic research is necessary to clarify this.
Two confirmed HBOC families have special features. The proband who carried two mutations is the youngest patient in her family, thus it is not possible to ignore the effects of paternal inherited BRCA2 c.9090dup (novel) on the proband given her uncle has lung cancer (Fig. 3A). BRCA1 c.5431C>T pathogenicity shows a gender trend: It appears harmful for women, and silent for men (Fig. 3B).
All the information on the mutation sites reported above suggest quite different BRCA mutation spectrum and features that exit in Chinese BC patients compared with well-known white populations.
Similar to other studies, we came to the conclusion that BRCA1 mutation is concerned with TNBC. However, BRCA2 mutations tend to be HRs+ BC, which is inconsistent with results from other studies (37,38). The different results show heterogeneous of BRCA2 mutant BC beyond different study populations and regions (39,40). The present study suggests that BRCA2 mutant BC may responds better to endocrine therapy due to high proportion of HRs+ tumor with the same background of hereditary risk of BC compared with BRCA− and BRCA1 mutant BC.
In summary, this study provides a general BRCA mutation profile in China, which enhances the prevalence of BRCA mutations in non-white populations. The BRCA screening provides a distinguishing BRCA mutation profile in China, which compared to the West reveals lower mutation prevalence, and special mutation spectrum. Cutoff ages for diagnosis of early-onset and BC/OC family history should be re-evaluated based on population screening data to improve BRCA test indications. BRCA2 mutation suggests the best response to endocrine therapy among BRCA mutant and BRCA− BCs in this selected hereditary risk population. However, further studies are necessary to confirm precise BRCA mutation situation in China.
Acknowledgements
The authors would like to thank Zefei Jiang, Mengmeng Zhang, Shaohua Wei, Yuanyuan Wang, Dawei Yun, Huiquan Jiang, Yang Li, Yimeng Hu, Yong Yang and other medical staff for their involvement in the study design, BRCA lab test, information collection, data analysis and manuscript writing. The present study was supported by the China Health Promotion Foundation.
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