Germline variation in BRCA1/2 is highly ethnic-specific: Evidence from over 30,000 Chinese hereditary breast and ovarian cancer patients

Abstract

BRCA1 and BRCA2 play essential roles in maintaining the genome stability. Pathogenic germline mutations in these two genes disrupt their function, lead to genome instability and increase the risk of developing breast and ovarian cancers. BRCA mutations have been extensively screened in Caucasian populations, and the resulting information are used globally as the standard reference in clinical diagnosis, treatment and prevention of BRCA-related cancers. Recent studies suggest that BRCA mutations can be ethnic-specific, raising the question whether a Caucasian-based BRCA mutation information can be used as a universal standard worldwide, or whether an ethnicity-based BRCA mutation information system need to be developed for the corresponding ethnic populations. In this study, we used Chinese population as a model to test ethnicity-specific BRCA mutations considering that China has one of the latest numbers of breast cancer patients therefore BRCA mutation carriers. Through comprehensive data mining, standardization and annotation, we collected 1,088 distinct BRCA variants derived from over 30,000 Chinese individuals, one of the largest BRCA data set from a non-Caucasian population covering nearly all known BRCA variants in the Chinese population (https://dbBRCA-Chinese.fhs.umac.mo). Using this data, we performed multi-layered analyses to determine the similarities and differences of BRCA variation between Chinese and non-Chinese ethnic populations. The results show the substantial differences of BRCA data between Chinese and non-Chinese ethnicities. Our study indicates that the current Caucasian population-based BRCA data is not adequate to represent the BRCA status in non-Caucasian populations. Therefore, ethnic-based BRCA standards need to be established to serve for the non-Caucasian populations.

Keywords: BRCA1; BRCA2; Chinese; breast cancer; ethnic-specific; mutation; population.

Figure 1

BRCA data. (a) Clinical classification of Chinese BRCA data as pathogenic, likely pathogenic, uncertain significance, likely benign, benign and unclassified. The pathogenic and likely pathogenic variants accounted for 49.5%. (b) Relationship between population sizes and their contribution to current BRCA data. The proportions of different human ethnic populations were from the database (http://www.worldometers.info/world‐population/), the ethnic origins of BRCA data were from different BRCA databases. It shows that the current BRCA data is not proportional to the human ethnic populations. (c) Comparison of BRCA data between Chinese and non‐Chinese populations. A total of 557 BRCA1 and 531 BRCA2 Chinese variants were compared to 6,344 BRCA1 and 8,886 BRCA2 non‐Chinese variants compiled from all existing BRCA databases. The results show that 38% of Chinese BRCA variants were present only in the Chinese population.