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.

Translational Health Disparities Research in a Data-Rich World

“…36 This concern was confirmed in an analysis of germline variation in BRCA genes among over 30,000 Chinese individuals, revealing substantial differences in variants present between Chinese and non-Chinese ethnicities. 37 Additional novel ancestry-specific associations were confirmed using a new study of nearly 50,000 non-European individuals. 38 Thus, ML and AI that rely on feeder data likely produce biased results because the input data are biased.…”

Investigation into the origins of an ancient BRCA1 founder mutation identified among Chinese families in Singapore

“…These data however have derived predominantly from studies involving populations of European descent. 9 This raises concerns as genetic variation can be ancestry-specific, indicating that current data may not be applicable as a reference for other populations. 9 Variants in BRCA1/2 identified in Asian populations for example differ substantially from other populations.…”

“…9 This raises concerns as genetic variation can be ancestry-specific, indicating that current data may not be applicable as a reference for other populations. 9 Variants in BRCA1/2 identified in Asian populations for example differ substantially from other populations. 10 Development of ancestrybased BRCA1/2 reference data is thus imperative, as current databases lacking such data may result in inadequate power in identifying carriers from other populations.…”

“…10 Development of ancestrybased BRCA1/2 reference data is thus imperative, as current databases lacking such data may result in inadequate power in identifying carriers from other populations. 9,11 Furthermore, individuals of non-European descent are more likely to have variants reported with unknown clinical significance, for which no medical management recommendations can be offered. 12 Among current databases, pathogenic variants have been reported with high-frequency in certain ancestry groups, often as a result of a founder effect.…”

“…15 Identification of founder mutations in non-European populations is however less established. 9 The aim of our study was to determine the clinical significance of a recurrent intronic BRCA1 c.442-22_442-13del variant of uncertain clinical significance (VUS), identified among Chinese families with breast and/or ovarian cancer. Furthermore, we aimed to establish whether it was due to a founder effect and explore its origins.…”