Assessing the variations in breast/ovarian cancer risk for Chinese BRCA1/2 carriers

Abstract

BackgroundCancer risks vary in different BRCA1/2 mutations. Previous studies based on Caucasian population have identified regions associated with elevated/reduced risks of breast/ovarian cancers. Since ethnic differences are known to affect BRCA1/2 mutation spectra, we are interested in defining Chinese-specific ovarian/breast cancer cluster regions (OCCR/BCCR) and comparing with previously reported Caucasian-based cluster regions. We also aim to characterize the distribution and estimate the cancer risks of different Chinese recurrent mutations. Methods7,919 (3,641 unselected cancer-free women + 4,278 female cancer patients) individuals were included in the study. Germline BRCA1/2 status were detected with amplicon-based next-generation sequencing. BRCA1/2 carriers were defined as bearing likely pathogenic or pathogenic mutations. We calculated odds ratio (OR) of breast cancer and OR of ovarian cancer, and their ratio of the two ORs (ROR) for each region. ROR > 1 indicated elevated odds of breast cancer and/or decreasing odds of ovarian cancer; ROR < 1 indicated increasing odds of ovarian cancer and/or decreasing breast cancer odds. The frequency, distribution and penetrance of six known Chinese founder mutations were characterize respectively. Haplotype analysis and age estimation were performed on the most prevalent and widely-spread founder mutation BRCA1:c.5470_5477del. ResultsA total of 729 subjects were detected with germline BRCA1/2 deleterious mutations, including 236 BRCA1 and 122 BRCA2 mutations. The putative Chinese OCCR/BCCR are partially overlapped with Caucasian-based OCCR/BCCR and shared structural-functional characteristics. The six known Chinese founder mutations vary greatly in both distribution and penetrance. The two most prevalent and widely-spread mutations are estimated to convey low penetrance, while the area-restricted founder mutations seemed to confer higher or nearly complete penetrance. The most prevalent founder mutation BRCA1:c.5470_5477del accounting for 9.5% - 18% of BRCA1 carriers is estimated to have emerged [~]2,090 years ago (70 B.C.) during the Han Dynasty, about 290 years ([~]14.5 generations) prior to the Three Kingdoms Period when a major population migration occurred. ConclusionBRCA1/2 carriers with different genotypes have significantly different cancer risks. Hence ideally risk assessment should be mutation-specific, rather than concerning a single figure. The probably most ancient Chinese founder mutation may have originated more than 2,000 years ago.