Prevalence and clinical outcomes of germline mutations in BRCA1/2 and PALB2 genes in 2769 unselected breast cancer patients in China

Abstract

To gain more information on the prevalence of germline mutations in BRCA1/2 and PALB2 genes in the Chinese population, and to explore the effects of the mutation status of these genes on clinical outcomes in patients with breast cancer, we performed a screening for BRCA1/2 and PALB2 mutations in a consecutive series of unselected breast cancer patients in the Chinese population. A total of 2,769 cases were enrolled between June 1993 and September 2017. All of the exons and exon-intron boundaries of the BRCA1/2 and PALB2 genes were screened with next-generation sequencing. Of the 2,769 breast cancer patients, BRCA1, BRCA2 and PALB2 mutations accounted for 2.7% (n = 74), 2.7% (n = 76), and 0.9% (n = 24), respectively. The BRCA1 gene had the highest mutation frequency in patients with triple-negative breast cancer (TNBC), which was 9.6% (n = 42), while the BRCA2 gene had the highest mutation frequency in patients with Luminal, which was 3.2% (n = 58). The disease-free survival (DFS) of BRCA1 mutation carriers was significantly lower than that of noncarriers (adjusted HR = 2.20, 95% CI = 1.15-4.18, p = 0.017). The mutation status of the PALB2 gene was significantly associated with the decline in overall survival (OS) (adjusted HR = 8.38, 95% CI = 2.19-32.11, p = 0.002). No significant difference was found between BRCA2 pathogenic mutation carriers and noncarriers. These results demonstrate that BRCA1 mutation status may be associated with a worse disease progression in patients with breast cancer, and women who harbored a PALB2 mutation might be at a higher risk of death due to breast cancer compared to noncarriers.

BRCA1 c.5470_5477del, a founder mutation in Chinese Han breast cancer patients

“…Previously, BRCA1 c.5470_5477del was reported as a high‐frequency recurrent pathogenic variant in Chinese BC patients and ovarian cancer patients . Only one previous study performed a haplotype analysis for BRCA1 c.5470_5477del, in which three independent families shared the same haplotype, whereas two additional BC patients had similar but not exactly the same haplotype .…”

“…Previously, BRCA1 c.5470_5477del was reported as a highfrequency recurrent pathogenic variant in Chinese BC patients and ovarian cancer patients. 16,19,24 Only one previous study performed a haplotype analysis for BRCA1 c.5470_5477del, in which three independent families shared the same haplotype, whereas two additional BC patients had similar but not exactly the same haplotype. 16 Because of the small sample size (n = 489) and mixed ethnicity of the subjects, this previous study was not sufficient to demonstrate whether BRCA1 c.5470_5477del is a Chinese Han founder mutation.…”

“…There may thus be some Chinese‐specific founder mutations. To date, some recurrent BRCA1/2 pathogenic variants have been identified in China . However, these studies involved various ethnicities and had quite small sample sizes.…”

“…To date, some recurrent BRCA1/2 pathogenic variants have been identified in China. [16][17][18][19] However, these studies involved various ethnicities and had quite small sample sizes. The Chinese Han group accounts for 92% of the total Chinese population, but whether high-frequency founder mutations are present in women of Chinese Han ethnicity is currently unclear.…”

Prelude and premise to the special issue: disruption of homeostasis-induced signaling and crosstalk in the carcinogenesis paradigm “Epistemology of the origin of cancer”

“…Most recently, the breast cancer type 1/2 susceptibility protein (BRCA1/2) mutation prevalence in 5122 unselected Swedish breast cancer patients was shown to be <2% [55] and the prevalence of BRCA1/2 and partner and localizer of BRCA2 (PALB2) germline mutations in 2769 unselected breast cancer patients the Chinese population were 2.7% (BRCA1), 2.7% (BRCA2) and 0.9% (PALB2) [56]. The scientific community should be asking how it can be justified that BRCA genetic testing is already demanded by some biotechnology companies?…”