Prevalence of BRCA1 and BRCA2 pathogenic variants in a large, unselected breast cancer cohort

Abstract

Breast cancer patients with BRCA1/2-driven tumors may benefit from targeted therapy. It is not clear whether current BRCA screening guidelines are effective at identifying these patients. The purpose of our study was to evaluate the prevalence of inherited BRCA1/2 pathogenic variants in a large, clinically representative breast cancer cohort and to estimate the proportion of BRCA1/2 carriers not detected by selectively screening individuals with the highest probability of being carriers according to current clinical guidelines. The study included 5,122 unselected Swedish breast cancer patients diagnosed from 2001 to 2008. Target sequence enrichment (48.48 Fluidigm Access Arrays) and sequencing were performed (Illumina Hi-Seq 2,500 instrument, v4 chemistry). Differences in patient and tumor characteristics of BRCA1/2 carriers who were already identified as part of clinical BRCA1/2 testing routines and additional BRCA1/2 carriers found by sequencing the entire study population were compared using logistic regression models. Ninety-two of 5,099 patients with valid variant calls were identified as BRCA1/2 carriers by screening all study participants (1.8%). Only 416 study participants (8.2%) were screened as part of clinical practice, but this identified 35 out of 92 carriers (38.0%). Clinically identified carriers were younger, less likely postmenopausal and more likely to be associated with familiar ovarian cancer compared to the additional carriers identified by screening all patients. More BRCA2 (34/42, 81.0%) than BRCA1 carriers (23/50, 46%) were missed by clinical screening. In conclusion, BRCA1/2 mutation prevalence in unselected breast cancer patients was 1.8%. Six in ten BRCA carriers were not detected by selective clinical screening of individuals.

The intronic BRCA1 c.5407-25T>A variant causing partly skipping of exon 23—a likely pathogenic variant with reduced penetrance?

“…However, it is higher than reported in a large international prospective study of clinically ascertained carriers of a BRCA1 pathogenic variant, with median age at diagnosis of breast and ovarian cancer of 44 and 54 years, respectively [23]. On the other hand, a recent large study on unselected women with breast cancer in Sweden found a mean age at diagnosis of 50.3 years in women with a pathogenic BRCA1 variant [24]. This illustrates that the penetrance of BRCA1 pathogenic variants may differ, depending on the mode of ascertainment.…”

“…The PCR products were analysed by agarose gel electrophoresis and Sanger sequencing. The reference sequence NG_005905.2 (NM_007294.3) and traditional numbering of exons [1][2][3][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] was used.…”

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?…”

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

“…3,5 Identification of individuals with inherited BRCA1/2 pathogenic variants is beneficial as knowledge of this fundamentally impacts medical management. [6][7][8] Extensive efforts have developed databases with well-documented, annotated and freely accessible BRCA1/2 variant information used as a universal reference for diagnostic, treatment and prevention strategies. These data however have derived predominantly from studies involving populations of European descent.…”