The contribution of large genomic rearrangements in BRCA1 and BRCA2 to South African familial breast cancer

Abstract

Background Pathogenic variants that occur in the familial breast cancer genes (BRCA1/2) lead to truncated ineffective proteins in the majority of cases. These variants are mostly represented by small deletions/insertions, nonsense- and splice-site variants, although some larger pathogenic rearrangements occur. Currently, their contribution to familial breast cancer (BC) and ovarian cancer (OVC) in South Africa (SA) is unknown. Methods Seven hundred and forty-four patients affected with BC or OVC were screened for larger genomic rearrangements (LGRs) by means of multiplex ligation-dependent probe amplification or Next Generation Sequencing using the Oncomine™ BRCA research assay. Results The patients represented mostly medium to high-risk families, but also included lower risk patients without a family history of the disease, diagnosed at an early age of onset (< 40 years). Eight LGRs were detected (1.1%); seven in BRCA1 with a single whole gene deletion (WGD) detected for BRCA2. These eight LGRs accounted for 8.7% of the 92 BRCA1/2 pathogenic variants identified in the 744 cases. The pathogenic LGRs ranged from WGDs to the duplication of a single exon. Conclusions Larger rearrangements in BRCA1/2 contributed to the overall mutational burden of familial BC and OVC in SA. Almost a quarter of all pathogenic variants in BRCA1 were LGRs (7/30, 23%). The spectrum observed included two WGDs, one each for BRCA1 and BRCA2.

Breast cancer in East Africa: Prevalence and spectrum of germline SNV/indel and CNVs in BRCA1 and BRCA2 genes among breast cancer patients in Tanzania

“…Two of 277 (0.7%) black Africans in their series were positive for CNVs. 22 Taken together, our results and that from the Republic of South Africa, the prevalence of CNVs in BRCA1/2 genes among black Africans seems to be lower. The role of BRCA1/2 CNVs among black Africans needs further investigation in larger cohorts in order to understand their contribution to BC incidence.…”

“… 18 The identification of germline BRCA1/2 population‐specific variants is a crucial milestone toward establishing and incorporating BRCA1/2 genetic testing and counseling into clinical practice. The BRCA1/2 information regarding the prevalence and spectrum is limited in the fast‐growing African populations, with a few findings from Northern Africa, 19 , 20 , 21 Southern Africa, 22 , 23 and Western Africa. 24 , 25 In an attempt to understanding the prevalence and spectrum of germline BRCA1/2 variants in indigenous populations of Eastern Africa, we initiated a study that analyzed the prevalence of germline SNV/indel pathogenic variants and CNVs in BRCA1/2 in Tanzanian BC patients unselected for age at diagnosis and family history of cancer.…”

Increased Co-Occurrence of Pathogenic Variants in Hereditary Breast and Ovarian Cancer and Lynch Syndromes: A Consequence of Multigene Panel Genetic Testing?

“…Segregation in her relatives with CRC and PrC could not be ascertained. To date, around 25 cases of BRCA1 deletion have been reported, [ 16 ], and most of them are of Spanish and Hispanic origin. BRCA2 -c.5796_5797delTA has mostly been reported in Italian and Greek families with cases of BC, OC, or PaC.…”

Detection of BRCA1/2 pathogenic variants in patients with breast and/or ovarian cancer and their families. Analysis of 3,458 cases from Lower Silesia (Poland) according to the diagnostic algorithm of the National Cancer Control Programme

“…Large genomic rearrangements (LGRs) involving BRCA1/2 genes are rare in populations (and less frequently observed for BRCA2 ), but their detection is still important ( Ewald et al, 2009 ). Their frequency varies from 0% to 28% in different populations ( Engert et al, 2008 ; Ewald et al, 2009 ; El Ansari et al, 2020 ; Van Der Merwe et al, 2020 ). In our study group, 273 patients were tested for CNVs, and they accounted for 2.1% (3/144 patients with variants), although the CNV was familial.…”