Division of Human Genetics, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa.
Division of Human Genetics, National Health Laboratory Services, Universitas Academic Hospital, Bloemfontein, South Africa.
BMC Cancer. 2020 May 6;20(1):391. doi: 10.1186/s12885-020-06917-y.
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.
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.
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.
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.
在大多数情况下，发生在家族性乳腺癌基因（BRCA1/2）中的致病性变异会导致截短的无效蛋白。这些变体主要由小的缺失/插入、无义突变和剪接位点变体组成，尽管也存在一些较大的致病性重排。目前，它们在南非（SA）对家族性乳腺癌（BC）和卵巢癌（OVC）的贡献尚不清楚。
通过多重连接依赖性探针扩增或使用 Oncomine™BRCA 研究检测试剂盒进行下一代测序，对 744 例受 BC 或 OVC 影响的患者进行较大基因组重排（LGRs）的筛查。
这些患者主要代表中高危家族，但也包括没有家族病史、发病年龄较早（<40 岁）的低危患者。检测到 8 种 LGR（1.1%）；BRCA2 中仅检测到一种全基因缺失（WGD）的 BRCA1 中有 7 种。这 8 种 LGRs占 744 例中 92 种 BRCA1/2 致病性变异的 8.7%。致病性 LGR 范围从 WGD 到单个外显子的重复。
BRCA1/2 中的较大重排在南非家族性 BC 和 OVC 的整体突变负担中起作用。BRCA1 中所有致病性变异的近四分之一（7/30，23%）为 LGR。观察到的谱包括 2 个 WGD，分别发生在 BRCA1 和 BRCA2 中。
