Machackova Eva, Foretova Lenka, Lukesova Mirka, Vasickova Petra, Navratilova Marie, Coene Ilse, Pavlu Hana, Kosinova Veronika, Kuklova Jitka, Claes Kathleen
Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
BMC Cancer. 2008 May 20;8:140. doi: 10.1186/1471-2407-8-140.
The incidence of breast cancer has doubled over the past 20 years in the Czech Republic. Hereditary factors may be a cause of young onset, bilateral breast or ovarian cancer, and familial accumulation of the disease. BRCA1 and BRCA2 mutations account for an important fraction of hereditary breast and ovarian cancer cases. One thousand and ten unrelated high-risk probands with breast and/or ovarian cancer were analysed for the presence of a BRCA1 or BRCA2 gene mutation at the Masaryk Memorial Cancer Institute (Czech Republic) during 1999-2006.
The complete coding sequences and splice sites of both genes were screened, and the presence of large intragenic rearrangements in BRCA1 was verified. Putative splice-site variants were analysed at the cDNA level for their potential to alter mRNA splicing.
In 294 unrelated families (29.1% of the 1,010 probands) pathogenic mutations were identified, with 44 different BRCA1 mutations and 41 different BRCA2 mutations being detected in 204 and 90 unrelated families, respectively. In total, three BRCA1 founder mutations (c.5266dupC; c.3700_3704del5; p.Cys61Gly) and two BRCA2 founder mutations (c.7913_7917del5; c.8537_8538del2) represent 52% of all detected mutations in Czech high-risk probands. Nine putative splice-site variants were evaluated at the cDNA level. Three splice-site variants in BRCA1 (c.302-3C>G; c.4185G>A and c.4675+1G>A) and six splice-site variants in BRCA2 (c.475G>A; c.476-2>G; c.7007G>A; c.8755-1G>A; c.9117+2T>A and c.9118-2A>G) were demonstrated to result in aberrant transcripts and are considered as deleterious mutations.
This study represents an evaluation of deleterious genetic variants in the BRCA1 and 2 genes in the Czech population. The classification of several splice-site variants as true pathogenic mutations may prove useful for genetic counselling of families with high risk of breast and ovarian cancer.
在过去20年中，捷克共和国乳腺癌的发病率翻了一番。遗传因素可能是乳腺癌发病年龄较轻、双侧乳腺癌或卵巢癌以及家族性疾病聚集的原因。BRCA1和BRCA2基因突变在遗传性乳腺癌和卵巢癌病例中占重要比例。1999年至2006年期间，在捷克共和国马萨里克纪念癌症研究所对1010名患有乳腺癌和/或卵巢癌的无血缘关系的高危先证者进行了BRCA1或BRCA2基因突变检测。
对两个基因的完整编码序列和剪接位点进行筛查，并验证BRCA1基因内是否存在大片段重排。对推测的剪接位点变异体在cDNA水平分析其改变mRNA剪接的可能性。
在294个无血缘关系的家族（1010名先证者中的29.1%）中鉴定出致病突变，分别在204个和90个无血缘关系的家族中检测到44种不同的BRCA1突变和41种不同的BRCA2突变。总共，三个BRCA1始祖突变（c.5266dupC；c.3700_3704del5；p.Cys61Gly）和两个BRCA2始祖突变（c.7913_7917del5；c.8537_8538del2）占捷克高危先证者中所有检测到突变的52%。在cDNA水平评估了9个推测的剪接位点变异体。BRCA1基因中的三个剪接位点变异体（c.302-3C>G；c.4185G>A和c.4675+1G>A）以及BRCA2基因中的六个剪接位点变异体（c.475G>A；c.476-2>G；c.7007G>A；c.8755-1G>A；c.9117+2T>A和c.9118-2A>G）被证明会导致异常转录本，被视为有害突变。
本研究对捷克人群中BRCA1和BRCA2基因的有害遗传变异进行了评估。将几种剪接位点变异体分类为真正的致病突变可能对乳腺癌和卵巢癌高危家族的遗传咨询有用。
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