Abstract：
BACKGROUND: While BRCA1/2 gene mutational spectrum and clinical features are widely studied, there is limited data on breast cancer-predisposing non-BRCA pathogenic/likely pathogenic variants (PV/LPVs) in the Baltic states region. According to previous studies, CHEK2 is the most frequent moderate-risk breast cancer predisposition gene. The study aimed to analyse the frequency and mutational spectrum of CHEK2 PV/LPVs in the Baltic states region and perform a literature review on the subject.
METHODS: The study includes two cohorts - population-based Estonian biobank (EstBB) (N-152 349) and breast cancer affected cases from Latvia (N-105). In the cohort from Latvia, CHEK2, BRCA1, BRCA2, PALB2 testing with next-generation sequencing (NGS) was carried out in selected breast cancer cases. In the EstBB, the full SNP genotyped dataset Global Screening Array (GSA) (N-152 349) was used to screen CHEK2 PV/LPVs and variants c.319+2T > A (p.(?)), c.444+1G>A (p.(?)), c.433C > T (p.Arg145Trp), c.283C > T (p.Arg95*) in CHEK2 are reported from this dataset. In addition, a subset of the EstBB (N-4776) underwent whole-genome sequencing (WGS, N-2420) and whole-exome sequencing (WES, N-2356) and founder variants c.470T > C (p.Ile157Thr), c.444+1G>A (p.(?)), c.1100delC (p.Thr367Metfs*15) in CHEK2 were reported from this dataset. Moreover, a literature overview was performed on April 1, 2021, using the PubMed search of keywords \'CHEK2\', \'breast cancer\', \'Estonia\', \'Lithuania\', \'Latvia\', \'Poland\', \'Belarus\' and \'Russia\'.
RESULTS: In the breast cancer affected cohort from Latvia 6 CHEK2 variants, classified as PV/LPVs, were observed (6/105; 5.7%), including recurrent ones c.470T > C (p.Ile157Thr) (1.9%) and del5395(ex9-10del; (p.Met304Leufs*16)) (1.9%), as well as single ones - c.1100delC (p.Thr367Metfs*15) (1%) and c.444+1G>A (p.(?)) (1%). From EstBB NGS data (N-4776) CHEK2 variant c.470T > C (p.Ile157Thr) was detected in 8.6% of cases, c.1100delC (p.Thr367Metfs*15) in 0.6% and c.444+1G>A (p.(?)) in 0.2% of cases. In the EstBB full cohort of SNP array data (N-152 349) CHEK2 variant c.444+1G>A (p.(?)) was detected in 0.02% of cases, c.319+2T > A (p.(?)) in 0.09% of cases, c.433C > T (p.Arg145Trp) in 0.02% of cases and c.283C > T (p.Arg95*) in <0.001% of cases. For the literature review altogether, 49 PubMed articles were found, 23 of which were relevant, representing CHEK2 PV/LPVs in the population of interest. Ten publications are from Poland, eight from Russia, three from Latvia and two from Belarus.
CONCLUSIONS: This study is the first combined report on complete CHEK2 PV/LPVs screening in selected breast cancer affected cases in Latvia and large-scale population screening in Estonia, providing insight into the CHEK2 mutational spectrum in the Baltic states region. The initial results are in line with other studies that CHEK2 PV/LPVs frequency is around 5-6% of selected breast cancer cases. Here we report three CHEK2 PV/LPV - c.319+2T > A (p.(?)), c.433C > T (p.Arg145Trp), c.283C > T (p.Arg95*), that are novel for the Baltic states region. This is also the first report on c.1100delC (p.Thr367Metfs*15) and c.444+1G>A (p.(?)) from the Baltic states. High population frequency of c.470T > C (p. Ile157Thr) (8.6%) continues to question the variant\'s pathogenicity in particular populations. Other findings are concordant with previous reports from Latvia and neighbouring populations.
METHODS: The study includes two cohorts - population-based Estonian biobank (EstBB) (N-152 349) and breast cancer affected cases from Latvia (N-105). In the cohort from Latvia, CHEK2, BRCA1, BRCA2, PALB2 testing with next-generation sequencing (NGS) was carried out in selected breast cancer cases. In the EstBB, the full SNP genotyped dataset Global Screening Array (GSA) (N-152 349) was used to screen CHEK2 PV/LPVs and variants c.319+2T > A (p.(?)), c.444+1G>A (p.(?)), c.433C > T (p.Arg145Trp), c.283C > T (p.Arg95*) in CHEK2 are reported from this dataset. In addition, a subset of the EstBB (N-4776) underwent whole-genome sequencing (WGS, N-2420) and whole-exome sequencing (WES, N-2356) and founder variants c.470T > C (p.Ile157Thr), c.444+1G>A (p.(?)), c.1100delC (p.Thr367Metfs*15) in CHEK2 were reported from this dataset. Moreover, a literature overview was performed on April 1, 2021, using the PubMed search of keywords \'CHEK2\', \'breast cancer\', \'Estonia\', \'Lithuania\', \'Latvia\', \'Poland\', \'Belarus\' and \'Russia\'.
RESULTS: In the breast cancer affected cohort from Latvia 6 CHEK2 variants, classified as PV/LPVs, were observed (6/105; 5.7%), including recurrent ones c.470T > C (p.Ile157Thr) (1.9%) and del5395(ex9-10del; (p.Met304Leufs*16)) (1.9%), as well as single ones - c.1100delC (p.Thr367Metfs*15) (1%) and c.444+1G>A (p.(?)) (1%). From EstBB NGS data (N-4776) CHEK2 variant c.470T > C (p.Ile157Thr) was detected in 8.6% of cases, c.1100delC (p.Thr367Metfs*15) in 0.6% and c.444+1G>A (p.(?)) in 0.2% of cases. In the EstBB full cohort of SNP array data (N-152 349) CHEK2 variant c.444+1G>A (p.(?)) was detected in 0.02% of cases, c.319+2T > A (p.(?)) in 0.09% of cases, c.433C > T (p.Arg145Trp) in 0.02% of cases and c.283C > T (p.Arg95*) in <0.001% of cases. For the literature review altogether, 49 PubMed articles were found, 23 of which were relevant, representing CHEK2 PV/LPVs in the population of interest. Ten publications are from Poland, eight from Russia, three from Latvia and two from Belarus.
CONCLUSIONS: This study is the first combined report on complete CHEK2 PV/LPVs screening in selected breast cancer affected cases in Latvia and large-scale population screening in Estonia, providing insight into the CHEK2 mutational spectrum in the Baltic states region. The initial results are in line with other studies that CHEK2 PV/LPVs frequency is around 5-6% of selected breast cancer cases. Here we report three CHEK2 PV/LPV - c.319+2T > A (p.(?)), c.433C > T (p.Arg145Trp), c.283C > T (p.Arg95*), that are novel for the Baltic states region. This is also the first report on c.1100delC (p.Thr367Metfs*15) and c.444+1G>A (p.(?)) from the Baltic states. High population frequency of c.470T > C (p. Ile157Thr) (8.6%) continues to question the variant\'s pathogenicity in particular populations. Other findings are concordant with previous reports from Latvia and neighbouring populations.
摘要：
背景：虽然BRCA1/2基因突变谱和临床特征被广泛研究，波罗的海国家地区关于乳腺癌易感的非BRCA致病性/可能致病性变异体(PV/LPV)的数据有限.根据以前的研究,CHEK2是最常见的中度风险乳腺癌易感基因。该研究旨在分析波罗的海国家地区CHEK2PV/LPV的频率和突变谱，并对该主题进行文献综述。
方法：该研究包括两个队列-基于人群的爱沙尼亚生物样本库（EstBB）（N-152.349）和来自拉脱维亚的乳腺癌患者（N-105）。在来自拉脱维亚的队列中，在选定的乳腺癌病例中进行CHEK2，BRCA1，BRCA2，PALB2测试和下一代测序（NGS）。在EstBB中，完整的SNP基因型数据集全局筛选阵列（GSA）（N-152.349）用于筛选CHEK2PV/LPV和变体c.3192T>A（p。(?)),c.444+1G>A（p。(?)),c.433C>T（p。Arg145Trp），c.283C>T（p。从该数据集报告CHEK2中的Arg95*）。此外,EstBB(N-4776)的一个子集接受了全基因组测序(WGS，N-2420）和全外显子组测序（WES，N-2356）和创始人变体c.470T>C（第Ile157Thr),c.444+1G>A（p。(?)),c.1100delC（p.从该数据集报告了CHEK2中的Thr367Metfs*15）。此外，2021年4月1日，使用PubMed搜索关键字“CHEK2”进行了文献综述，\'乳腺癌\',\'爱沙尼亚\',\'立陶宛\',\'拉脱维亚\',\'波兰\',\'白俄罗斯\'和\'俄罗斯\'。
结果：在来自拉脱维亚的乳腺癌影响队列中，有6个CHEK2变体，分类为PV/LPV，观察到(6/105；5.7%)，包括反复发作的c.470T>C（p。Ile157Thr）（1.9%）和del5395（ex9-10del；（p。Met304Leufs*16））（1.9%），以及单个-c.1100delC（p.Thr367Metfs*15）（1%）和c.444+1G>A（p。（？））（1%）。来自EstBBNGS数据（N-4776）CHEK2变体c.470T>C（p。Ile157Thr）在8.6%的病例中检测到，c.1100delC（p.Thr367Metfs*15）在0.6%和c.444+1G>A（p。（？））在0.2％的情况下。在SNP阵列数据的EstBB完整队列中（N-152.349）CHEK2变体c.4441G>A（p。（？））在0.02％的病例中检测到，c.319+2T>A（p。（？））在0.09%的案例中，c.433C>T（p。Arg145Trp）在0.02％的病例中，c.283C>T（p。Arg95*）在<0.001%的病例中。对于文献综述，找到了49篇PubMed文章，其中23个是相关的，代表感兴趣群体中的CHEK2PV/LPV。十本出版物来自波兰，八位来自俄罗斯,三个来自拉脱维亚，两个来自白俄罗斯。
结论：本研究是拉脱维亚某些乳腺癌患者的完整CHEK2PV/LPV筛查和爱沙尼亚大规模人群筛查的第一份综合报告。深入了解波罗的海国家地区的CHEK2突变谱。初步结果与其他研究一致，即CHEK2PV/LPV频率约为选定乳腺癌病例的5-6％。在这里，我们报告了三个CHEK2PV/LPV-c.319+2T>A（p。(?)),c.433C>T（p。Arg145Trp），c.283C>T（p。Arg95*),这对波罗的海国家地区来说是新颖的。这也是c.1100delC的第一份报告（p。Thr367Metfs*15）和c.444+1G>A（p。（？））来自波罗的海国家。高人口频率c.470T>C（p。Ile157Thr）（8.6％）继续质疑该变体在特定人群中的致病性。其他发现与拉脱维亚和邻国以前的报告一致。
方法：该研究包括两个队列-基于人群的爱沙尼亚生物样本库（EstBB）（N-152.349）和来自拉脱维亚的乳腺癌患者（N-105）。在来自拉脱维亚的队列中，在选定的乳腺癌病例中进行CHEK2，BRCA1，BRCA2，PALB2测试和下一代测序（NGS）。在EstBB中，完整的SNP基因型数据集全局筛选阵列（GSA）（N-152.349）用于筛选CHEK2PV/LPV和变体c.3192T>A（p。(?)),c.444+1G>A（p。(?)),c.433C>T（p。Arg145Trp），c.283C>T（p。从该数据集报告CHEK2中的Arg95*）。此外,EstBB(N-4776)的一个子集接受了全基因组测序(WGS，N-2420）和全外显子组测序（WES，N-2356）和创始人变体c.470T>C（第Ile157Thr),c.444+1G>A（p。(?)),c.1100delC（p.从该数据集报告了CHEK2中的Thr367Metfs*15）。此外，2021年4月1日，使用PubMed搜索关键字“CHEK2”进行了文献综述，\'乳腺癌\',\'爱沙尼亚\',\'立陶宛\',\'拉脱维亚\',\'波兰\',\'白俄罗斯\'和\'俄罗斯\'。
结果：在来自拉脱维亚的乳腺癌影响队列中，有6个CHEK2变体，分类为PV/LPV，观察到(6/105；5.7%)，包括反复发作的c.470T>C（p。Ile157Thr）（1.9%）和del5395（ex9-10del；（p。Met304Leufs*16））（1.9%），以及单个-c.1100delC（p.Thr367Metfs*15）（1%）和c.444+1G>A（p。（？））（1%）。来自EstBBNGS数据（N-4776）CHEK2变体c.470T>C（p。Ile157Thr）在8.6%的病例中检测到，c.1100delC（p.Thr367Metfs*15）在0.6%和c.444+1G>A（p。（？））在0.2％的情况下。在SNP阵列数据的EstBB完整队列中（N-152.349）CHEK2变体c.4441G>A（p。（？））在0.02％的病例中检测到，c.319+2T>A（p。（？））在0.09%的案例中，c.433C>T（p。Arg145Trp）在0.02％的病例中，c.283C>T（p。Arg95*）在<0.001%的病例中。对于文献综述，找到了49篇PubMed文章，其中23个是相关的，代表感兴趣群体中的CHEK2PV/LPV。十本出版物来自波兰，八位来自俄罗斯,三个来自拉脱维亚，两个来自白俄罗斯。
结论：本研究是拉脱维亚某些乳腺癌患者的完整CHEK2PV/LPV筛查和爱沙尼亚大规模人群筛查的第一份综合报告。深入了解波罗的海国家地区的CHEK2突变谱。初步结果与其他研究一致，即CHEK2PV/LPV频率约为选定乳腺癌病例的5-6％。在这里，我们报告了三个CHEK2PV/LPV-c.319+2T>A（p。(?)),c.433C>T（p。Arg145Trp），c.283C>T（p。Arg95*),这对波罗的海国家地区来说是新颖的。这也是c.1100delC的第一份报告（p。Thr367Metfs*15）和c.444+1G>A（p。（？））来自波罗的海国家。高人口频率c.470T>C（p。Ile157Thr）（8.6％）继续质疑该变体在特定人群中的致病性。其他发现与拉脱维亚和邻国以前的报告一致。
