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笑对人生 (2022-10-08 00:00):
#paper doi: 10.1038/s41523-018-0066-6. Migrating the SNP array-based homologous recombination deficiency measures to next generation sequencing data of breast cancer.  NPJ Breast Cancer.  2018 Jul 2;4:16. 同源重组修复(homologous recombination repair,HRR)是DNA双链断裂(double strand break,DSB)的首选修复方式。同源重组修复缺陷(homologous recombination defificiency,HRD)通常指细胞水平上的HRR功能障碍状态,可由HRR相关基因胚系突变或体细胞突变以及表观遗传失活等诸多因素导致,常存在于多种恶性肿瘤中,其中在卵巢癌、乳腺癌、胰腺导管癌、前列腺癌等肿瘤尤其突出。当HRD存在时,DSB会过度依赖非同源末端连接(non-homologous end joining,NHEJ)、微同源末端连接(microhomology mediated end joining,MMEJ)和单链退火途径(single-strand annealing,SSA)等低保真、高易错的替代性DNA损伤修复途径,从而极可能造成核酸序列的插入/缺失,拷贝数异常,并引起染色体交联,造成基因组和染色体不稳定。HRD临床检验所描述的是肿瘤基因组特定改变,也称为基因组瘢痕(genomic scar)。HRD评分(HRD score)可以用来反映肿瘤样本因HRR通路异常而导致的肿瘤样本基因组不稳定的情况。HRD score计算了三种得分的和:端粒等位基因不平衡(telomeric allelic imbalance,TAI或NtAI)评分,杂合缺失(loss of heterozygosity,LOH)评分和大片段迁移(large-scale state transition)评分。HRD评分的检测可采用SNP芯片或NGS平台。 本研究开发了一个名为scarHRD的软件包。利用scarHRD对SNP芯片和NGS平台(WES或WGS)的数据计算HRD评分,结果发现两个平台之间具有很好的相关性(Pearson相关系数在0.73-0.87之间)。对来自TCGA的三阴性乳腺癌BRCA突变和BRCA野生型队列进行分析,发现与BRCA1/2野生型患者相比,利用scarHRD计算HRD评分在突变型患者中更高,ROC曲线对应的AUC面积达80.8%,表明scarHRD能够成功反映真实的生物学功能。乳腺癌1号基因(breast cancer 1,BRCA1)是抑癌基因,主要参与DNA断裂修复过程。当BRCA发生功能缺失会导致双链断裂的DNA修复不能通过同源重组修复,进而引起基因组不稳定(genomic instability,GI)。
Abstract:
The first genomic scar-based homologous recombination deficiency (HRD) measures were produced using SNP arrays. As array-based technology has been largely replaced by next generation sequencing approaches, it has become important … >>>
The first genomic scar-based homologous recombination deficiency (HRD) measures were produced using SNP arrays. As array-based technology has been largely replaced by next generation sequencing approaches, it has become important to develop algorithms that derive the same type of genomic scar scores from next generation sequencing (whole exome "WXS", whole genome "WGS") data. In order to perform this analysis, we introduce here the scarHRD R package and show that using this method the SNP array-based and next generation sequencing-based derivation of HRD scores show good correlation (Pearson correlation between 0.73 and 0.87 depending on the actual HRD measure) and that the NGS-based HRD scores distinguish similarly well between BRCA mutant and BRCA wild-type cases in a cohort of triple-negative breast cancer patients of the TCGA data set. <<<
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