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Abstract
BackgroundThe gain or loss of large chromosomal regions or even whole chromosomes is termed as genomic scarring and can be observed as copy number variations resulting from the failure of DNA damage repair.ResultsIn this study, a new algorithm called genomic scar analysis (GSA) has developed and validated to calculate homologous recombination deficiency (HRD) score. The two critical submodules were tree recursion (TR) segmentation and filtering, and the estimation and correction of the tumor purity and ploidy. Then, this study evaluated the rationality of segmentation and genotype identification by the GSA algorithm and compared with other two algorithms, PureCN and ASCAT, found that the segmentation result of GSA algorithm was more logical. In addition, the results indicated that the GSA algorithm had an excellent predictive effect on tumor purity and ploidy, if the tumor purity was more than 20%. Furtherly, this study evaluated the HRD scores and BRCA1/2 deficiency status of 195 clinical samples, and the results indicated that the accuracy was 0.98 (comparing with Affymetrix OncoScan™ assay) and the sensitivity was 95.2% (comparing with BRCA1/2 deficiency status), both were well-behaved. Finally, HRD scores and 16 genes mutations (TP53 and 15 HRR pathway genes) were analyzed in 17 cell lines, the results showed that there was higher frequency in HRR pathway genes in high HRD score samples.ConclusionsThis new algorithm, named as GSA, could effectively and accurately calculate the purity and ploidy of tumor samples through NGS data, and then reflect the degree of genomic instability and large-scale copy number variations of tumor samples.
Highlights
The gain or loss of large chromosomal regions or even whole chromosomes is termed as genomic scarring and can be observed as copy number variations resulting from the failure of DNA damage repair
The Affymetrix OncoScanTM Assay is a SNP-array based on molecular inversion probe technology, a proven technology for identifying copy number variation (CNV), loss of heterozygosity (LOH), and detecting somatic mutations
Homologous recombination deficiency (HRD) panel is designed for detecting largescale CNVs to calculate LOH, telomeric allelic imbalance (TAI), large-scale state transition (LST), and HRD score, the total number of SNP sites could reduce appropriately, but not uniformity
Summary
The gain or loss of large chromosomal regions or even whole chromosomes is termed as genomic scarring and can be observed as copy number variations resulting from the failure of DNA damage repair. Some drugs based on DSB or single-strand break (SSB) repair have been developed and used successfully in clinical trials. PARP inhibitors (PARPi) are based on inhibiting the SSBs repairing and the accumulation of SSBs would lead to the development of fatal DSBs. PARPi are more sensitive to HRD-positive tumors through synthetic lethal interaction [10, 11]. Several studies have shown that HRD is a potential biomarker for platinum salts and PARPi in many cancers, especially in ovarian and breast cancer, and PARPi have attracted widespread attention in the targeted therapies of multiple cancers due to better efficacy and fewer side effects [12,13,14]. FDA has approved niraparib and olaparib combined with bevacizumab, for specific patients with HRD-positive status, according to two critical clinical trials, QUADRA and PAOLA-1 [15, 16]
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