Abstract
Simple SummaryHomologous recombination repair deficiency (HRD) is a biomarker for the response to PARP inhibitor anti-cancer treatment. Therefore, methods that detect the HRD phenotype in cancers in a (cost-)effective manner are pivotal. In this respect, the HRDetect and CHORD algorithms were developed to classify (the type of) HRD cancers from whole genome sequencing data. In addition, functional assays have also been established, but these require fresh cancer tissue. Here we present a novel method to specifically classify BRCA1-type HRD from RNA-sequencing data with high sensitivity. BRCA1-type cancers typically display small (<10 kb) tandem duplications, in contrast to BRCA2-type cancers. By detecting these small TDs among transcripts, we increase the toolbox for detecting HRD with a method that does not require whole genome sequencing of both tumor and normal tissue. Patients with cancers that are deficient for homologous recombination repair (HRD) may benefit from PARP inhibitor treatment. Therefore, methods that identify such cancers are crucial. Using whole genome sequencing data, specific genomic scars derived from somatic mutations and genomic rearrangements can identify HRD tumors, with only BRCA1-like HRD cancers profoundly displaying small (<10 kb) tandem duplications (TDs). In this manuscript we describe a method of detecting BRCA1-type HRD in breast cancer (BC) solely from RNA sequencing data by identifying TDs surfacing in transcribed genes. We find that the number of identified TDs (TD-score) is significantly higher in BRCA1-type vs. BRCA2-type BCs, or vs. HR-proficient BCs (p = 2.4 × 10−6 and p = 2.7 × 10−12, respectively). A TD-score ≥2 shows an 88.2% sensitivity (30 out of 34) to detect a BRCA1-type BC, with a specificity of 64.7% (143 out of 221). Pathway enrichment analyses showed genes implicated in cancer to be affected by TDs of which PTEN was found significantly more frequently affected by a TD in BRCA1-type BC. In conclusion, we here describe a novel method to identify TDs in transcripts and classify BRCA1-type BCs with high sensitivity.
Highlights
The incidence of breast cancer (BC) is regarded as the highest among malignancies in women worldwide and is still climbing by 0.3% per year [1]
Small tandem duplications (TDs) of mainly 1–10 kb in size are one of the genomic scars that BRCA1-type BCs uniquely produce [14]. We investigated whether these small TDs can be identified in the transcriptome, using RNA sequencing (RNAseq) data from a total of 266 primary BCs with matching whole genome sequencing (WGS) data available
With the knowledge that no golden-standard HRD test exists to identify patients that may benefit from PARP inhibitors, and that about half of the HRD patients may be missed when solely focusing on bi-allelic BRCA1 or BRCA2 inactivation [16], we argue that standardized studies are needed to evaluate if the balance tips in favor of the precision of WGS or the ease-of-use of RNAseq to fully establish theeffectiveness of a HRD test
Summary
The incidence of breast cancer (BC) is regarded as the highest among malignancies in women worldwide and is still climbing by 0.3% per year [1]. About 20–25% of familial BC patients inherit mutations in BC susceptibility genes BRCA1, BRCA2, PALB2, CHEK2 or ATM. BRCA1 is regarded as a high-risk BC susceptibility gene [4]. The first is the RING domain, which is positioned on the amino-terminal end of the protein and functions as an E3 ubiquitin ligase. The third is the serine containing domain (SCD), which contains a large number of phosphorylation sites and gets phosphorylated by ATM/ATR kinases upon DNA damage [6]. With these different domains, BRCA1 is equipped with multiple functions, consisting of interacting with other tumor suppressors, cell cycle checkpoint regulation and mediating DNA repair [4]
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