Homologous repair deficiency score for identifying breast cancers with defective DNA damage response

Abstract

Breast cancer (BC) in patients with germline mutations of BRCA1/BRCA2 are associated with benefit from drugs targeting DNA damage response (DDR), but they account for only 5-7% of overall breast cancer. To define the characteristics of these tumors and also to identify tumors without BRCA mutation but with homologous recombination deficiency (HRD) is clinically relevant. To define characteristic features of HRD tumors and analyze the correlations between BRCA1/BRCA2 and BC subtypes, we analyzed 981 breast tumors from the TCGA database using the signature analyzer. The BRCA signature was strongly associated with the HRD score top 10% (score ≥ 57) population. This population showed a high level of mutations in DDR genes, including BRCA1/BRCA2. HRD tumors were associated with high expression levels of BARD1 and BRIP1. Besides, BRCA1/2 mutations were dominantly observed in basal and luminal subtypes, respectively. A comparison of HRD features in BC revealed that BRCA1 exerts a stronger influence inducing HRD features than BRCA2 does. It reveals genetic differences between BRCA1 and BRCA2 and provides a basis for the identification of HRD and other BRCA-associated tumors. Depending on hormone receptor and human epidermal growth factor type II receptor (HER2) oncoprotein expression, breast cancer (BC) is traditionally classified into luminal A or B (i.e., estrogen and/or progesterone receptor-positive), HER2-enriched, or triple-negative BC (TNBC). However, there is high heterogeneity, even within subtypes, making treatment difficult 1,2. To improve treatment, understanding tumor heterogeneity within and across subtypes and proper treatment strategies for each tumor is crucial. One approach is examining the mutations of each tumor and defining distinct molecular signatures for categorization. The Cancer Genome Project (TCGA) serves as an important basis for understanding the genomics of tumor heterogeneity 2. Poly (ADP-ribose) polymerase (PARP) inhibitors are clinically beneficial in patients with BRCA-deficient ovarian, breast, and prostate cancer. In a global phase III trial involving patients with metastatic BC with germline BRCA1 or BRCA2 mutation, olaparib increased progression-free survival (PFS) by 2.8 months 3. In an olaparib maintenance clinical phase II trial of patients with relapsed platinum-sensitive ovarian cancer in addition to BRCA-deficient tumors, one-third of patients with wild-type BRCA showed improvements in PFS 4,5. Based on this, olaparib was additionally approved by the FDA for maintenance treatment in platinum-sensitive patients, regardless of BRCA status. These results suggest that BRCA and other homologous repair deficiency (HRD) markers determine response to PARP inhibitors and that these should be applied to patients with other HRD markers as well. In fact, tumors lacking BRCA mutation but with HRD, similar responses to DNA damaging agents, and similar clinicopathologic features are referred to as having "BRCAness, " and the use of PARP

Discovering a qualitative transcriptional signature of homologous recombination defectiveness for prostate cancer

“…As shown in Figure 7 , the 82 DEGs regulated by SRPX were significantly enriched in genetic instability and DNA damage repair (DDR)-related biological pathway, namely “cGmp-pkg signaling pathway,” and an immune-related “ErbB signaling pathway” (p < 0.05, hypergeometric distribution model). Similarly, using the hypergeometric distribution model and 121 DEGs linked with UBE2W (p < 0.05), some HRD- and/or immune-related pathways were also observed, such as “cell cycle” and the “mTOR signaling pathway.” Focusing on HRR genes, we found one key HRR gene, viz., NBN , which was simultaneously connected to several signature genes, including ATP6V1C1 , ESRP1 , UBE2W , and NUCKS1 , and was upregulated in the HRDness group, consistent with the results of previous research ( Min et al., 2020 ); the result may be due to the significantly higher frequency of copy number gain of NBN in HRDness tumors (Fisher’s exact test, p < 0.0001). Likewise, another HRR gene, viz., UBR5 , was linked with ATP6V1C1 and UBE2W .…”

A Novel Signature for Predicting Prognosis of Smoking-Related Squamous Cell Carcinoma

“…Therefore, better biomarkers should be identified to screen a more effective platinum/PARP population. HRD scores, which are comprehensively calculated based on loss of heterozygosis (LOH), telomeric-allelic imbalance (TAI), and large-scale state transitions (LST), are considered as biomarkers of genomic instability with mutation (Takaya et al, 2020), which were applied in drug efficacy and tumor susceptibility evaluation (do Canto et al, 2019;Min et al, 2020).…”

The Role of BRCA1/2-Mutated Tumor Microenvironment in Breast Cancer

“…While BRCA1 -associated tumors are most commonly a high-grade invasive ductal carcinoma of no special type and the majority fall into the “basal-like” subtype of breast cancer, the BRCA2 -associated tumors are very similar to sporadically occurring “luminal-type” tumors [ 112 ]. BRCA signature was previously correlated with a high mutation burden [ 113 ], which was specified by distinct mutational landscape in BRCA1 - and BRCA2 -deficient tumors revealed by Samstein et al (discussed below) ( Figure 2 ). Min et al also showed that BRCA1 mutation results in higher homologous recombination deficiency scores than BRCA2 mutation and that germline BRCA1- and BRCA2 -mutated tumors exhibit various differentially expressed genes.…”