Abstract
Homologous recombination deficiency (HRD) has been used to predict both cancer prognosis and the response to DNA-damaging therapies in many cancer types. HRD has diverse manifestations in different cancers and even in different populations. Many screening strategies have been designed for detecting the sensitivity of a patient’s HRD status to targeted therapies. However, these approaches suffer from low sensitivity, and are not specific to each cancer type and population group. Therefore, identifying race-specific and targetable HRD-related genes is of clinical importance. Here, we conducted analyses using genomic sequencing data that was generated by the Pan-Cancer Atlas. Collapsing non-synonymous variants with functional damage to HRD-related genes, we analyzed the association between these genes and race within cancer types using the optimal sequencing kernel association test (SKAT-O). We have identified race-specific mutational patterns of curated HRD-related genes across cancers. Overall, more significant mutation sites were found in ATM, BRCA2, POLE, and TOP2B in both the ‘White’ and ‘Asian’ populations, whereas PTEN, EGFG, and RIF1 mutations were observed in both the ‘White’ and ‘African American/Black’ populations. Furthermore, supported by pathogenic tendency databases and previous reports, in the ‘African American/Black’ population, several associations, including BLM with breast invasive carcinoma, ERCC5 with ovarian serous cystadenocarcinoma, as well as PTEN with stomach adenocarcinoma, were newly described here. Although several HRD-related genes are common across cancers, many of them were found to be specific to race. Further studies, using a larger cohort of diverse populations, are necessary to identify HRD-related genes that are specific to race, for guiding gene testing methods.
Highlights
Homologous recombination deficiency (HRD) is a dysfunction of the homologous recombination repair (HRR) pathway, which is responsible for the repair of DNA doublestrand breaks [1]
The ‘White’ group contained 83.04% (n = 6013) of the cohort, and the rest of the cohort consisted of 10.04% (n = 727) African American/Black and
We investigated the association of the HRD scores that were defined by the different genesets with overall survival
Summary
Homologous recombination deficiency (HRD) is a dysfunction of the homologous recombination repair (HRR) pathway, which is responsible for the repair of DNA doublestrand breaks [1]. Aside from genetic mutations, structural aberrations of DNA, such as a loss of heterozygosity (LOH), large-scale state transitions (LST), and telomeric allelic imbalance (TAI), have been recognized as defining characteristics of HRD [3,4,5] These genetic features are associated with an increased sensitivity to DNAdamaging agents, such as poly ADP-ribose polymerase (PARP) inhibitors and platinumbased antitumor drugs [6]. For this reason, they have served as targets of chemotherapy and immunotherapy agents for several cancers, especially in breast cancer, ovarian cancer, pancreatic cancer, and prostate cancer [7,8,9,10]. In addition to their response to drugs, the survival outcomes of many cancer patients are associated with the degree of HRD in
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