skip to main content


Title: Identifying gene expression patterns associated with drug-specific survival in cancer patients
Abstract The ability to predict the efficacy of cancer treatments is a longstanding goal of precision medicine that requires improved understanding of molecular interactions with drugs and the discovery of biomarkers of drug response. Identifying genes whose expression influences drug sensitivity can help address both of these needs, elucidating the molecular pathways involved in drug efficacy and providing potential ways to predict new patients’ response to available therapies. In this study, we integrated cancer type, drug treatment, and survival data with RNA-seq gene expression data from The Cancer Genome Atlas to identify genes and gene sets whose expression levels in patient tumor biopsies are associated with drug-specific patient survival using a log-rank test comparing survival of patients with low vs. high expression for each gene. This analysis was successful in identifying thousands of such gene–drug relationships across 20 drugs in 14 cancers, several of which have been previously implicated in the respective drug’s efficacy. We then clustered significant genes based on their expression patterns across patients and defined gene sets that are more robust predictors of patient outcome, many of which were significantly enriched for target genes of one or more transcription factors, indicating several upstream regulatory mechanisms that may be involved in drug efficacy. We identified a large number of genes and gene sets that were potentially useful as transcript-level biomarkers for predicting drug-specific patient survival outcome. Our gene sets were robust predictors of drug-specific survival and our results included both novel and previously reported findings, suggesting that the drug-specific survival marker genes reported herein warrant further investigation for insights into drug mechanisms and for validation as biomarkers to aid cancer therapy decisions.  more » « less
Award ID(s):
2007029 1552784
NSF-PAR ID:
10253382
Author(s) / Creator(s):
; ;
Date Published:
Journal Name:
Scientific Reports
Volume:
11
Issue:
1
ISSN:
2045-2322
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. Background: Though the development of targeted cancer drugs continues to accelerate, doctors still lack reliable methods for predicting patient response to standard-of-care therapies for most cancers. DNA methylation has been implicated in tumor drug response and is a promising source of predictive biomarkers of drug efficacy, yet the relationship between drug efficacy and DNA methylation remains largely unexplored. Method: In this analysis, we performed log-rank survival analyses on patients grouped by cancer and drug exposure to find CpG sites where binary methylation status is associated with differential survival in patients treated with a specific drug but not in patients with the same cancer who were not exposed to that drug. We also clustered these drug-specific CpG sites based on co-methylation among patients to identify broader methylation patterns that may be related to drug efficacy, which we investigated for transcription factor binding site enrichment using gene set enrichment analysis. Results: We identified CpG sites that were drug-specific predictors of survival in 38 cancer-drug patient groups across 15 cancers and 20 drugs. These included 11 CpG sites with similar drug-specific survival effects in multiple cancers. We also identified 76 clusters of CpG sites with stronger associations with patient drug response, many of which contained CpG sites in gene promoters containing transcription factor binding sites. Conclusion: These findings are promising biomarkers of drug response for a variety of drugs and contribute to our understanding of drug-methylation interactions in cancer. Investigation and validation of these results could lead to the development of targeted co-therapies aimed at manipulating methylation in order to improve efficacy of commonly used therapies and could improve patient survival and quality of life by furthering the effort toward drug response prediction. 
    more » « less
  2. Wei, Yanjie ; Li, Min ; Skums, Pavel ; Cai, Zhipeng (Ed.)
    Novel discoveries of biomarkers predictive of drug-specific responses not only play a pivotal role in revealing the drug mechanisms in cancers, but are also critical to personalized medicine. In this study, we identified drug-specific biomarkers by integrating protein expression data, drug treatment data and survival outcome of 7076 patients from The Cancer Genome Atlas (TCGA). We first defined cancer-drug groups, where each cancer-drug group contains patients with the same cancer and treated with the same drug. For each protein, we stratified the patients in each cancer-drug group by high or low expression of the protein, and applied log-rank test to examine whether the stratified patients show significant survival difference. We examined 336 proteins in 98 cancer-drug groups and identified 65 protein-cancer-drug combinations involving 55 unique proteins, where the protein expression levels are predictive of drug-specific survival outcomes. Some of the identified proteins were supported by published literature. Using the gene expression data from TCGA, we found the mRNA expression of ∼11% of the drug-specific proteins also showed significant correlation with drug-specific survival, and most of these drug-specific proteins and their corresponding genes are strongly correlated. 
    more » « less
  3. Abstract Biomarkers predictive of drug-specific outcomes are important tools for personalized medicine. In this study, we present an integrative analysis to identify miRNAs that are predictive of drug-specific survival outcome in cancer. Using the clinical data from TCGA, we defined subsets of cancer patients who suffered from the same cancer and received the same drug treatment, which we call cancer-drug groups. We then used the miRNA expression data in TCGA to evaluate each miRNA’s ability to predict the survival outcome of patients in each cancer-drug group. As a result, the identified miRNAs are predictive of survival outcomes in a cancer-specific and drug-specific manner. Notably, most of the drug-specific miRNA survival markers and their target genes showed consistency in terms of correlations in their expression and their correlations with survival. Some of the identified miRNAs were supported by published literature in contexts of various cancers. We explored several additional breast cancer datasets that provided miRNA expression and survival data, and showed that our drug-specific miRNA survival markers for breast cancer were able to effectively stratify the prognosis of patients in those additional datasets. Together, this analysis revealed drug-specific miRNA markers for cancer survival, which can be promising tools toward personalized medicine. 
    more » « less
  4. Similar molecular and genetic aberrations among diseases can lead to the discovery of jointly important treatment options across biologically similar diseases. Oncologists closely looked at several hormone-dependent cancers and identified remarkable pathological and molecular similarities in their DNA repair pathway abnormalities. Although deficiencies in Homologous Recombination (HR) pathway plays a significant role towards cancer progression, there could be other DNA-repair pathway deficiencies that requires careful investigation. In this paper, through a biomarker-driven drug repurposing model, we identified several potential drug candidates for breast and prostate cancer patients with DNA-repair deficiencies based on common specific biomarkers and irrespective of the organ the tumors originated from. Normalized discounted cumulative gain (NDCG) and sensitivity analysis were used to assess the performance of the drug repurposing model. Our results showed that Mitoxantrone and Genistein were among drugs with high therapeutic effects that significantly reverted the gene expression changes caused by the disease (FDR adjusted p-values for prostate cancer =1.225e-4 and 8.195e-8, respectively) for patients with deficiencies in their homologous recombination (HR) pathways. The proposed multi-cancer treatment framework, suitable for patients whose cancers had common specific biomarkers, has the potential to identify promising drug candidates by enriching the study population through the integration of multiple cancers and targeting patients who respond poorly to organ-specific treatments.

     
    more » « less
  5. There is currently no gene expression assay that can assess if premalignant lesions will develop into invasive breast cancer. This study sought to identify biomarkers for selecting patients with a high potential for developing invasive carcinoma in the breast with normal histology, benign lesions, or premalignant lesions. A set of 26-gene mRNA expression profiles were used to identify invasive ductal carcinomas from histologically normal tissue and benign lesions and to select those with a higher potential for future cancer development (ADHC) in the breast associated with atypical ductal hyperplasia (ADH). The expression-defined model achieved an overall accuracy of 94.05% (AUC = 0.96) in classifying invasive ductal carcinomas from histologically normal tissue and benign lesions (n = 185). This gene signature classified cancer development in ADH tissues with an overall accuracy of 100% (n = 8). The mRNA expression patterns of these 26 genes were validated using RT-PCR analyses of independent tissue samples (n = 77) and blood samples (n = 48). The protein expression of PBX2 and RAD52 assessed with immunohistochemistry were prognostic of breast cancer survival outcomes. This signature provided significant prognostic stratification in The Cancer Genome Atlas breast cancer patients (n = 1100), as well as basal-like and luminal A subtypes, and was associated with distinct immune infiltration and activities. The mRNA and protein expression of the 26 genes was associated with sensitivity or resistance to 18 NCCN-recommended drugs for treating breast cancer. Eleven genes had significant proliferative potential in CRISPR-Cas9/RNAi screening. Based on this gene expression signature, the VEGFR inhibitor ZM-306416 was discovered as a new drug for treating breast cancer.

     
    more » « less