Shedding light on the hidden human proteome expands immunopeptidome in cancer.

Unrestrained cellular growth and immune escape of a tumor are associated with the incidental errors of the genome and transcriptome. Advances in next-generation sequencing have identified thousands of genomic and transcriptomic aberrations that generate variant peptides that assemble the hidden proteome, further expanding the immunopeptidome. Emerging next-generation sequencing technologies and a number of computational methods estimated the abundance of immune infiltration from bulk transcriptome have advanced our understanding of tumor microenvironments. Here, we will characterize several major types of tumor-specific antigens arising from single-nucleotide variants, insertions and deletions, gene fusion, alternative splicing, RNA editing and non-coding RNAs. Finally, we summarize the current state-of-the-art computational and experimental approaches or resources and provide an integrative pipeline for the identification of candidate tumor antigens. Together, the systematic investigation of the hidden proteome in cancer will help facilitate the development of effective and durable immunotherapy targets for cancer.

Pan-cancer assessment of mutational landscape in intrinsically disordered hotspots reveals potential driver genes.

Large-scale cancer genome sequencing has enabled the catalogs of somatic mutations; however, the mutational impact on intrinsically disordered protein regions (IDRs) has not been systematically investigated to date. Here, we comprehensively characterized the mutational landscapes of IDRs and found that IDRs have higher mutation frequencies across diverse cancers. We thus developed a computational method, ROI-Driver, to identify putative driver genes enriching IDR and domain hotspots in cancer. Numerous well-known cancer-related oncogenes or tumor suppressors that play important roles in cancer signaling regulation, development and immune response were identified at a higher resolution. In particular, the incorporation of IDR structures helps in the identification of novel potential driver genes that play central roles in human protein-protein interaction networks. Interestingly, we found that the putative driver genes with IDR hotspots were significantly enriched with predicted phase separation propensities, suggesting that IDR mutations disrupt phase separation in key cellular pathways. We also identified an appreciable number of clinically relevant genes enriching IDR mutational hotspots that exhibited differential expression patterns and are associated with cancer patient survival. In summary, combinations of mutational effects on IDRs significantly increase the sensitivity of driver detection and are likely to open new therapeutic avenues for various cancers.

Clinical and genomic characterization of mutational signatures across human cancers.

Mutational signatures, the generic patterns of mutations, are the footprints of both endogenous and exogenous factors that have influenced cancer development. To date, dozens of mutational signatures have been discerned through computational methods. However, the etiology, mutational properties, clonality, immunology and prognostic value of mutation signatures across cancer types are poorly understood. To address this, we extensively characterized mutational signatures across 8836 cancer samples spanning 42 cancer types. We confirmed and extended clinical and genomic features associated with mutation signatures. Mutation distribution analysis showed that most mutation processes were depleted in exons and APOBEC signatures (SBS2 and SBS13), the Pol-η related signature (SBS9) and SBS40 tended to contribute clustered mutations. We observed that age-related signatures (SBS1 and SBS5) and SBS40 tended to induce mutations affecting cancer genes and subclonal drivers posted by specific signatures (eg, mismatch repair deficiency-related signature SBS44) were unlikely subjected to positive selection. We also revealed early mutation signatures (eg, UV light exposure-related signature SBS7a) and signatures (eg, reactive oxygen species-related signature SBS18) predominated in the late stage of tumorigenesis. Comprehensive association analysis of mutation processes with microenvironment revealed that APOBEC- and mismatch repair deficiency-related signatures were positively associated with immune parameters, while age-related signatures showed negative correlations. In addition, prognostic association analysis showed that many signatures were favorable (eg, SBS9) or adverse factors (eg, SBS18) of patient survival. Our findings enhance appreciation of the role of mutational signatures in tumor evolution and underline their potential in immunotherapy guidance and prognostic prediction.

Pan-cancer illumination of TRIM gene family reveals immunology regulation and potential therapeutic implications.

BACKGROUND: The tripartite motif (TRIM) proteins function as important regulators in innate immunity, tumorigenesis, cell differentiation and ontogenetic development. However, we still lack knowledge about the genetic and transcriptome alterations landscape of TRIM proteins across cancer types. METHODS: We comprehensively reviewed and characterized the perturbations of TRIM genes across > 10,000 samples across 33 cancer types. Genetic mutations and transcriptome of TRIM genes were analyzed by diverse computational methods. A TRIMs score index was calculated based on the expression of TRIM genes. The correlation between TRIMs scores and clinical associations, immune cell infiltrations and immunotherapy response were analyzed by correlation coefficients and gene set enrichment analysis. RESULTS: Alterations in TRIM genes and protein levels frequently emerge in a wide range of tumors and affect expression of TRIM genes. In particular, mutations located in domains are likely to be deleterious mutations. Perturbations of TRIM genes are correlated with expressions of immune checkpoints and immune cell infiltrations, which further regulated the cancer- and immune-related pathways. Moreover, we proposed a TRIMs score index, which can accurately predict the clinical outcome of cancer patients. TRIMs scores of patients are correlated with clinical survival and immune therapy response across cancer types. Identifying the TRIM genes with genetic and transcriptome alterations will directly contribute to cancer therapy in the context of predictive, preventive, and personalized medicine. CONCLUSIONS: Our study provided a comprehensive analysis and resource for guiding both mechanistic and therapeutic analyses of the roles of TRIM genes in cancer.

Bioinformatics Methods for Modeling microRNA Regulatory Networks in Cancer.

MicroRNAs (miRNAs) play important roles in the physiology and development of cancers. The increase of multidimensional molecular profiles of tumor patients generated by high-throughput sequencing technologies has enabled computational analysis of miRNA regulatory networks in cancer. In this chapter, we first summarized currently widely used computational methods for identifying miRNA-gene interactions. In addition, crosstalk among miRNAs and competitive endogenous RNAs (ceRNAs) represent novel layers of gene regulation mediated by miRNAs, which also play important roles in cancer. We next reviewed computational methods for modeling miRNA-miRNA crosstalk and ceRNA-ceRNA interactions in cancer. These methods integrate multi-omics data and range from genomics to phenomics. MiRNA-miRNA networks are generally constructed based on genomic sequences, transcriptomes, miRNA-gene regulation, and functional pathways. Moreover, five types of computational methods for identifying ceRNA-ceRNA interactions are summarized in this chapter. Among these methods, two types of global ceRNA regulation and three types of context-specific methods are included. The application of these computational methods focused on miRNA regulation in cancer provides valuable functional insights into the underlying mechanism of cancer, as well as future precision medicine.

Current Progress on Antibiotic Sensing Based on Ratiometric Fluorescent Sensors.

Antibiotics, which can be used as veterinary drugs, are widely used in the prevention and treatment of infectious diseases for animals. However, overuse of antibiotics had caused serious problems on food contamination and human harm. For control such public issues, several of techniques have been in recent years. Ratiometric fluorescent (RF) technique, as one of the most promising strategies for quantitatively evaluated analytes, had been extensively developed for the readily measurements on the two different fluorescent emission intensities. In this review, the construction strategies for recent RF sensors will be mainly focused on. Meanwhile, the recent advances and new tendencies for detection of antibiotics based on RF technique shall be introduced. Finally, outlooks on the opportunities and challenges for quantitative fluorescence sensing on antibiotics will be summarized.

Sensitive Techniques for POCT Sensing on the Residues of Pesticides and Veterinary Drugs in Food.

For the immense requirement on agriculture and animal husbandry, application of pesticides and veterinary drugs had become a normal state in the farming and ranching areas. However, to intently pursue the yields, large quantities of residues of pesticides and veterinary drugs have caused serious harm to both the environment and the food industry. To control and solve such an issue, a variety of novel techniques were developed in recent years. In this review, the development and features about point-of-care-testing (POCT) detection on the residues of pesticides and veterinary drugs, such as, electrochemistry (EC), enzyme-linked immunosorbent assay (ELISA) and nano-techniques, were systematically introduced. For each topic, we first interpreted the strategies and detailed account of such technical contributions on detection and assessment of the residues. Finally, the advantages and perspectives about mentioned techniques for ultrasensitive assessment and sensing on pesticides and veterinary drugs were summarized.

Visible-light photocatalytic aerobic oxidation of sulfides to sulfoxides with a perylene diimide photocatalyst.

Photosensitized oxygenation has been recognised as a modern method of incorporating oxygen into a substrate, as it offers environmentally benign alternatives to several conventional synthetic procedures. A metal-free aerobic selective sulfoxidation photosensitized by a perylene diimide photocatalyst has been developed. The reaction utilizes visible light as the driving force and molecular oxygen as the oxidant. The advantages of the developed method include high efficiency and selectivity, extremely simple operation and work-up procedure, mild reaction conditions, and practical application in late-stage functionalization.

The Effect of Food is Medicine Interventions on Diabetes-related Health Outcomes Among Low-income and Food-insecure Individuals: A Systematic Review and Meta-analysis.

OBJECTIVE: In this study, we aim to review the current evidence of Food is Medicine interventions on diabetes outcomes among low-income or food-insecure individuals. METHODS: Seven databases were searched from January 1, 2000 to October 26, 2021 for full-text articles written in English. The studies included experimental studies of any duration and design which addressed the effect of Food is Medicine interventions on fruit and vegetable (F&V) intake and glycated hemoglobin (A1C) levels among low-income or food-insecure populations with prediabetes or diabetes of any age group. Only direction of effect of interventions on F&V intake were ascertained due to high variability in outcome measurement. A1C results were pooled using generic inverse variance with a fixed-effects model. Heterogeneity was assessed using Cochran's Q and quantified by I2. RESULTS: Sixteen studies were included. Five of the 8 studies reported a significant increase in F&V intake. Seven of the 14 studies reported a significant decrease in A1C levels. A meta-analysis of 5 randomized controlled trials (n=843) resulted in clinically meaningful reductions in A1C compared with control (mean difference, -0.47%; 95% confidence interval, -0.66 to -0.29, I2=88%, p<0.0001). Half (n=8) of the studies have a high risk of bias due to missing data, detection bias, and confounding. CONCLUSIONS: Food is Medicine interventions are effective in increasing F&V intake and reducing A1C levels of the target population. More randomized controlled studies are needed to validate the results.

Multi-omics characterization of RNA binding proteins reveals disease comorbidities and potential drugs in COVID-19.

The COVID-19 has led to a devastating global health crisis, which emphasizes the urgent need to deepen our understanding of the molecular mechanism and identifying potential antiviral drugs. Here, we comprehensively analyzed the transcriptomic and proteomic profiles of 178 COVID-19 patients, ranging from asymptomatic to critically ill. Our analyses found that the RNA binding proteins (RBPs) were likely to be perturbed in infection. Interactome analysis revealed that RBPs interact with virus proteins and the viral interacting RBPs were likely to locate in central regions of human protein-protein interaction network. Functional enrichment analysis revealed that the viral interacting RBPs were likely to be enriched in RNA transport, apoptosis and viral genome replication-related pathways. Based on network proximity analyses of 299 human complex-disease genes and COVID-19-related RBPs in the human interactome, we revealed the significant associations between complex diseases and COVID-19. Network analysis also implicated potential antiviral drugs for treatment of COVID-19. In summary, our integrative characterization of COVID-19 patients may thus help providing evidence regarding pathophysiology and potential therapeutic strategies for COVID-19.

Dynamic transcriptome analyses reveal m6A regulated immune non-coding RNAs during dengue disease progression.

Dengue infection is one of the most prevalent arthropod-borne viral diseases, which can result in severe complications. Identification of genes and long non-coding RNAs (lncRNAs) involved in dengue infection would help in deciphering potential mechanisms responsible for the disease progression. We comprehensively analyzed the dynamic transcriptome during dengue disease progression and identified critical genes and lncRNAs with expression perturbations. Our findings revealed that the expression of genes (i.e., CCR10 and GNG7) and lncRNAs (i.e., CTBP1-AS and MAFG-AS1) were potentially regulated by m6A RNA methylation. Interestingly, dengue viral proteins prevalently interact with genes or lncRNAs with expression perturbations, which are involved in cell cycle, inflammation signaling pathways and immune response. Dynamically expressed genes and lncRNAs were likely to locate in the central regions of human protein-protein network, which play crucial roles in mediating signaling spread and helping viral replication. Immune microenvironments analysis revealed that plasma cells levels were increased and T cells infiltrations were decreased during dengue disease progression. Dynamically expressed genes and lncRNAs were correlated with immune cell infiltrations. Moreover, network analysis reveals the associations between dengue viral infections and human complex diseases (i.e., digestive diseases and neoplasms). Our comprehensive transcriptome analysis of dengue disease progression identified potential gene and lncRNA biomarkers, providing novel insights for understanding the pathogenesis of and developing effective therapeutic strategies for dengue infection.

Widespread transcriptomic alterations of transient receptor potential channel genes in cancer.

Ion channels, in particular transient-receptor potential (TRP) channels, are essential genes that play important roles in many physiological processes. Emerging evidence has demonstrated that TRP genes are involved in a number of diseases, including various cancer types. However, we still lack knowledge about the expression alterations landscape of TRP genes across cancer types. In this review, we comprehensively reviewed and summarised the transcriptomes from more than 10 000 samples in 33 cancer types. We found that TRP genes were widespreadly transcriptomic dysregulated in cancer, which was associated with clinical survival of cancer patients. Perturbations of TRP genes were associated with a number of cancer pathways across cancer types. Moreover, we reviewed the functions of TRP family gene alterations in a number of diseases reported in recent studies. Taken together, our study comprehensively reviewed TRP genes with extensive transcriptomic alterations and their functions will directly contribute to cancer therapy and precision medicine.

Deep immunophenotyping reveals clinically distinct cellular states and ecosystems in large-scale colorectal cancer.

Determining the diverse cell types in the tumor microenvironment (TME) and their organization into cellular communities, is critical for understanding the biological heterogeneity and therapy of cancer. Here, we deeply immunophenotype the colorectal cancer (CRC) by integrative analysis of large-scale bulk and single cell transcriptome of 2350 patients and 53,137 cells. A rich landscape of 42 cellular states and 7 ecosystems in TMEs is uncovered and extend the previous immune classifications of CRC. Functional pathways and potential transcriptional regulators analysis of cellular states and ecosystems reveal cancer hallmark-related pathways and several critical transcription factors in CRC. High-resolution characterization of the TMEs, we discover the potential utility of cellular states (i.e., Monocytes/Macrophages and CD8 T cell) and ecosystems for prognosis and clinical therapy selection of CRC. Together, our results expand our understanding of cellular organization in TMEs of CRC, with potential implications for the development of biomarkers and precision therapies.

Systematical analyses of large-scale transcriptome reveal viral infection-related genes and disease comorbidities.

Perturbation of transcriptome in viral infection patients is a recurrent theme impacting symptoms and mortality, yet a detailed understanding of pertinent transcriptome and identification of robust biomarkers is not complete. In this study, we manually collected 23 datasets related to 6,197 blood transcriptomes across 16 types of respiratory virus infections. We applied a comprehensive systems biology approach starting with whole-blood transcriptomes combined with multilevel bioinformatics analyses to characterize the expression, functional pathways, and protein-protein interaction (PPI) networks to identify robust biomarkers and disease comorbidities. Robust gene markers of infection with different viruses were identified, which can accurately classify the normal and infected patients in train and validation cohorts. The biological processes (BP) of different viruses showed great similarity and enriched in infection and immune response pathways. Network-based analyses revealed that a variety of viral infections were associated with nervous system diseases, neoplasms and metabolic diseases, and significantly correlated with brain tissues. In summary, our manually collected transcriptomes and comprehensive analyses reveal key molecular markers and disease comorbidities in the process of viral infection, which could provide a valuable theoretical basis for the prevention of subsequent public health events for respiratory virus infections.

Histone acetyltransferase CSRP2BP promotes the epithelial-mesenchymal transition and metastasis of cervical cancer cells by activating N-cadherin.

BACKGROUND: Dysregulated epithelial-mesenchymal transition (EMT) is involved in cervical cancer metastasis and associated with histone acetylation. However, the underlying molecular mechanisms of histone acetylation in cervical cancer EMT and metastasis are still elusive. METHODS: We systematically investigated the expression patterns of histone acetylation genes and their correlations with the EMT pathway in cervical cancer. The expression of CSRP2BP among cervical cancer tissues and cell lines was detected using Western blotting and immunohistochemistry analyses. The effects of CSRP2BP on cervical cancer cell proliferation and tumorigenicity were examined by cell growth curve, EdU assay, flow cytometry and xenotransplantation assays. Wound healing assays, transwell migration assays and pulmonary metastasis model were used to evaluate the effects of CSRP2BP on cell invasion and metastasis of cervical cancer cells in vivo and in vitro. RNA-seq, chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP) and luciferase reporter assays were used to uncover the molecular mechanisms of CSRP2BP in promoting cervical cancer EMT and metastasis. RESULTS: We prioritized a top candidate histone acetyltransferase, CSRP2BP, as a key player in cervical cancer EMT and metastasis. The expression of CSRP2BP was significantly increased in cervical cancer tissues and high CSRP2BP expression was associated with poor prognosis. Overexpression of CSRP2BP promoted cervical cancer cell proliferation and metastasis both in vitro and in vivo, while knockdown of CSRP2BP obtained the opposite effects. In addition, CSRP2BP promoted resistance to cisplatin chemotherapy. Mechanistically, CSRP2BP mediated histone 4 acetylation at lysine sites 5 and 12, cooperated with the transcription factor SMAD4 to bind to the SEB2 sequence in the N-cadherin gene promotor and upregulated N-cadherin transcription. Consequently, CSRP2BP promoted cervical cancer cell EMT and metastasis through activating N-cadherin. CONCLUSIONS: This study demonstrates that the histone acetyltransferase CSRP2BP promotes cervical cancer metastasis partially through increasing the EMT and suggests that CSRP2BP could be a prognostic marker and a potential therapeutic target for combating cervical cancer metastasis.

Highly sensitive sensing and quantitative detection of sulfate ion with a SERS chip-based on boric acid's Lewis effect.

Based on the Lewis acid's coordination principle, a surface-enhanced Raman scattering (SERS) chip strategy had been developed for the ultrasensitive quantitation of SO42-. Through the immobilization of silver nanoparticles (Ag NPs) and the construction of the boric acid-based sensing unit, the chip system displayed outstanding merits on the direct sensing of SO42-, e.g., simple operation, ultra-high sensitivity, reproducibility, excellent selectivity and specificity. Moreover, an accurate evaluation was obtained by ratiometric calculations on characteristic peaks (1382 and 1070 cm-1) for quantitative detection of SO42-. The detection limit was down to 10 nM. Tap water, beer, and mineral water samples were tested, and high recoveries were achieved (97.12-110.12%). Besides, such SERS chip also displayed strong applicability for the evaluation of SO32-. Therefore, this SERS chip provided a promising idea for the quantification of trace amounts of SO42- and SO32- in the fields of food safety and environmental monitoring.

How Outpatient Diabetes Education Programs Can Support Local Hospitals to Reduce Emergency Department Visits for Adults With Diabetes.

OBJECTIVES: Our aim in this study was to assess the level of collaboration between a hospital-based outpatient diabetes education program (DEP) and emergency departments (EDs) for reducing number of ED revisits and hospital admissions by implementing intervention strategies to promote education services and streamlining referral and appointment intake processes. METHODS: Patients (≥18 years of age) with an ED visit for hyper- or hypoglycemia were analyzed in 2 cohorts based on their intervention exposure. We conducted a single-cohort analysis of the exposed cohort (exposure to the intervention strategies) and compared 2-year outcomes with those of the unexposed cohort. Primary outcomes were hyper- or hypoglycemia-related ED revisit and hospitalization rates. Process outcomes included DEP referrals and DEP attendance. RESULTS: There were no significant differences in ED revisits and hospital admissions between the exposed and unexposed cohorts. However, patients were more likely to be referred to a DEP by ED physicians (odds ratio [OR], 1.76; p=0.02) and to attend a DEP appointment (OR, 1.96; p<0.01) after intervention exposure. DEP attendees from both cohorts became less likely to revisit an ED (exposed: OR, 0.41; 95% confidence interval [CI], 0.23 to 0.71; unexposed: OR, 0.4; 95% CI, 0.15 to 1.15) at 12-month follow up; however, this reduction was sustained only among the exposed cohort (OR, 0.5; 95% CI, 0.31 to 0.81) and not the unexposed cohort (OR, 1.32; 95% CI, 0.60 to 2.91) at 24 months (p=0.04 when comparing the 2 cohorts). CONCLUSIONS: Collaboration between outpatient DEPs with local EDs could effectively reduce diabetes-related ED revisits by increasing diabetes program utilization.

Long noncoding RNA LINC01132 enhances immunosuppression and therapy resistance via NRF1/DPP4 axis in hepatocellular carcinoma.

BACKGROUND: Long noncoding RNAs (lncRNAs) are emerging as critical regulators of gene expression and play fundamental roles in various types of cancer. Current developments in transcriptome analyses unveiled the existence of lncRNAs; however, their functional characterization remains a challenge. METHODS: A bioinformatics screen was performed by integration of multiple omics data in hepatocellular carcinoma (HCC) prioritizing a novel oncogenic lncRNA, LINC01132. Expression of LINC01132 in HCC and control tissues was validated by qRT-PCR. Cell viability and migration activity was examined by MTT and transwell assays. Finally, our results were confirmed in vivo mouse model and ex vivo patient derived tumor xenograft experiments to determine the mechanism of action and explore LINC01132-targeted immunotherapy. RESULTS: Systematic investigation of lncRNAs genome-wide expression patterns revealed LINC01132 as an oncogene in HCC. LINC01132 is significantly overexpressed in tumor and associated with poor overall survival of HCC patients, which is mainly driven by copy number amplification. Functionally, LINC01132 overexpression promoted cell growth, proliferation, invasion and metastasis in vitro and in vivo. Mechanistically, LINC01132 acts as an oncogenic driver by physically interacting with NRF and enhancing the expression of DPP4. Notably, LINC01132 silencing triggers CD8+ T cells infiltration, and LINC01132 knockdown combined with anti-PDL1 treatment improves antitumor immunity, which may prove a new combination therapy in HCC. CONCLUSIONS: LINC01132 functions as an oncogenic driver that induces HCC development via the NRF1/DPP4 axis. Silencing LINC01132 may enhance the efficacy of anti-PDL1 immunotherapy in HCC patients.

Dynamic immune ecosystem of dengue infection revealed by single-cell sequencing.

Dengue is the most common human arboviral disease worldwide, which can result in severe complications. A dysfunctional immune response in dengue infective patients is a recurrent theme impacting symptoms and mortality, but the heterogeneity and dynamics of immune infiltrates during dengue infection remain poorly characterized. Here, we identified the immune cell types in scRNA-seq data from 13127 cells of 10 dengue infective patients and discovered the dynamic immune ecosystems of dengue infection. Notably, genes that exhibited higher expression in specific cell types play important roles in response to virus infection in a module manner. Transcription factors (TFs) are the major regulators (i.e., PAX5, IRF7, KLF4, and IRF8) that can potentially regulate infection-related genes. We demonstrated that the dynamic rewired regulatory network during dengue infection. Moreover, our data revealed the complex cell-cell communications from control to fever and severe dengue patients and prevalent cell-cell communication rewiring was observed. We further identified the IFN-II and CXCL signaling pathways that medicated the communications and play important roles in dengue infection. Together, our comprehensive analysis of dynamic immune ecosystem of dengue infection provided novel insights for understanding the pathogenesis of and developing effective therapeutic strategies for dengue infection.

Pan-cancer analyses reveal the genetic and pharmacogenomic landscape of transient receptor potential channels.

Transient-receptor potential (TRP) channels comprise a diverse family of ion channels, which play important roles in regulation of intracellular calcium. Emerging evidence has revealed the critical roles of TRP channels in tumor development and progression. However, we still lack knowledge about the genetic and pharmacogenomics landscape of TRP genes across cancer types. Here, we comprehensively characterized the genetic and transcriptome alterations of TRP genes across >10,000 patients of 33 cancer types. We revealed prevalent somatic mutations and copy number variation in TRP genes. In particular, mutations located in transmembrane regions of TRP genes were likely to be deleterious mutations (p-values < 0.001). Genetic alterations were correlated with transcriptome dysregulation of TRP genes, and we found that TRPM2, TRPM8, and TPRA1 showed extent dysregulation in cancer. Patients with TRP gene alterations were with significantly higher hypoxia scores, tumor mutation burdens, tumor stages and grades, and poor survival. The alterations of TRP genes were significantly associated with the activity of cancer-related pathways. Moreover, we found that the expression of TRP genes were potentially useful for development of targeted therapies. Our study provided the landscape of genomic and transcriptomic alterations of TPRs across 33 cancer types, which is a comprehensive resource for guiding both mechanistic and therapeutic analyses of the roles of TRP genes in cancer. Identifying the TRP genes with extensive genetic alterations will directly contribute to cancer therapy in the context of predictive, preventive, and personalized medicine.