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Background Despite advances in cancer care and detection, >65% of patients with squamous cell cancer of the head and neck (HNSCC) will develop recurrent and/or metastatic disease. The prognosis for these patients is poor with a 5-year overall survival of 39%. Recent treatment advances in immunotherapy, including immune checkpoint inhibitors like pembrolizumab and nivolumab, have resulted in clinical benefit in a subset of patients. There is a critical clinical need to identify patients who benefit from these antiprogrammed cell death protein 1 (anti-PD-1) immune checkpoint inhibitors.Methods Here, we report findings from a multicenter observational study, PREDicting immunotherapy efficacy from Analysis of Pre-treatment Tumor biopsies (PREDAPT), conducted across 17 US healthcare systems. PREDAPT aimed to validate OncoPrism-HNSCC, a clinical biomarker assay predictive of disease control in patients with recurrent or metastatic HNSCC treated with anti-PD-1 immune checkpoint inhibitors as a single agent (monotherapy) and in combination with chemotherapy (chemo-immunotherapy). The test used RNA-sequencing data and machine learning models to score each patient and place them into groups of low, medium, or high.Results The OncoPrism-HNSCC prediction significantly correlated with disease control in both the monotherapy cohort (n=62, p=0.004) and the chemo-immunotherapy cohort (n=50, p=0.01). OncoPrism-HNSCC also significantly predicted progression-free survival in both cohorts (p=0.015 and p=0.037, respectively). OncoPrism-HNSCC had more than threefold higher specificity than programmed death-ligand 1 combined positive score and nearly fourfold higher sensitivity than tumor mutational burden for predicting disease control.Conclusions Here, we demonstrate the clinical validity of the OncoPrism-HNSCC assay in identifying patients with disease control in response to anti-PD-1 immune checkpoint inhibitors.Trial registration number NCT04510129.

Abstract Background Herein, we report results from a genome-wide study conducted to identify protein quantitative trait loci (pQTL) for circulating angiogenic and inflammatory protein markers in patients with metastatic colorectal cancer (mCRC). The study was conducted using genotype, protein marker, and baseline clinical and demographic data from CALGB/SWOG 80405 (Alliance), a randomized phase III study designed to assess outcomes of adding VEGF or EGFR inhibitors to systemic chemotherapy in mCRC patients. Germline DNA derived from blood was genotyped on whole-genome array platforms. The abundance of protein markers was quantified using a multiplex enzyme-linked immunosorbent assay from plasma derived from peripheral venous blood collected at baseline. A robust rank-based method was used to assess the statistical significance of each variant and protein pair against a strict genome-wide level. A given pQTL was tested for validation in two external datasets of prostate (CALGB 90401) and pancreatic cancer (CALGB 80303) patients. Bioinformatics analyses were conducted to further establish biological bases for these findings. Results The final analysis was carried out based on data from 540,021 common typed genetic variants and 23 protein markers from 869 genetically estimated European patients with mCRC. Correcting for multiple testing, the analysis discovered a novel cis-pQTL in LINC02869, a long non-coding RNA gene, for circulating TGF-β2 levels (rs11118119; AAF = 0.11; P-value

Abstract Background Genetic variants associated with acute side effects of radiotherapy in nasopharyngeal carcinoma (NPC) remain largely unknown. Methods We performed a two-stage genome-wide association analysis including a total of 1084 patients, where 319 individuals in the discovery stage were genotyped for 688,783 SNPs using whole genome-wide screening microarray. Significant variants were then validated in an independent cohort of 765 patients using the MassARRAY system. Gene mapping, linkage disequilibrium, genome-wide association analysis, and polygenic risk score were conducted or calculated using FUMA, LDBlockShow, PLINK, and PRSice software programs, respectively. Results Five SNPs (rs6711678, rs4848597, rs4848598, rs2091255, and rs584547) showed statistical significance after validation. Radiotherapy toxicity was more serious in mutant minor allele carriers of all five SNPs. Stratified analysis further indicated that rs6711678, rs4848597, rs4848598, and rs2091255 correlated with skin toxicity in patients of EBV positive, late stage (III and IV), receiving both concurrent chemoradiotherapy and induction/adjuvant chemotherapy, and with OR values ranging from 1.92 to 2.66. For rs584547, high occurrence of dysphagia was found in A allele carriers in both the discovery (P = 1.27 × 10− 6, OR = 1.55) and validation (P = 0.002, OR = 4.20) cohorts. Furthermore, prediction models integrating both genetic and clinical factors for skin reaction and dysphagia were established. The area under curve (AUC) value of receiver operating characteristic (ROC) curves were 0.657 (skin reaction) and 0.788 (dysphagia). Conclusions Rs6711678, rs4848597, rs4848598, and rs2091255 on chromosome 2q14.2 and rs584547 were found to be novel risk loci for skin toxicity and dysphagia in NPC patients receiving radiotherapy. Trial registration Chinese Clinical Trial Register (registration number: ChiCTR-OPC-14005257 and CTXY-140007-2).

Abstract Background Oncolytic viruses (OVs) are considered a promising therapeutic alternative for cancer. However, OVs could activate the host innate immunity, then impair the viral propagation in tumor cells. In this study, we explored the effect of propranolol, a non-selective β-blocker, on the antitumor efficacy of T1012G virus in gastric cancer models. Methods The proliferation of gastric cancer cells treated with monotherapy or combination treatment was detected by CCK8 cell proliferation assay. The effect of propranolol was further evaluated by in vitro viral replication assays. In vivo tumor xenograft experiments were used to observe the effect of combination therapy on gastric cancer growth in mice. The expression levels of viral proteins and interferon responsive genes were detected in the gastric cancer cell lines treated with combined treatment by western blot. The impact of propranolol on IFN-α/β-mediated inhibition of viral propagation and the expression of antiviral gene PKR was detected by viral replication assays and western blot. Results Cell viability assay detected a 97.9% decrease of T1012G IC50 in HGC-27 when it was pretreated with propranolol along with a sevenfold increase of virus titers compared with T1012G only group (P

Monoclonal antibody (mAb) therapy directed against CD20 is an important tool in the treatment of B cell disorders. However, variable patient response and acquired resistance remain important clinical challenges. To identify genetic factors that may influence sensitivity to treatment, the cytotoxic activity of three CD20 mAbs: rituximab; ofatumumab; and obinutuzumab, were screened in high-throughput assays using 680 ethnically diverse lymphoblastoid cell lines (LCLs) followed by a pharmacogenomic assessment. GWAS analysis identified several novel gene candidates. The most significant SNP, rs58600101, in the gene MKL1 displayed ethnic stratification, with the variant being significantly more prevalent in the African cohort and resulting in reduced transcript levels as measured by qPCR. Functional validation of MKL1 by shRNA-mediated knockdown of MKL1 resulted in a more resistant phenotype. Gene expression analysis identified the developmentally associated TGFB1I1 as the most significant gene associated with sensitivity. qPCR among a panel of sensitive and resistant LCLs revealed immunoglobulin class-switching as well as differences in the expression of B cell activation markers. Flow cytometry showed heterogeneity within some cell lines relative to surface Ig isotype with a shift to more IgG+ cells among the resistant lines. Pretreatment with prednisolone could partly reverse the resistant phenotype. Results suggest that the efficacy of anti-CD20 mAb therapy may be influenced by B cell developmental status as well as polymorphism in the MKL1 gene. A clinical benefit may be achieved by pretreatment with corticosteroids such as prednisolone followed by mAb therapy.

Temozolomide (TMZ) chemotherapy is an important tool in the treatment of glioma brain tumors. However, variable patient response and chemo-resistance remain exceptionally challenging. Our previous genome-wide association study (GWAS) identified a suggestively significant association of SNP rs4470517 in the RYK (receptor-like kinase) gene with TMZ drug response. Functional validation of RYK using lymphocytes and glioma cell lines resulted in gene expression analysis indicating differences in expression status between genotypes of the cell lines and TMZ dose response. We conducted univariate and multivariate Cox regression analyses using publicly available TCGA and GEO datasets to investigate the impact of RYK gene expression status on glioma patient overall (OS) and progression-free survival (PFS). Our results indicated that in IDH mutant gliomas, RYK expression and tumor grade were significant predictors of survival. In IDH wildtype glioblastomas (GBM), MGMT status was the only significant predictor. Despite this result, we revealed a potential benefit of RYK expression in IDH wildtype GBM patients. We found that a combination of RYK expression and MGMT status could serve as an additional biomarker for improved survival. Overall, our findings suggest that RYK expression may serve as an important prognostic or predictor of TMZ response and survival for glioma patients.

Oxaliplatin (OXAL) is a commonly used chemotherapy for treating colorectal cancer (CRC). A recent genome wide association study (GWAS) showed that a genetic variant (rs11006706) in the lncRNA gene MKX-AS1 and partnered sense gene MKX could impact the response of genetically varied cell lines to OXAL treatment. This study found that the expression levels of MKX-AS1 and MKX in lymphocytes (LCLs) and CRC cell lines differed between the rs11006706 genotypes, indicating that this gene pair could play a role in OXAL response. Further analysis of patient survival data from the Cancer Genome Atlas (TCGA) and other sources showed that patients with high MKX-AS1 expression status had significantly worse overall survival (HR = 3.2; 95%CI = (1.17–9); p = 0.024) compared to cases with low MKX-AS1 expression status. Alternatively, high MKX expression status had significantly better overall survival (HR = 0.22; 95%CI = (0.07–0.7); p = 0.01) compared to cases with low MKX expression status. These results suggest an association between MKX-AS1 and MKX expression status that could be useful as a prognostic marker of response to OXAL and potential patient outcomes in CRC.

Oncolytic viruses (OVs) are considered a promising therapeutic alternative for cancer. However, despite the development of novel OVs with improved efficacy and tumor selectivity, their limited efficacy as monotherapeutic agents remains a significant challenge. This study extended our previously observed combination effects of propranolol, a nonselective β-blocker, and the T1012G oncolytic virus into colorectal cancer models. A cell viability assay showed that cotreatment could induce synergistic killing effects on human and murine colorectal cell lines. Moreover, cotreatment caused sustained tumor regression compared with T1012G monotherapy or propranolol monotherapy in human HCT116 and murine MC38 tumor models. The propranolol activity was not via a direct effect on viral replication in vitro or in vivo. Western blotting showed that cotreatment significantly enhanced the expression of cleaved caspase-3 in HCT116 and MC38 cells compared with the propranolol or T1012G alone. In addition, propranolol or T1012G treatment induced a 35.06% ± 0.53% or 35.49% ± 2.68% reduction in VEGF secretion in HUVECs (p < 0.01/p < 0.01). Cotreatment further inhibited VEGF secretion compared with the monotherapies (compared with propranolol treatment: 75.06% ± 1.50% decrease, compared with T1012G treatment: 74.91% ± 0.68%; p＜0.001, p < 0.001). Consistent with the in vitro results, in vivo data showed that cotreatment could reduce Ki67 and enhance cleaved caspase 3 and CD31 expression in human HCT116 and murine MC38 xenografts. In summary, β-blockers could improve the therapeutic potential of OVs by enhancing oncolytic virus-mediated killing of colorectal cancer cells and colorectal tumors.

BackgroundSelf-management of ambulatory cancer pain is full of challenges. Motivated by the need for better pain management, we developed a WeChat-supported platform, Medication Housekeeper (MediHK), to enhance communication, optimize outcomes, and promote self-management in the home setting. ObjectiveWe conducted a randomized controlled trial to assess whether the joint physician-pharmacist team through MediHK would provide better self-management of ambulatory patients with cancer pain. MethodsPatients were randomly assigned to either an intervention group or control group. During the 4-week study period, the pharmacist would send 24-hour pain diaries daily, adverse drug reaction (ADR) forms every 3 days, and the Brief Pain Inventory form every 15 days to patients in the intervention group via MediHK. If a patient needed a change in drug/dosage or treatment of an ADR after the comprehensive review, the pharmacist would propose pharmacological interventions to the attending physician, who was then responsible for prescribing or adjusting pain medications. If no adjustments were needed, the pharmacist provided appropriate targeted education based on knowledge deficits. Patients in the control group received conventional care and did not receive reminders to fill out the forms. However, if the control group patients filled out a form via MediHK, the pain management team would review and respond in the same way as for the intervention group. The primary outcomes included pain intensity and pain interference in daily life. Secondary outcomes included patient-reported outcome measures, medication adherence, ADRs, and rehospitalization rates. ResultsA total of 100 patients were included, with 51 (51%) in the intervention group and 49 (49%) in the control group. The worst pain scores, least pain scores, and average pain scores in the intervention group and the control group were statistically different, with median values of 4 (IQR 3-7) vs 7 (IQR 6-8; P=.001), 1 (IQR 0-2) vs 2 (IQR 1-3; P=.02), and 2 (IQR 2-4) vs 4 (IQR 3-5; P=.001), respectively, at the end of the study. The pain interference on patients' general activity, mood, relationships with others, and interests was reduced, but the difference was not statistically significant compared with the control group (Ps=.10-.76). The medication adherence rate increased from 43% to 63% in the intervention group, compared with an increase of 33% to 51% in the control group (P

Cancer patients exhibit a broad range of inter-individual variability in response and toxicity to widely used anticancer drugs, and genetic variation is a major contributor to this variability. To identify new genes that influence the response of 44 FDA-approved anticancer drug treatments widely used to treat various types of cancer, we conducted high-throughput screening and genome-wide association mapping using 680 lymphoblastoid cell lines from the 1000 Genomes Project. The drug treatments considered in this study represent nine drug classes widely used in the treatment of cancer in addition to the paclitaxel + epirubicin combination therapy commonly used for breast cancer patients. Our genome-wide association study (GWAS) found several significant and suggestive associations. We prioritized consistent associations for functional follow-up using gene-expression analyses. The NAD(P)H quinone dehydrogenase 1 (NQO1) gene was found to be associated with the dose-response of arsenic trioxide, erlotinib, trametinib, and a combination treatment of paclitaxel + epirubicin. NQO1 has previously been shown as a biomarker of epirubicin response, but our results reveal novel associations with these additional treatments. Baseline gene expression of NQO1 was positively correlated with response for 43 of the 44 treatments surveyed. By interrogating the functional mechanisms of this association, the results demonstrate differences in both baseline and drug-exposed induction.

Gastric cancer has one of the highest mortality rate in the world, but the treatment is still limited. Building on previous studies, mechanistic studies on propranolol in gastric cancer mice models and gastric cancer patients were performed. Propranolol inhibited the in vitro proliferation of gastric cancer cells in a time- and concentration-dependent manner. Consistent findings were observed in MFC tumors engrafted 615 mice, which were treated with propranolol at 10 mg/kg daily for 14 days. Propranolol inhibited the phosphorylation of AKT, MEK, and ERK proteins than control in mice tumor tissues respectively (p-AKT 26.16 vs. 56.82, P = 0.0196, p-MEK 28.27 vs. 59.28, P = 0.1102, p-ERK 48.2 vs. 107.4, P = 0.0062). Propranolol had antiproliferative activity in gastric cancer patients receiving 60 mg daily for 7 days prior to surgery(ki67 44.8 vs 125.3 for placebo; P = 0.02). Phosphorylated AKT, MEK, and ERK did not differ between propranolol and placebo treatment in gastric cancer patients. The expression of molecules on CD8+ T cells was not changed both in mice model and patients nor was there a statistically significant difference in CD8+ T cell subsets in patients, although suggestion of an effect was evident. These results prove that propranolol may inhibit the growth of gastric cancer in mice model and patients and the possible mechanism was via inhibiting the AKT and MAPK pathways, but the frequency of tumor infiltration CD8+ T cells did not increase significantly.

Abstract Background EphA2 is a crucial oncogene in gastric cancer (GC) development and metastasis, this study aims to identify microRNAs that target it and serve as key regulators of gastric carcinogenesis. Methods We identified several potential microRNAs targeting EphA2 by bioinformatics websites and then analyzed the role of miR-302b in modulating EphA2 in vitro and in vivo of GC, and it’s mechanism. Results Our analysis identified miR-302b, a novel regulator of EphA2, as one of the most significantly downregulated microRNA (miRNA) in GC tissues. Overexpression of miR-302b impaired GC cell migratory and invasive properties robustly and suppressed cell proliferation by arresting cells at G0–G1 phase in vitro. miR-302b exhibited anti-tumor activity by reversing EphA2 regulation, which relayed a signaling transduction cascade that attenuated the functions of N-cadherin, β-catenin, and Snail (markers of Wnt/β-catenin and epithelial-mesenchymal transition, EMT). This modulation of EphA2 also had distinct effects on cell proliferation and migration in GC in vivo. Conclusions miR-302b serves as a critical suppressor of GC cell tumorigenesis and metastasis by targeting the EphA2/Wnt/β-catenin/EMT pathway.

Lymphoblastoid cell lines (LCLs) are a highly successful model for evaluating the genetic etiology of cancer drug response, but applications using this model have typically focused on single drugs. Combination therapy is quite common in modern chemotherapy treatment since drugs often work synergistically, and it is an important progression in the use of the LCL model to expand work for drug combinations. In the present work, we demonstrate that synergy occurs and can be quantified in LCLs across a range of clinically important drug combinations. Lymphoblastoid cell lines have been commonly employed in association mapping in cancer pharmacogenomics, but it is so far untested as to whether synergistic effects have a genetic etiology. Here we use cell lines from extended pedigrees to demonstrate that there is a substantial heritable component to synergistic drug response. Additionally, we perform linkage mapping in these pedigrees to identify putative regions linked to this important phenotype. This demonstration supports the premise of expanding the use of the LCL model to perform association mapping for combination therapies.

Abstract Background To truly achieve personalized medicine in oncology, it is critical to catalog and curate cancer sequence variants for their clinical relevance. The Somatic Working Group (WG) of the Clinical Genome Resource (ClinGen), in cooperation with ClinVar and multiple cancer variant curation stakeholders, has developed a consensus set of minimal variant level data (MVLD). MVLD is a framework of standardized data elements to curate cancer variants for clinical utility. With implementation of MVLD standards, and in a working partnership with ClinVar, we aim to streamline the somatic variant curation efforts in the community and reduce redundancy and time burden for the interpretation of cancer variants in clinical practice. Methods We developed MVLD through a consensus approach by i) reviewing clinical actionability interpretations from institutions participating in the WG, ii) conducting extensive literature search of clinical somatic interpretation schemas, and iii) survey of cancer variant web portals. A forthcoming guideline on cancer variant interpretation, from the Association of Molecular Pathology (AMP), can be incorporated into MVLD. Results Along with harmonizing standardized terminology for allele interpretive and descriptive fields that are collected by many databases, the MVLD includes unique fields for cancer variants such as Biomarker Class, Therapeutic Context and Effect. In addition, MVLD includes recommendations for controlled semantics and ontologies. The Somatic WG is collaborating with ClinVar to evaluate MVLD use for somatic variant submissions. ClinVar is an open and centralized repository where sequencing laboratories can report summary-level variant data with clinical significance, and ClinVar accepts cancer variant data. Conclusions We expect the use of the MVLD to streamline clinical interpretation of cancer variants, enhance interoperability among multiple redundant curation efforts, and increase submission of somatic variants to ClinVar, all of which will enhance translation to clinical oncology practice.

Various studies have shown that people of Eurasian origin contain traces of DNA inherited from interbreeding with Neanderthals. Recent studies have demonstrated that these Neanderthal variants influence a range of clinically important traits and diseases. Thus, understanding the genetic factors responsible for the variability in individual response to drug or chemical exposure is a key goal of pharmacogenomics and toxicogenomics, as dose responses are clinically and epidemiologically important traits. It is well established that ethnic and racial differences are important in dose response traits, but to our knowledge the influence of Neanderthal ancestry on response to xenobiotics is unknown. Towards this aim, we examined if Neanderthal ancestry plays a role in cytotoxic response to anti-cancer drugs and toxic environmental chemicals. We identified common Neanderthal variants in lymphoblastoid cell lines (LCLs) derived from the globally diverse 1000 Genomes Project and Caucasian cell lines from the Children’s Hospital of Oakland Research Institute. We analyzed the effects of these Neanderthal alleles on cytotoxic response to 29 anti-cancer drugs and 179 environmental chemicals at varying concentrations using genome-wide data. We identified and replicated single nucleotide polymorphisms (SNPs) from these association results, including a SNP in the SNORD-113 cluster. Our results also show that the Neanderthal alleles cumulatively lead to increased sensitivity to both the anti-cancer drugs and the environmental chemicals. Our results demonstrate the influence of Neanderthal ancestry-informative markers on cytotoxic response. These results could be important in identifying biomarkers for personalized medicine or in dissecting the underlying etiology of dose response traits.

Background Individuals with type 2 diabetes are at an increased risk of cardiovascular disease. Alterations in circulating lipid levels, total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides (TG) are heritable risk factors for cardiovascular disease. Here we conduct a genome-wide association study (GWAS) of common and rare variants to investigate associations with baseline lipid levels in 7,844 individuals with type 2 diabetes from the ACCORD clinical trial. Methods DNA extracted from stored blood samples from ACCORD participants were genotyped using the Affymetrix Axiom Biobank 1 Genotyping Array. After quality control and genotype imputation, association of common genetic variants (CV), defined as minor allele frequency (MAF) ≥ 3%, with baseline levels of TC, LDL, HDL, and TG was tested using a linear model. Rare variant (RV) associations (MAF < 3%) were conducted using a suite of methods that collapse multiple RV within individual genes. Results Many statistically significant CV (p