Genomic and bioinformatic profiling of mutational neoepitopes reveals new rules to predict anticancer immunogenicity.
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ABSTRACT:
SUBMITTER: Duan F
PROVIDER: S-EPMC4203949 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Parathyroid carcinoma (PC) is an extremely rare malignancy lacking effective therapeutic intervention. We generated and analyzed whole-exome sequencing data from 17 patients to identify somatic and germline genetic alterations. A panel of selected genes was sequenced in a 7-tumor expansion cohort. We show that 47% (8 of 17) of the tumors harbor somatic mutations in the CDC73 tumor suppressor, with germline inactivating variants in 4 of the 8 patients. The PI3K/AKT/mTOR pathway was altered in 21% of the 24 cases, revealing a major oncogenic pathway in PC. We observed CCND1 amplification in 29% of the 17 patients, and a previously unreported recurrent mutation in putative kinase ADCK1. We identified the first sporadic PCs with somatic mutations in the Wnt canonical pathway, complementing previously described epigenetic mechanisms mediating Wnt activation. This is the largest genomic sequencing study of PC, and represents major progress toward a full molecular characterization of this rare malignancy to inform improved and individualized treatments.
| S-EPMC5358487 | biostudies-literature
Project description:Peri-hilar cholangiocarcinoma (pCCA) is chemorefractory and limited genomic analyses have been undertaken in Western idiopathic disease. We undertook comprehensive genomic analyses of a U.K. idiopathic pCCA cohort to characterize its mutational profile and identify new targets. Whole exome and targeted DNA sequencing was performed on forty-two resected pCCA tumors and normal bile ducts, with Gene Set Enrichment Analysis (GSEA) using one-tailed testing to generate false discovery rates (FDR). 60% of patients harbored one cancer-associated mutation, with two mutations in 20%. High frequency somatic mutations in genes not typically associated with cholangiocarcinoma included mTOR, ABL1 and NOTCH1. We identified non-synonymous mutation (p.Glu38del) in MAP3K9 in ten tumors, associated with increased peri-vascular invasion (Fisher's exact, p < 0.018). Mutation-enriched pathways were primarily immunological, including innate Dectin-2 (FDR 0.001) and adaptive T-cell receptor pathways including PD-1 (FDR 0.007), CD4 phosphorylation (FDR 0.009) and ZAP70 translocation (FDR 0.009), with overlapping HLA genes. We observed cancer-associated mutations in over half of our patients. Many of these mutations are not typically associated with cholangiocarcinoma yet may increase eligibility for contemporary targeted trials. We also identified a targetable MAP3K9 mutation, in addition to oncogenic and immunological pathways hitherto not described in any cholangiocarcinoma subtype.
| S-EPMC10126102 | biostudies-literature
Project description:BackgroundTumor neoantigens are drivers of cancer immunotherapy response; however, current prediction tools produce many candidates requiring further prioritization. Additional filtration criteria and population-level understanding may assist with prioritization. Herein, we show neoepitope immunogenicity is related to measures of peptide novelty and report population-level behavior of these and other metrics.MethodsWe propose four peptide novelty metrics to refine predicted neoantigenicity: tumor vs. paired normal peptide binding affinity difference, tumor vs. paired normal peptide sequence similarity, tumor vs. closest human peptide sequence similarity, and tumor vs. closest microbial peptide sequence similarity. We apply these metrics to neoepitopes predicted from somatic missense mutations in The Cancer Genome Atlas (TCGA) and a cohort of melanoma patients, and to a group of peptides with neoepitope-specific immune response data using an extension of pVAC-Seq (Hundal et al., pVAC-Seq: a genome-guided in silico approach to identifying tumor neoantigens. Genome Med 8:11, 2016).ResultsWe show neoepitope burden varies across TCGA diseases and HLA alleles, with surprisingly low repetition of neoepitope sequences across patients or neoepitope preferences among sets of HLA alleles. Only 20.3% of predicted neoepitopes across TCGA patients displayed novel binding change based on our binding affinity difference criteria. Similarity of amino acid sequence was typically high between paired tumor-normal epitopes, but in 24.6% of cases, neoepitopes were more similar to other human peptides, or bacterial (56.8% of cases) or viral peptides (15.5% of cases), than their paired normal counterparts. Applied to peptides with neoepitope-specific immune response, a linear model incorporating neoepitope binding affinity, protein sequence similarity between neoepitopes and their closest viral peptides, and paired binding affinity difference was able to predict immunogenicity (AUROC = 0.66).ConclusionsOur proposed prioritization criteria emphasize neoepitope novelty and refine patient neoepitope predictions for focus on biologically meaningful candidate neoantigens. We have demonstrated that neoepitopes should be considered not only with respect to their paired normal epitope, but to the entire human proteome, and bacterial and viral peptides, with potential implications for neoepitope immunogenicity and personalized vaccines for cancer treatment. We conclude that putative neoantigens are highly variable across individuals as a function of cancer genetics and personalized HLA repertoire, while the overall behavior of filtration criteria reflects predictable patterns.
| S-EPMC5899330 | biostudies-literature
Project description:ObjectiveNeoantigens arising from gene mutations in tumors can induce specific immune responses, and neoantigen-based immunotherapies have been tested in clinical trials. Here, we characterized the efficacy of altered neoepitopes in improving immunogenicity against gastric cancer.MethodsRaw data of whole-exome sequencing derived from a patient with gastric cancer were analyzed using bioinformatics methods to identify neoepitopes. Neoepitopes were modified by P1Y (the first amino acid was replaced by tyrosine) and P2L (the second amino acid was replaced by leucine). T2 binding and stability assays were used to detect the affinities between the neoepitopes and the HLA molecules, as well as the stabilities of complexes. Dendritic cells (DCs) presented with neoepitopes stimulated naïve CD8+ T cells to induce specific cytotoxic T lymphocytes. ELISA and carboxyfluorescein succinimidyl ester were used to detect IFN-γ and TNF-α levels, and T cell proliferation. Perforin was detected by flow cytometry. The cytotoxicity of T cells was determined using the lactate dehydrogenase assay.ResultsBioinformatics analysis, T2 binding, and stability assays indicated that residue substitution increased the affinity between neoepitopes and HLA molecules, as well as the stabilities of complexes. DCs presented with altered neoepitopes stimulated CD8+T cells to release more IFN-γ and had a greater effect on promoting proliferation than wild-type neoepitopes. CD8+T cells stimulated with altered neoepitopes killed more wild-type neoepitope-pulsed T2 cells than those stimulated with wild-type neoepitopes, by secreting more IFN-γ, TNF-α, and perforin.ConclusionsAltered neoepitopes exhibited greater immunogenicity than wild-type neoepitopes. Residue substitution could be used as a new strategy for immunotherapy to target neoantigens.
| S-EPMC8610152 | biostudies-literature
Project description:BackgroundPediatric brain tumors are the leading cause of death for children with cancer in the U.S. Incorporating next-generation sequencing data for both pediatric low-grade (pLGGs) and high-grade gliomas (pHGGs) can inform diagnostic, prognostic, and therapeutic decision-making.Materials and methodsWe performed comprehensive genomic profiling on 282 pediatric gliomas (157 pHGGs, 125 pLGGs), sequencing 315 cancer-related genes and calculating the tumor mutational burden (TMB; mutations per megabase [Mb]).ResultsIn pLGGs, we detected genomic alterations (GA) in 95.2% (119/125) of tumors. BRAF was most frequently altered (48%; 60/125), and FGFR1 missense (17.6%; 22/125), NF1 loss of function (8.8%; 11/125), and TP53 (5.6%; 7/125) mutations were also detected. Rearrangements were identified in 35% of pLGGs, including KIAA1549-BRAF, QKI-RAF1, FGFR3-TACC3, CEP85L-ROS1, and GOPC-ROS1 fusions. Among pHGGs, GA were identified in 96.8% (152/157). The genes most frequently mutated were TP53 (49%; 77/157), H3F3A (37.6%; 59/157), ATRX (24.2%; 38/157), NF1 (22.2%; 35/157), and PDGFRA (21.7%; 34/157). Interestingly, most H3F3A mutations (81.4%; 35/43) were the variant K28M. Midline tumor analysis revealed H3F3A mutations (40%; 40/100) consisted solely of the K28M variant. Pediatric high-grade gliomas harbored oncogenic EML4-ALK, DGKB-ETV1, ATG7-RAF1, and EWSR1-PATZ1 fusions. Six percent (9/157) of pHGGs were hypermutated (TMB >20 mutations per Mb; range 43-581 mutations per Mb), harboring mutations deleterious for DNA repair in MSH6, MSH2, MLH1, PMS2, POLE, and POLD1 genes (78% of cases).ConclusionComprehensive genomic profiling of pediatric gliomas provides objective data that promote diagnostic accuracy and enhance clinical decision-making. Additionally, TMB could be a biomarker to identify pediatric glioblastoma (GBM) patients who may benefit from immunotherapy.Implications for practiceBy providing objective data to support diagnostic, prognostic, and therapeutic decision-making, comprehensive genomic profiling is necessary for advancing care for pediatric neuro-oncology patients. This article presents the largest cohort of pediatric low- and high-grade gliomas profiled by next-generation sequencing. Reportable alterations were detected in 95% of patients, including diagnostically relevant lesions as well as novel oncogenic fusions and mutations. Additionally, tumor mutational burden (TMB) is reported, which identifies a subpopulation of hypermutated glioblastomas that harbor deleterious mutations in DNA repair genes. This provides support for TMB as a potential biomarker to identify patients who may preferentially benefit from immune checkpoint inhibitors.
| S-EPMC5728033 | biostudies-literature
Project description:The genomic and clinical information used to develop and implement therapeutic approaches for acute myelogenous leukemia (AML) originated primarily from adult patients and has been generalized to patients with pediatric AML. However, age-specific molecular alterations are becoming more evident and may signify the need to age-stratify treatment regimens. The NCI/COG TARGET-AML initiative used whole exome capture sequencing (WXS) to interrogate the genomic landscape of matched trios representing specimens collected upon diagnosis, remission, and relapse from 20 cases of de novo childhood AML. One hundred forty-five somatic variants at diagnosis (median 6 mutations/patient) and 149 variants at relapse (median 6.5 mutations) were identified and verified by orthogonal methodologies. Recurrent somatic variants [in (greater than or equal to) 2 patients] were identified for 10 genes (FLT3, NRAS, PTPN11, WT1, TET2, DHX15, DHX30, KIT, ETV6, KRAS), with variable persistence at relapse. The variant allele fraction (VAF), used to measure the prevalence of somatic mutations, varied widely at diagnosis. Mutations that persisted from diagnosis to relapse had a significantly higher diagnostic VAF compared with those that resolved at relapse (median VAF 0.43 vs. 0.24, P < 0.001). Further analysis revealed that 90% of the diagnostic variants with VAF >0.4 persisted to relapse compared with 28% with VAF <0.2 (P < 0.001). This study demonstrates significant variability in the mutational profile and clonal evolution of pediatric AML from diagnosis to relapse. Furthermore, mutations with high VAF at diagnosis, representing variants shared across a leukemic clonal structure, may constrain the genomic landscape at relapse and help to define key pathways for therapeutic targeting. Cancer Res; 76(8); 2197-205. ©2016 AACR.
| S-EPMC4873364 | biostudies-literature
Project description:BackgroundThe genetics of advanced biliary tract cancers (BTC), which encompass intra- and extra-hepatic cholangiocarcinomas as well as gallbladder carcinomas, are heterogeneous and remain to be fully defined.MethodsTo better characterize mutations in established known oncogenes and tumor suppressor genes we tested a mass spectrometric based platform to interrogate common cancer associated mutations across a panel of 77 formalin fixed paraffin embedded archived BTC cases.ResultsMutations among three genes, KRAS, NRAS and PIK3CA were confirmed in this cohort. Activating mutations in PIK3CA were identified exclusively in GBC (4/32, 12.5%). KRAS mutations were identified in 3 (13%) intra-hepatic cholangiocarcinomas and 1 (33%) perihillar cholangiocarcinoma but were not identified in gallbladder carcinomas and extra-hepatic cholangiocarcinoma.ConclusionsThe presence of activating mutations in PIK3CA specifically in GBC has clinical implications in both the diagnosis of this cancer type, as well as the potential utility of targeted therapies such as PI3 kinase inhibitors.
| S-EPMC3045359 | biostudies-literature
Project description:PURPOSE:Breast cancers with BRCA1/2 alterations have a relatively high mutational load, suggesting that immune checkpoint blockade may be a potential treatment option. However, the degree of immune cell infiltration varies widely, and molecular features contributing to this variability remain unknown. EXPERIMENTAL DESIGN:We hypothesized that genomic signatures might predict immunogenicity in BRCA1/2 breast cancers. Using The Cancer Genome Atlas (TCGA) genomic data, we compared breast cancers with (89) and without (770) either germline or somatic BRCA1/2 alterations. We also studied 35 breast cancers with germline BRCA1/2 mutations from Penn using WES and IHC. RESULTS:We found that homologous recombination deficiency (HRD) scores were negatively associated with expression-based immune indices [cytolytic index (P = 0.04), immune ESTIMATE (P = 0.002), type II IFN signaling (P = 0.002)] despite being associated with a higher mutational/neoantigen burden, in BRCA1/2 mutant breast cancers. Further, absence of allele-specific loss of heterozygosity (LOH negative; P = 0.01) or subclonality (P = 0.003) of germline and somatic BRCA1/2 mutations, respectively, predicted for heightened cytolytic activity. Gene set analysis found that multiple innate and adaptive immune pathways that converge on NF-κB may contribute to this heightened immunogenicity. IHC of Penn breast cancers demonstrated increased CD45+ (P = 0.039) and CD8+ infiltrates (P = 0.037) and increased PDL1 expression (P = 0.012) in HRD-low or LOH-negative cancers. Triple-negative cancers with low HRD had far greater CD8+ T cells (P = 0.0011) and Perforin 1 expression (P = 0.014) compared with hormone receptor-positive HRD-high cancers. CONCLUSIONS:HRD scores and hormone receptor subtype are predictive of immunogenicity in BRCA1/2 breast cancers and may inform the design of optimal immune therapeutic strategies.
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Project description:Inflammatory breast cancer (IBC) is a rare and aggressive type of breast cancer whose molecular basis is poorly understood. We performed a comprehensive molecular analysis of 24 IBC biopsies naïve of treatment, using a high-resolution microarray platform and targeted next-generation sequencing (105 cancer-related genes). The genes more frequently affected by gains were MYC (75%) and MDM4 (71%), while frequent losses encompassed TP53 (71%) and RB1 (58%). Increased MYC and MDM4 protein expression levels were detected in 18 cases. These genes have been related to IBC aggressiveness, and MDM4 is a potential therapeutic target in IBC. Functional enrichment analysis revealed genes associated with inflammatory regulation and immune response. High homologous recombination (HR) deficiency scores were detected in triple-negative and metastatic IBC cases. A high telomeric allelic imbalance score was found in patients having worse overall survival (OS). The mutational profiling was compared with non-IBC (TCGA, n = 250) and IBC (n = 118) from four datasets, validating our findings. Higher frequency of TP53 and BRCA2 variants were detected compared to non-IBC, while PIKC3A showed similar frequency. Variants in mismatch repair and HR genes were associated with worse OS. Our study provided a framework for improved diagnosis and therapeutic alternatives for this aggressive tumor type.
| S-EPMC7650681 | biostudies-literature
Project description:In recent years, the study of anticancer bioactive compounds from marine sources has received wide interest. Contextually, world regulatory authorities have approved several marine molecules, and new synthetic derivatives have also been synthesized and structurally improved for the treatment of numerous forms of cancer. However, the administration of drugs in cancer patients requires careful evaluation since their interaction with individual biological macromolecules, such as proteins or nucleic acids, determines variable downstream effects. This is reflected in a constant search for personalized therapies that lay the foundations of modern medicine. The new knowledge acquired on cancer mechanisms has certainly allowed advancements in tumor prevention, but unfortunately, due to the huge complexity and heterogeneity of cancer, we are still looking for a definitive therapy and clinical approaches. In this review, we discuss the significance of recently approved molecules originating from the marine environment, starting from their organism of origin to their structure and mechanism of action. Subsequently, these bio-compounds are used as models to illustrate possible bioinformatics approaches for the search of new targets that are useful for improving the knowledge on anticancer therapies.
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