Not all genomic mutations are expressed at the transcript/protein level, which may explain variation in cancer development, prognosis, and treatment response/resistance. In this study, our aim was to ...describe the prevalence of somatic mutation loss of expression ('variant silencing') in a large collection of human samples, and the potential impact of such variant silencing on tumor immunogenicity. Whole-exome mutation description and tumor-normal paired mRNA expression data originating from 636 unique patients diagnosed with 21 distinct tumor types (all solid tumors) were retrieved from The Cancer Genome Atlas (TCGA). Antigenicity and immunogenicity of neo-peptides originating from mutated proteins within a same tumor sample were predicted using the tools available from the Immune Epitope Database (IEDB). A total of 65,072 missense mutations were studied. We demonstrated that 9.06% (N=10,604 silenced/117,505 total variants) somatic variants were silenced in human tumors. Transciptomic silencing is significantly associated with proteins presenting better peptide processing, MHC-I binding, and T-cell recognition; and is more likely observed in lymphocyte-depleted tumors. Silencing may participate in tumor resistance by clonal selection and immune evasion. In the era of precision medicine, we suggest that therapeutic choices should be informed by both the presence of a genomic mutation and its actual transcript expression.
Angiosarcoma is an aggressive tumor. Recent case series describe exceptional responses to checkpoint blockade in this disease.
Herein, we explored the genomic correlates of 48 angiosarcomas from the ...Angiosarcoma Project (12,499 variants analyzed in 6603 genes; whole-exome sequencing) versus 10,106 pan-cancer tumors in The Cancer Genome Atlas including 235 sarcomas but no angiosarcoma.
At the molecular level, angiosarcomas were heterogeneous. Those located in the face and scalp presented high tumor mutation burden, missense amino acid variations biased towards more hydrophobic (and therefore more immunogenic) peptides, and ultra-violet mutational signature.
Angiosarcoma molecular features are similar to those observed in melanoma and other skin tumors and may explain comparable immunotherapy sensitivity of these tumor types.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Immunotherapy with checkpoint inhibitors, such as antibodies blocking the programmed cell-death receptor-1 (PD-1), has resulted in remarkable responses in patients having traditionally refractory ...cancers. Although response to PD-1 inhibitors correlates with PD-1 ligand (PD-L1 or PD-L2) expression, PD-1 ligand positivity represents only a part of the predictive model necessary for selecting patients predisposed to respond to immunotherapy. We used all genomic, transcriptomic, proteomic and phenotypic data related to 8,475 pan-cancer samples available in The Cancer Genome Atlas (TCGA) and conducted a logistic regression analysis based on a large set of variables, such as microsatellite instability (MSI-H), mismatch repair (MMR) alterations, polymerase δ (POLD1) and polymerase ϵ (POLE) mutations, activation-induced/apolipoprotein-B editing cytidine deaminases (AID/APOBEC) alterations, lymphocyte markers and mutation burden estimates to determine independent factors that associate with PD-1 ligand overexpression. PD-1 ligand overexpression was independently and significantly correlated with overexpression of and mutations in APOBEC3 paralogs. Additionally, while high tumor mutation burden and overexpression of PD-L1 have been previously correlated with each other, we demonstrate that the specific mutation pattern caused by APOBEC enzymes and called kataegis-rather than overall mutation burden, MSI-H or MMR alterations-correlates independently with PD-L1/PD-L2 expression. These observations suggest that APOBEC3 alterations, APOBEC3 overexpression and kataegis play an important role in the regulation of PD-1 ligand overexpression, and thus, their relationship with immune checkpoint inhibitor response warrants exploration.
Anti-angiogenic therapies are an important class of anti-cancer treatment drugs. However, their efficacy is limited to certain tumors and would benefit from identifying a biomarker predictive of ...therapeutic response. TP53 (tumor protein p53) is a tumor suppressor gene frequently mutated in cancer and implicated in cell-cycle regulation, apoptosis, and angiogenesis. Data from 7,525 unique tumor samples (representing 30 tumor cohorts) were retrieved from the TCGA database to analyze the relationship between TP53-mutation status and VEGFA (vascular endothelial growth factor A) expression. Univariate analyses were done using a Mann-Whitney univariate test or Fisher's exact test. Parameters with a p-value (p)≤0.1 in univariate analysis were selected for follow-up multivariate analyses, including TP53-mutation status, cancer cohorts, cancer subtypes, and VEGFA expression. Our analysis demonstrates statistically significant increases in VEGFA mRNA tissue expression in TP53-mutated adenocarcinomas (but not in squamous cancers) compared to TP53 wild-type tumors. This association holds true in multivariate analyses and remains independent of HIF-1α and MDM2 overexpression. Our findings provide additional evidence that TP53 mutations are linked to the VEGF pathway, potentially offering insight into the mechanism behind increased sensitivity to anti-angiogenic therapies observed in some TP53-mutant tumors.
Hydrophobic neoantigens are more immunogenic because they are better presented by the major histocompatibility complex and better recognized by T cells. Tumor cells can evade the immune response by ...expressing checkpoints such as programmed death ligand 1. Checkpoint blockade reactivates immune recognition and can be effective in diseases such as melanoma, which harbors a high tumor mutational burden (TMB). Cancers presenting low or intermediate TMB can also respond to checkpoint blockade, albeit less frequently, suggesting the need for biological markers predicting response. We calculated the hydrophobicity of neopeptides produced by probabilistic in silico simulation of the genomic UV exposure mutational signature. We also computed the hydrophobicity of potential neopeptides and extent of UV exposure based on the UV mutational signature enrichment (UVMSE) score in The Cancer Genome Atlas (TCGA; N = 3543 tumors), and in our cohort of 151 immunotherapy‐treated patients. In silico simulation showed that UV exposure significantly increased hydrophobicity of neopeptides, especially over multiple mutagenic cycles. There was also a strong correlation (R2 = 0.953) between weighted UVMSE and hydrophobicity of neopeptides in TCGA melanoma patients. Importantly, UVMSE was able to predict better response (P = 0.0026), progression‐free survival (P = 0.036), and overall survival (P = 0.052) after immunotherapy in patients with low/intermediate TMB, but not in patients with high TMB. We show that higher UVMSE scores could be a useful predictor of better immunotherapy outcome, especially in patients with low/intermediate TMB, likely due to increased hydrophobicity (and hence immunogenicity) of neopeptides.
The mutational pattern induced by ultraviolet radiation changes the exome to encode for more hydrophobic antigens. When these more lipophilic antigens are presented on the cell surface to T cells by major histocompatibility complex I molecules, they could induce a stronger immune response. This was demonstrated in a cohort of 151 patients from the Moores Cancer Center, particularly in the low TMB subset.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Amplifications of oncogenic genes are often considered actionable. However, not all patients respond. Questions have therefore arisen regarding the degree to which amplifications, especially ...non-focal ones, mediate overexpression. We found that a subset of high-level gene amplifications (≥ 6 copies) (from The Cancer Genome Atlas database) was not over-expressed at the RNA level. Unexpectedly, focal amplifications were more frequently silenced than non-focal amplifications. Most non-focal amplifications were not silenced; therefore, non-focal amplifications, if over-expressed, may be therapeutically tractable. Furthermore, specific silencing of high-level focal or non-focal gene amplifications may explain resistance to drugs that target the relevant gene product.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Display omitted
•Some EGFR exon 20 alterations confer resistance to several EGFR inhibitors.•Poziotinib is able to target the small kinase pocket created by exon 20 insertions.•EGFR exon 20 ...insertions lock the dimerization domains in an active state.•EGFR antibodies disrupt the active dimers created by EGFR exon 20 insertions.•Other EGFR exon 20 alterations, such as S768I, remain sensitive to traditional TKIs.
EGFR exon 20 alterations are rare events seen mainly in non-small cell lung cancer (NSCLC). They include EGFR T790 and C797S mutations (associated with secondary resistance to classic EGFR tyrosine kinase inhibitors (TKIs)), and EGFR exon 20 in-frame insertions (associated with resistance to first- and second-generation EGFR TKIs). In silico modeling of structural changes in aberrant proteins has informed selection of compounds with potential clinical activity: poziotinib (whose smaller size permits access to the restricted kinase pocket created by EGFR and ERBB2 exon 20 insertions); cetuximab (an antibody that attenuates dimerization caused by EGFR exon 20 insertions), and TAK-788 (another EGFR/ERBB2 TKI). Other alterations, such as EGFR T790 M, are responsive to osimertinib, while the EGFR C797S alteration seen in osimertinib resistance demonstrates preclinical sensitivity to combined brigatinib and cetuximab. These observations indicate that clinical resistance can be overcome by utilizing advanced genomic interrogation coupled with computer modeling.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Plasma cell‐free DNA (cfDNA) is emerging as an important diagnostic tool in cancer. However, cfDNA alterations may differ from those in tissue and sometimes may reflect processes unrelated to the ...cancer, including clonal hematopoiesis (CH). We examined plasma cfDNA, tested by next‐generation sequencing (NGS), for characterized alterations (excluding variants of unknown significance) in 135 patients with invasive glioma. Overall, 21% (28/135) had ≥1 alteration; 17% (23/135) had CH‐type cfDNA mutations. Temozolomide (a mutagenic alkylating agent) with concurrent radiation therapy prior to blood draw was significantly associated with an increase in CH‐type mutations, even after age, race/ethnicity, and WHO‐grade were considered as confounders (odds ratio 95% confidence interval, CI 8.98 1.13‐71.46; P = .04; multivariable analysis). Further, of 18 patients with invasive glioma who had both cfDNA and tissue DNA NGS and had ≥1 cfDNA alteration, 16 (89%) had ≥1 cfDNA alteration not found in their tissue DNA, including CH‐type alterations in genes such as TP53 (most common), ATM, GNAS, and JAK2. Altogether, 87% of cfDNA alterations (20/23) observed in the 18 patients were implicated in CH. Finally, examining all 135 patients, CH‐type cfDNA mutations were an independent prognostic factor for shorter survival (hazard ratio 95% CI 3.28 1.28‐8.40; P = .01). These findings emphasize that not all characterized cfDNA alterations detected in patients with solid tumors are cancer‐related. Importantly, in patients with invasive gliomas who have had prior temozolomide and radiation, CH‐related alterations in cfDNA are frequent and correlate with poor outcomes.
What's new?
Tissue biopsy for brain tumors presents significant challenges, making less‐invasive molecular profiling with plasma cell‐free DNA (cfDNA) an appealing alternative. However, whether alterations detected in cfDNA, including clonal hematopoiesis (CH), reflect processes in brain tumor tissue remains uncertain. In this investigation of CH‐associated mutations in plasma‐derived cfDNA from patients with invasive gliomas, 87 percent of characterized cfDNA alterations were implicated in CH, indicating that not all cfDNA alterations are cancer‐related. In addition, temozolomide/radiation therapy prior to blood draw for cfDNA was associated with potential CH‐type cfDNA mutation detection. Potential CH‐type cfDNA alterations were an independent predictor of shorter overall survival.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK