Gliomas are the most prevalent neurological cancer in the USA and care modalities are not able to effectively combat these aggressive malignancies. Identifying new, more effective treatments require a deep understanding of the complex genetic variations and relevant pathway associations behind these cancers. Drawing connections between gene mutations with a responsive genetic target can help drive therapy selections to enhance patient survival. We have performed extensive molecular profiling of the Capicua gene (CIC), a tumor and transcriptional suppressor gene, and its mutation prevalence in reference to MAPK activation within clinical glioma tissue. CIC mutations occur far more frequently in oligodendroglioma (52.1%) than in low-grade astrocytoma or glioblastoma. CIC-associated mutations were observed across all glioma subtypes, and MAPK-associated mutations were most prevalent in CIC wild-type tissue regardless of the glioma subtype. MAPK activation, however, was enhanced in CIC-mutated oligodendroglioma. The totality of our observations reported supports the use of CIC as a relevant genetic marker for MAPK activation. Identification of CIC mutations, or lack thereof, can assist in selecting, implementing, and developing MEK/MAPK-inhibitory trials to improve patient outcomes potentially.

The expression of the protein Mesothelin (MSLN) is highly variable in several malignancies, including colorectal cancer (CRC), and high levels are associated with aggressive clinicopathological features and worse patient survival. Colorectal cancer is both a common and deadly cancer; being the third most common in incidence and second most common cause of cancer-related death. While systemic therapy remains the primary therapeutic option for most patients with stage IV (metastatic; m) CRC, their disease eventually becomes treatment refractory, and 85% succumb within 5 years. Microsatellite-stable (MSS) CRC tumors, which constitute more than 90% of patients with mCRC, are generally refractory to immunotherapeutic interventions. In our current work, we characterize MSLN levels in CRC, specifically correlating expression with clinical outcomes in relevant CRC subtypes, and explore how MSLN expression impacts the status of immune activation and suppression in the peritumoral microenvironment. Higher MSLN expression is prevalent in CMS1 and CMS4 CRC subtypes and correlates with higher gene mutation rates across the patient cohorts. Further, MSLN-high patients exhibit increased M1/M2 macrophage infiltration, PD-L1 staining, immune-inhibitory gene expression, enrichment in inflammatory, TGF-β, IL6/JAK/STAT3, IL2/STAT5 signaling pathways, and mutation in KRAS and FBXW7. Together, these results suggest that MSLN protein is a potential target for antigen-specific therapy and supports investigation into its tumorigenic effects to identify possible therapeutic interventions for patients with high MSLN expressing MSS CRC.

Cyclin E overexpression as a result of CCNE1 amplification is a critical driver of genomic instability in gastric cancer, but its clinical implication is largely unknown. Thus, we integrated genomic, transcriptomic, and immune profiling analysis of 7,083 esophagogastric tumors and investigated the impact of CCNE1 amplification on molecular features and treatment outcomes. We identified CCNE1 amplification in 6.2% of esophageal adenocarcinoma samples, 7.0% of esophagogastric junction carcinoma, 4.2% of gastric adenocarcinoma samples, and 0.8% of esophageal squamous cell carcinoma. Metastatic sites such as lymph node and liver showed an increased frequency of CCNE1 amplification relative to primary tumors. Consistent with a chromosomal instability phenotype, CCNE1 amplification was associated with decreased CDH1 mutation and increased TP53 mutation and ERBB2 amplification. We observed no differences in immune biomarkers such as PD-L1 expression and tumor mutational burden comparing CCNE1-amplified and nonamplified tumors, although CCNE1 amplification was associated with changes in immune populations such as decreased B cells and increased M1 macrophages from transcriptional analysis. Real-world survival analysis demonstrated that patients with CCNE1-amplified gastric cancer had worse survival after trastuzumab for HER2-positive tumors, but better survival after immunotherapy. These data suggest that CCNE1-amplified gastric cancer has a distinct molecular and immune profile with important therapeutic implications, and therefore further investigation of CCNE1 amplification as a predictive biomarker is warranted. Significance: Advanced gastric cancer has a relatively dismal outcome with a 5-year overall survival of less than 10%. Furthermore, while comprehensive molecular analyses have established molecular subtypes within gastric cancers, biomarkers of clinical relevance in this cancer type are lacking. Overall, this study demonstrates that CCNE1 amplification is associated with a distinct molecular profile in gastric cancer and may impact response to therapy, including targeted therapy and/or immunotherapy.

Tipifarnib is the only targeted therapy breakthrough for HRAS-mutant (HRASmt) recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). The molecular profiles of HRASmt cancers are difficult to explore given the low frequency of HRASmt. This study aims to understand the molecular co-alterations, immune profiles, and clinical outcomes of 524 HRASmt solid tumors including urothelial carcinoma (UC), breast cancer (BC), non-small-cell lung cancer (NSCLC), melanoma, and HNSCC. HRASmt was most common in UC (3.0%), followed by HNSCC (2.82%), melanoma (1.05%), BC (0.45%), and NSCLC (0.44%). HRASmt was absent in Her2+ BC regardless of hormone receptor status. HRASmt was more frequently associated with squamous compared to non-squamous NSCLC (60% vs. 40% in HRASwt, p = 0.002). The tumor microenvironment (TME) of HRASmt demonstrated increased M1 macrophages in triple-negative BC (TNBC), HNSCC, squamous NSCLC, and UC; increased M2 macrophages in TNBC; and increased CD8+ T-cells in HNSCC (all p < 0.05). Finally, HRASmt was associated with shorter overall survival in HNSCC (HR: 1.564, CI: 1.16–2.11, p = 0.003) but not in the other cancer types examined. In conclusion, this study provides new insights into the unique molecular profiles of HRASmt tumors that may help to identify new targets and guide future clinical trial design.

Male breast cancer (MaBC) represents ∼1% of breast malignancies and may have significant differences to female BC (FeBC) that impact prognosis and treatment response. In this work, we sought to characterize the molecular and immune landscape of MaBC. We analyzed whole-transcriptome (WTS) and whole exome sequencing from 19 697 deidentified tumor samples provided to Caris Life Sciences. Our study found significant sex-based differences in the molecular and immunological landscape within each tumor subtype between MaBC and FeBC, including increased M2 Mϕ, and decreased dendritic cells and immune-related gene expression. Genetic amplifications and mutation frequency differences between MaBC and FeBC across molecular subtypes included significant differences in TP53 and ESR1 mutation [2.4% versus 31.2%; 5.8% versus 13.3%, hormone receptor (HR)-positive/HER2-negative], and BRCA2 and CDH1 mutation [6.7% versus 2.1%, HER2-positive; 16.7% versus 5.6%, triple-negative breast cancer (TNBC)]. Immunologically, MaBC exhibited increased tumor-promoting M2 Mϕ (5.8% versus 3.0%, TNBC), decreased dendritic cell infiltration (2.2% versus 2.6%, HR-positive/HER2-negative) and decreased PDCD1 and LAG3 immune checkpoint gene expression (0.3% versus 0.4%; 2.3% versus 2.9%, HR-positive/HER2-negative) against FeBC. Our findings suggest a unique genomic and immunologic landscape in MaBC requiring a sex-informed approach and provide candidate therapeutic targets and mechanisms of resistance.

PURPOSE: The use of bevacizumab in glioblastoma has been associated with increased progression-free survival and improvement in symptoms and quality of life. There are no clinical indicators on how to choose patients who would benefit the most from this agent. We aim to describe molecular markers in patients with glioblastoma who may benefit from treatment. Methods: We analyzed glioblastoma tumor samples that underwent comprehensive molecular profiling analysis at Caris Life Sciences. RESULTS: The data set consisted of 3,106 glioblastoma tumor samples, of which 571 were from patients treated with bevacizumab. The majority were males (65%) and older than 60 years. Median survival was 17.5 months in patients receiving bevacizumab. In patients who were treated with bevacizumab for ≥1 year, median survival was 33.8 months, compared with 15 months in those treated for ≤6 months. Patients who received bevacizumab for ≥1 year had higher prevalence of LRIG3 (9% v 1%), CDK4 (22% v 8%), and DDIT3 amplification (14% v 4%), SETD2 mutations (10% v 3%), and MGMT methylation (66% v 32%). EGFR amplification was more frequent in patients who received bevacizumab for ≤6 months (46% v 20%). Multivariate analysis showed that CDK4 amplification was associated with longer time on bevacizumab, and EGFR amplification with shorter time after correcting for age, sex, and other molecular alterations. CONCLUSION: CDK4 amplification is a potential genetic biomarker to identify patients who may derive prolonged benefit from bevacizumab.