Background: Chordoma is a rare primary tumor originating from embryonic notochord remnants, with limited systemic therapeutic options due to a poor understanding of its genomic landscape. This study aims to characterize the genetic alterations in chordoma using a large national patient-level genomic repository, the AACR Project GENIE, to identify potential therapeutic targets and improve disease modeling. Methods: A retrospective analysis of chordoma samples was conducted using the AACR Project GENIE database. Targeted sequencing data were analyzed for recurrent somatic mutations, tumor mutational burden, and chromosomal copy number variations, with significance set at p < 0.05. Results: Frequent mutations were observed in genes associated with SWI/SNF complex affecting chromatin remodeling (SETD2, PBRM1, ARID1A). Mutations were also common among the TERT promoter regions, and cell cycle regulation (CDKN2A). Significant co-occurrences were identified among PBRM1, BRCA2, and KMT2D mutations. CDKN2A/B deletions were enriched in metastatic tumors, and pediatric cases demonstrated distinct mutation profiles compared to adults. Conclusions: This study provides a genomic profile of chordoma, identifying key mutations and potential therapeutic targets. These findings highlight the roles of chromatin remodeling and cell cycle pathways in chordoma biology, offering insights for future precision medicine approaches and therapeutic interventions.

Background: Nasopharyngeal carcinoma (NPC) is a rare head and neck cancer arising from the mucosal lining of the nasopharynx, for which systemic therapeutic options remain scarce, reflecting the limited characterization of its genomic profile. This study utilized a large patient-level genomic repository to characterize genetic alterations, identify potential therapeutic targets, and improve disease modeling in NPC. Methods: A retrospective analysis of NPC samples was conducted using the AACR Project GENIE database. Targeted sequencing data were analyzed for recurrent somatic mutations, tumor mutational burden, and chromosomal copy number variations, with significance set at p < 0.05. Results: Frequent mutations were identified in KMT2D (20%), TP53 (16%), CYLD (9.6%), NFKBIA (6.4%), and PIK3CA (5.6%), implicating the p53, NF-κB, and PI3K pathways in NPC development. Notably, significantly distinct mutational profiles were observed based on both sex and race, with female patients exhibiting higher frequencies of PIK3C2G, ETV6, and CDKN1B mutations and non-Asian patients showing enrichment in KDM5A, CCND2, and TP53 mutations. Conclusions: This study presents a detailed genomic profile of NPC, identifying key mutations within established cancer-associated pathways. The identification of frequently mutated pathways (p53, NF-κB, and PI3K) suggests potential targets for novel therapies. Furthermore, distinct mutational landscapes in female and Asian NPC patients offer possibilities for precision therapeutic interventions.

Sinonasal cancers are malignant neoplasms arising from the nasal cavity and paranasal sinuses, including squamous cell carcinoma (SCC), adenocarcinoma, and undifferentiated carcinoma. Due to their rarity, comprehensive genomic data remain limited. Treatments include surgery, radiation, and chemotherapy, with ongoing trials investigating agents like cetuximab, cisplatin, and Tazemetostat. We analyzed sinonasal cancer cases from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database via cBioPortal (v16.1-public, accessed July 22, 2024). Common gene mutations, correlations, and mutual exclusivities were assessed using statistical analyses with false discovery rate correction. Of 2,595 head and neck cancer samples, 122 (4.7%) were sinonasal carcinoma: 70 (57.4%) SCC, 31 (25.4%) undifferentiated carcinoma, and 21 (17.2%) adenocarcinomas. The most frequent mutations were TP53 (tumor protein 53; 40%), PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; 14%), KMT2D (lysine methyltransferase 2D; 11%), and CDKN2A (cyclin-dependent kinase inhibitor 2A; 9%). Subtype-specific mutations included IDH2 (isocitrate dehydrogenase; 230%) in undifferentiated carcinoma and FAT1 (15%) in adenocarcinoma. TP53 frequently co-occurred with PRKDC (protein kinase, DNA-activated, catalytic subunit; p = 0.020), while KMT2D co-occurred with PIK3CA (p = 0.018). TP53, PIK3CA, and KMT2D mutations are prevalent in sinonasal carcinoma, highlighting potential targets for therapy. Tazemetostat, targeting KMT2D-related DNA (deoxyribonucleic acid) methylation, and cetuximab, targeting the PIK3CA signaling cascade, may offer therapeutic benefits. Further research on mutation-specific therapies could improve treatment strategies.

The role of second-look endoscopy and debridement (SLED) remains uncertain in children due to the perceived need for additional general anesthesia following their initial functional endoscopic sinus surgery (FESS) while mitigating risks and healthcare costs. This comprehensive review synthesizes current evidence on SLED in children, focusing on its practice pattern and treatment outcomes. This review was designed and performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews Protocol. Independent queries of the PubMed Central, MEDLINE, and Bookshelf databases were performed. A total of 53 relevant, unique articles were initially identified; 12 articles were ultimately deemed appropriate for inclusion in final analysis. The most common indication for FESS was chronic rhinosinusitis or recurrent sinus infections while that for SLED under general anesthesia varied from institutional practice patterns to surgeon preference. No meaningful comparison of outcomes was possible as the “success rates” of FESS with or without SLED were largely based on unvalidated questionnaires and equally subjective surgeon assessments. Even when looking at outcomes based on revision rates, FESS with SLED was considered successful between 60.5% and 95.6% of the time, with a mean of 84.2%, while FESS without SLED was successful between 71.0% to 96.4% of the time, with a mean of 86.3%. However, no randomized, controlled studies were available in the pediatric literature pertaining to FESS with or without SLED. Moreover, it became apparent that previous conclusions on the utility of SLED were based on the outcomes of FESS following one single SLED under general anesthesia vs. no SLED. As such, there is an unmet need to examine the utility of serial, office-based SLED in children to better elucidate its utility in pediatric FESS.

Objective(s): To characterize the somatic mutational landscape of laryngeal squamous cell carcinoma (LSCC) using AACR Project GENIE data to identify potential biomarkers for tumor progression and guide precision therapy. Methods: Clinical and genomic data from 135 LSCC samples (primary and metastatic) were analyzed from the AACR Project GENIE database. Mutations were compared by tumor site and gender using chi-squared and Mann–Whitney U tests; co-occurrence and mutual-exclusivity analyses were performed. Results: TP53 mutations were most common (89.6%), followed by KMT2D (27.4%), FAT1 (20.7%), and NOTCH1 (20.7%). CDK8 mutations were enriched in females (p = 0.011) and ATP8B1 in males (p = 0.013). DMD mutations characterized primary tumors (p = 0.049), whereas ATP8B1 and SAMD9L were linked to metastases (p < 0.001). The cohort was 85.9% male and 71.5% White; 59.2% of samples were primary and 39.2% recurrent/metastatic. Co-occurrence analysis identified distinct molecular subtypes. The identification of distinct molecular subtypes and gender-specific mutations, such as CDK8 in females and ATP8B1 in males, suggests potential avenues for tailored therapeutic interventions. Conclusions: LSCC exhibits marked genetic heterogeneity dominated by TP53 alterations. ATP8B1 and SAMD9L mutations may mark metastatic disease, and gender-specific mutations suggest avenues for personalized therapy. These insights support development of targeted strategies, including immunotherapies such as pembrolizumab in TP53-altered tumors. These insights into the genomic heterogeneity of LSCC lay the groundwork for developing targeted therapeutic strategies and patient stratification, ultimately advancing a personalized medicine approach to this disease.

Objective: We aimed to characterize the somatic mutational landscape of oropharyngeal squamous cell carcinoma (OPSCC) and identify potential genomic drivers of tumor progression and therapeutic resistance using the AACR GENIE database. Study Design: Retrospective genomic analysis was employed. Setting: We used publicly available data from the American Association for Cancer Research (AACR) Project GENIE database accessed via cBioPortal. Methods: We analyzed 412 tumor samples from 401 patients diagnosed with OPSCC. Somatic mutations, clinical variables and tumor characteristics were extracted and analyzed. Statistical comparisons of mutation frequencies across gender and tumor stage (primary vs. metastatic) were conducted. Co-occurrence and mutual exclusivity analyses were performed to identify significant genomic patterns. Results: The most frequently mutated genes included TP53 (30.1%), PIK3CA (26.0%), and KMT2D (21.6%). Gender-specific analyses suggested potential enrichment of TP53 and MET mutations in females and of ZNF750 in males. Distinct mutation patterns were observed between primary and metastatic tumors; primary tumors were enriched for mutations in TP53 and CDKN2A, while metastatic lesions harbored unique alterations in genes like CBLB and BUB1B, suggesting pathways involved in immune evasion and chromosomal instability may drive disease progression. Co-occurrence was noted between PIK3CA and FBXW7, and mutual exclusivity between TP53 and CYLD. Conclusions: This study identifies distinct genomic signatures in OPSCC subgroups, highlighting candidate biomarkers in pathways like PI3K/AKT signaling that warrant further investigation. Validating these markers in prospective trials is a critical next step to translate these findings into personalized therapeutic strategies for OPSCC patients.