Shih Sheng Jiang

Background: Oral squamous cell carcinoma (OSCC), primarily caused by high exposure to betel quid, tobacco, and alcohol, remains a major public health burden in Taiwan. Although key mutations have been identified in OSCC, the population‐specific mutational landscape and its clinical relevance remain underexplored. Methods: A total of 106 OSCC tumors from Taiwanese patients were subjected to targeted gene sequencing with the Oncomine Comprehensive Assay v3 platform. High‐confidence exonic, nonsynonymous variants were identified from 161 cancer‐related genes. The resulting mutational landscape was compared with publicly available data from The Cancer Genome Atlas. Gene‐ and pathway‐level alterations were further correlated with clinicopathological parameters. Results: A total of 317 exonic, nonsynonymous variants were identified in 73 OSCC‐related genes, of which 52 were classified as driver genes. In addition to commonly mutated genes (e.g., TP53 , CDKN2A , NOTCH1 , HRAS , and PIK3CA ), PIK3R1 and MSH6 exhibited high mutation frequencies. A higher number of mutated genes per tumor was significantly correlated with poorer local‐relapse‐free survival (hazard ratio: 1.17, 95% CI: 1.04–1.31, p = 0.010). In the 83 advanced‐stage OSCC tumors, TP53 mutation was strongly associated with positive cervical lymph nodal metastasis ( p < 0.001). An inverse relationship was noted between nodal metastasis and NOTCH1 , HRAS , and PIK3CA mutations, possibly due to the mutually exclusive pattern observed between TP53 and NOTCH1 / HRAS mutations. Alteration of the cell cycle oncogene pathway was significantly associated with poor survival in advanced‐stage OSCC patients, which was subsequently confirmed as an independent prognostic factor for disease‐specific survival (hazard ratio: 3.2, 95% CI: 1.05–9.75, p = 0.040) in 89 patients with advanced‐stage OSCC from The Cancer Genome Atlas. Conclusions: This study uniquely illustrates the mutational landscape of OSCC in Taiwanese patients, highlighting clinically relevant genomic alterations that hold promise as prognostic biomarkers and candidates for targeted intervention.

Background: Lung adenocarcinoma (LUAD) is the most common type of lung cancer. A recent genome-wide association study of lung adenocarcinoma in East Asia reported 28 independent susceptibility variants across 25 loci and identified 2 genes whose genetically predicted expression levels are associated with lung adenocarcinoma risk, using an ancestry-matched lung tissue expression quantitative trait loci (QTL) dataset. It is desirable to identify additional susceptibility loci and to understand their underlying biological mechanisms. Methods: Using an expanded genome-wide association study of lung adenocarcinoma in East Asia and ancestry-matched lung tissue expression QTL and DNA methylation QTL datasets, we performed transcriptome-wide association studies and DNA methylome-wide association studies simultaneously and examined the association between measured expression of genes and DNA methylation of nearby CpGs. Genes and nearby CpGs are termed CpG–gene–LUAD trios if these 3 associations hold simultaneously. Results: At a Bonferroni-corrected P value less than .05, we identified a new susceptibility locus (6p21.31; lead single-nucleotide polymorphism rs7772643), 10 lung adenocarcinoma–associated genes, and 86 lung adenocarcinoma–associated CpGs. At a false discovery rate q value less than 0.05, we identified 28 lung adenocarcinoma–associated genes, 220 lung adenocarcinoma–associated CpGs, and 45 CpG–gene–LUAD trios; among them, 43 were direction-matched regarding these 3 associations. These show that 23 of the known 28 susceptibility variants for lung adenocarcinoma in East Asia are near these genes or CpGs and MARCH3, ELF5, IKZF3, GSDMB, CCDC116, and DSP are putative novel candidate genes. Few of them were reported in lung adenocarcinoma in European populations. Conclusions: This study substantially advances our understanding of the etiology of lung adenocarcinoma in East Asia and could be useful in developing translational applications.

Candida albicans has been implicated in oral carcinogenesis, but its role in the progression of oral potentially malignant disorders (OPMDs) remains unclear. We investigated whether high Candida burden in OPMD lesions predicts malignant transformation (MT) and whether this association varied by OPMD subtype. In a multicenter prospective cohort study across seven hospitals in Taiwan, 734 OPMD patients were followed for a mean of 2.4 years. Oral lesion swabs were cultured on chromogenic agar to quantify Candida albicans level. Cox models were used to estimate hazard ratios (HRs) for MT to oral cancer. MT occurred in 6.8% of patients. High Candida burden was independently associated with increased MT risk (aHR = 2.84; 95% CI: 1.40–5.75). Patients with oral submucous fibrosis (OSF) or verrucous hyperplasia (VH) also had elevated risk (aHR = 4.99; 95% CI: 1.54–10.38). Interaction analysis revealed strong individual risks for high Candida burden (aHR = 13.83) and OSF/VH (aHR = 13.67), with an attenuating interaction term (aHR = 0.11), yielding a substantial combined risk (HR ≈ 20.8). Stratified analysis showed the strongest effect in leukoplakia (HR = 12.19). High Candida albicans burden is a significant, subtype-dependent risk factor for malignant progression in OPMDs. These findings underline the role of fungal–host interactions in oral carcinogenesis and support the integration of fungal profiling into routine surveillance of OPMDs.

Lung adenocarcinoma (LUAD) remains a leading cause of cancer mortality, with limited treatment options for EGFR-wild-type patients and persistent intrinsic resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in some EGFR-mutated cases. Neuromedin U (NMU), which encodes a neuropeptide previously associated with poor prognosis, has emerged as a candidate gene linked to reduced EGFR-TKI efficacy. Here, we identify NMU as a multifaceted effector of LUAD progression. Transcriptomic analyses across LUAD cohorts revealed that NMU expression correlates with poor survival and enrichment of purine metabolism signatures. Mechanistically, NMU upregulates key purine biosynthesis genes, including IMPDH1 , GMPS , and RRM1 , in a NTSR1-dependent manner. Targeted metabolomic profiling and ¹⁵ N-glutamine isotope tracing confirmed that NMU enhances IMPDH1-mediated guanine nucleotide synthesis, supporting increased proliferative capacity. Pharmacologic inhibition of NMU signaling or IMPDH1 suppressed LUAD cell viability and AKT signaling, with guanosine supplementation partially rescuing these effects, functionally validating the NMU-IMPDH1 axis. Concurrently, NMU expression was associated with elevated levels of fibrosis-related markers including COL1A1 , FN1 , and ACTA2 , alongside transcriptomic and histological features of extracellular matrix remodeling and stromal expansion. These findings, supported by co-culture assays and in vivo models, suggest that NMU may influence stromal remodeling, possibly via TGF-β signaling. Notably, in vivo NMU inhibition reduced both tumor growth and fibrotic features, and combination therapy with SR48692 (NTSR1 inhibitor) and osimertinib yielded superior therapeutic efficacy. Together, these results identify NMU as a key mediator of LUAD progression through both tumor-intrinsic metabolic reprogramming and stromal remodeling pathways. Targeting the NMU-IMPDH1 axis may offer a novel strategy to suppress tumor proliferation and reshape the tumor microenvironment in LUAD patients with high NMU expressing tumors.

List of Western Blot antibodies, Flow Cytometry antibodies, and primers used in the study.

Suppl. Fig S3: Pathway analysis in human CD8⁺ T cells on day 28 and proliferation tracking on day 35.

Suppl. Fig S10: T cell activation status in dLNs after PD-1 blockade treatment.

Suppl. Fig S7: High Isg15 tumor expression was associated with reduced CD8+ T cell activity.

Suppl. Fig S9:Population of tumor infiltrated immune cells after PD-1 blockade treatment.

Suppl. Fig S1: List of Western Blot antibodies, Flow Cytometry antibodies, and primers used in the study.