👤 Hiroki Sunakawa

Advanced esophageal squamous cell carcinoma (ESCC) has a poor prognosis, and current treatments provide limited survival benefits. This study aimed to identify prognostic biomarkers and therapeutic targets by genomic profiling of advanced ESCC using circulating tumor DNA (ctDNA). The SCRUM-MONSTAR GOZILA study is a nationwide, plasma-based molecular profiling project using Guardant360, involving 31 core cancer institutions in Japan. We evaluated the genomic landscape of advanced ESCC and investigated associations between specific alterations and overall survival (OS). The correlation between blood tumor mutation burden (bTMB) and clinical outcomes in patients with PD-1 inhibitors was also assessed using multiple cutoff values (2, 4, 6, 8, and 10 mutations/Mb). Among 313 patients, alterations predominantly consisted of single nucleotide variants (SNVs, 68.9%) and copy number alterations (20.7%). ctDNA analysis identified key genomic alterations linked to poor outcomes in advanced ESCC, revealing potential prognostic biomarkers and therapeutic targets. In contrast, bTMB did not show predictive value for the efficacy of PD-1 inhibitors in this study. Show less

Gastrointestinal malignancies account for 25% of all cancer cases and 35% of cancer-related mortality. Next-generation sequencing (NGS) can elucidate the genomic landscape of gastrointestinal cancers; tissue-based genotyping has traditionally been used, but liquid biopsy-based genotyping is a noninvasive alternative. Moreover, geographical variations in the genomic landscape of gastrointestinal cancers have not been fully elucidated. This retrospective study aimed to gain insight into the genomic landscape of patients with gastrointestinal cancers from the Asia and Middle East (AME) region using plasma-derived circulating tumor DNA (ctDNA). From routine clinical practice, 2,601 plasma samples were collected from 2,062 patients with gastrointestinal cancers in the AME region. NGS profiling was conducted using the Guardant360® assay. The frequency of biomarkers that can aid decision-making in cancer patients was investigated. Single-nucleotide variants affected most commonly TP53 (70.4%), KRAS (44.0%), APC (25.7%), ATM (15.1%), and PIK3CA (12.3%). Copy number alterations were most often observed in EGFR (13.7%), CCNE1 (5.9%), PIK3CA (5.0%), MYC (4.7%), and FGFR1 (4.6%); fusions were detected in 1.6% of patients and most frequently affected FGFR2, RET, ALK, FGFR3, and NTRK1/3. In patients with pancreatic adenocarcinoma, the most frequently observed clinically informative genomic biomarkers occurred in KRAS (G12C, 1.6%; all others, 67.1%), BRCA1/2 (4.1%), BRAF (V600X, 1.5%), and microsatellite instability-high (MSI-H) (1.0%). In patients with colorectal cancer, the most common clinically relevant alterations were KRAS (49.0%), BRAF (V600E, 7.6%), and NRAS (5.7%) mutations; ERBB2 amplifications (2.5%); and MSI-H (1.8%). In patients with biliary tract cancers, actionable alterations included IDH1 mutations (11.1%), ERBB2 amplifications (4.6%), FGFR2 fusions (2.0%), MSI-H (2.0%), and BRAF V600E (1.5%). In patients with gastric or gastroesophageal junction adenocarcinomas, actionable alterations included ERBB2 amplifications (10.1%) and MSI-H (3.6%). Our data provide insight into the genomic landscape of patients with gastrointestinal cancers from the AME region using ctDNA analysis. These findings highlight the potential utility of liquid biopsy as a noninvasive tool for characterizing tumor genomic profiles and support its role in clinical practice. Show less

Transcriptional factors, such as Snail, Slug, and Smuc, that cause epithelial-mesenchymal transition are thought to regulate the expression of Ezrin, Radixin, and Moesin (ERM proteins), which serve as anchors for efflux transporters on the plasma membrane surface. Our previous results using lung cancer clinical samples indicated a correlation between Slug and efflux transporter MRP2. In the current study, we aimed to evaluate the relationships between MRP2, ERM proteins, and Slug in lung cancer cells. HCC827 cells were transfected by Mock and Slug plasmid. Both mRNA expression levels and protein expression levels were measured. Then, the activity of MRP2 was evaluated using CDCF and SN-38 (MRP2 substrates). HCC827 cells transfected with the Slug plasmid showed significantly higher mRNA expression levels of MRP2 than the Mock-transfected cells. However, the mRNA expression levels of ERM proteins did not show a significant difference between Slug-transfected cells and Mock-transfected cells. Protein expression of MRP2 was increased in Slug-transfected cells. The uptake of both CDCF and SN-38 was significantly decreased after transfection with Slug. This change was abrogated by treatment with MK571, an MRP2 inhibitor. The viability of Slug-transfected cells, compared to Mock cells, significantly increased after incubation with SN-38. Thus, Slug may increase the mRNA and protein expression of MRP2 without regulation by ERM proteins in HCC827 cells, thereby enhancing MRP2 activity. Inhibition of Slug may reduce the efficacy of multidrug resistance in lung cancer. Show less