Supplementary Material for: Real-World Genomic Landscape of Gastrointestinal Cancers in Asia and the Middle East Using Comprehensive Circulating Tumor DNA Next-Generation Sequencing

Introduction: 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 non-invasive 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). Methods: 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. Results: Single nucleotide variants (SNVs) affected most commonly TP53 (70.4%), KRAS (44.0%), APC (25.7%), ATM (15.1%), and PIK3CA (12.3%). Copy number alterations (CNAs) 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%), BRCA 1/2 (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%). Conclusion. 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 non-invasive tool for characterizing tumor genomic profiles and support its role in clinical practice.

引言：胃肠道恶性肿瘤占所有癌症病例的25%，占癌症相关死亡的35%。下一代测序（next-generation sequencing，NGS）可阐明胃肠道癌症的基因组图谱；传统上采用基于组织的基因分型，但基于液体活检的基因分型是一种非侵入性替代方案。此外，胃肠道癌症基因组图谱的地理差异尚未完全阐明。本回顾性研究旨在利用血浆来源的循环肿瘤DNA（circulating tumor DNA，ctDNA），深入了解亚太及中东（Asia and Middle East，以下简称AME）地区胃肠道癌症患者的基因组图谱。
研究方法：从临床常规实践中，收集了AME地区2062例胃肠道癌症患者的2601份血浆样本。采用Guardant360®检测开展NGS测序分析，对可辅助癌症患者临床决策的生物标志物的发生频率进行了探究。
研究结果：单核苷酸变异（single nucleotide variants，SNVs）最常累及TP53（70.4%）、KRAS（44.0%）、APC（25.7%）、ATM（15.1%）及PIK3CA（12.3%）。拷贝数变异（copy number alterations，CNAs）最常见于EGFR（13.7%）、CCNE1（5.9%）、PIK3CA（5.0%）、MYC（4.7%）及FGFR1（4.6%）；融合基因在1.6%的患者中被检出，最常累及FGFR2、RET、ALK、FGFR3及NTRK1/3。
在胰腺腺癌患者中，最常见的具有临床指导意义的基因组生物标志物为KRAS（G12C突变占1.6%，其他KRAS突变占67.1%）、BRCA1/2（4.1%）、BRAF（V600X突变，1.5%）及微卫星高度不稳定（microsatellite instability-high，MSI-H，1.0%）。
在结直肠癌患者中，最常见的临床相关变异为KRAS突变（49.0%）、BRAF（V600E突变，7.6%）及NRAS突变（5.7%）；ERBB2扩增（2.5%）及MSI-H（1.8%）。
在胆道系统癌症患者中，可靶向治疗的变异包括IDH1突变（11.1%）、ERBB2扩增（4.6%）、FGFR2融合（2.0%）、MSI-H（2.0%）及BRAF V600E突变（1.5%）。
在胃或胃食管结合部腺癌患者中，可靶向治疗的变异包括ERBB2扩增（10.1%）及MSI-H（3.6%）。
研究结论：本研究通过ctDNA分析，阐明了AME地区胃肠道癌症患者的基因组图谱。上述研究结果凸显了液体活检作为非侵入性工具表征肿瘤基因组图谱的潜在应用价值，并支持其在临床实践中的应用。