Data Sheet 2_The mutational landscape and actionable targets of gallbladder cancer: an ancestry-informed and comparative analysis of a Chilean population.pdf

IntroductionGallbladder cancer (GBC) is a highly aggressive malignancy with one of the highest incidence rates reported in Chile. Despite its clinical impact, molecular characterization of GBC in Latin American populations remains limited, and the absence of effective targeted therapies underscores the urgent need for new therapeutic strategies.
MethodsWe collected 118 tumor samples, of which 56 passed sequencing quality control using the Oncomine™ Comprehensive Assay v1. Somatic variants were identified with ANNOVAR and Cancer Genome Interpreter, and ancestry was inferred using ADMIXTURE and PCA with ancestry-informative markers. Comparative analyses were performed with Japanese, Singaporean, and U.S. cohorts.
ResultsA total of 535 somatic mutations were detected in 43 genes, with TP53 (30%), TSC2 (29%), and NOTCH1 (27%) being the most frequently mutated. We identified 121 clinically actionable variants in ATM, BRCA1/2, EGFR, ERBB2, and other genes. Exploratory analysis suggested an association between higher Mapuche ancestry and TP53 mutations. Comparative analyses revealed distinct mutational patterns in the Chilean cohort relative to Asian and U.S. datasets.
ConclusionThis ancestry-informed genomic analysis provides the first comprehensive landscape of Chilean GBC, identifying actionable alterations with potential therapeutic relevance and supporting the development of population-specific precision oncology strategies.

引言：胆囊癌（Gallbladder cancer, GBC）是一种高度侵袭性的恶性肿瘤，在智利的发病率位居前列。尽管其临床影响显著，但拉丁美洲人群中胆囊癌的分子特征研究仍较为有限，且缺乏有效的靶向治疗手段，这凸显了开发新型治疗策略的迫切需求。
方法：我们共收集了118份肿瘤样本，其中56份通过了Oncomine™ Comprehensive Assay v1的测序质量控制。使用ANNOVAR和癌症基因组解释器（Cancer Genome Interpreter）识别体细胞变异，通过ADMIXTURE、主成分分析（Principal Component Analysis）结合祖先信息标记推断祖先血统。与日本、新加坡及美国队列开展了比较分析。
结果：共在43个基因中检测到535个体细胞突变，其中突变频率最高的为TP53（30%）、TSC2（29%）和NOTCH1（27%）。我们在ATM、BRCA1/2、EGFR、ERBB2等基因中鉴定出121个临床可操作变异。探索性分析显示，更高的马普切（Mapuche）血统比例与TP53突变存在关联。比较分析结果表明，智利队列的突变模式与亚洲及美国数据集存在显著差异。
结论：这项基于祖先信息的基因组分析首次描绘了智利人群胆囊癌的全面突变图谱，鉴定出具有潜在治疗价值的可操作变异，为开发针对特定人群的精准肿瘤学（precision oncology）策略提供了支持。