PDF(Pubmed)
Abstract：
Introduction: Gastric cancer is one of the most prevalent types of cancer worldwide. The World Health Organization (WHO), the International Agency for Research on Cancer (IARC), and the Global Cancer Statistics (GLOBOCAN) reported an age standardized global incidence rate of 9.2 per 100,000 individuals for gastric cancer in 2022, with a mortality rate of 6.1. Despite considerable progress in precision oncology through the efforts of international consortia, understanding the genomic features and their influence on the effectiveness of anti-cancer treatments across diverse ethnic groups remains essential. Methods: Our study aimed to address this need by conducting integrated in silico analyses to identify actionable genomic alterations in gastric cancer driver genes, assess their impact using deleteriousness scores, and determine allele frequencies across nine global populations: European Finnish, European non-Finnish, Latino, East Asian, South Asian, African, Middle Eastern, Ashkenazi Jewish, and Amish. Furthermore, our goal was to prioritize targeted therapeutic strategies based on pharmacogenomics clinical guidelines, in silico drug prescriptions, and clinical trial data. Results: Our comprehensive analysis examined 275,634 variants within 60 gastric cancer driver genes from 730,947 exome sequences and 76,215 whole-genome sequences from unrelated individuals, identifying 13,542 annotated and predicted oncogenic variants. We prioritized the most prevalent and deleterious oncogenic variants for subsequent pharmacogenomics testing. Additionally, we discovered actionable genomic alterations in the ARID1A, ATM, BCOR, ERBB2, ERBB3, CDKN2A, KIT, PIK3CA, PTEN, NTRK3, TP53, and CDKN2A genes that could enhance the efficacy of anti-cancer therapies, as suggested by in silico drug prescription analyses, reviews of current pharmacogenomics clinical guidelines, and evaluations of phase III and IV clinical trials targeting gastric cancer driver proteins. Discussion: These findings underline the urgency of consolidating efforts to devise effective prevention measures, invest in genomic profiling for underrepresented populations, and ensure the inclusion of ethnic minorities in future clinical trials and cancer research in developed countries.
摘要：
简介：胃癌是全球最常见的癌症之一。世界卫生组织（WHO），国际癌症研究机构（IARC），全球癌症统计（GLOBOCAN）报告，2022年胃癌的年龄标准化全球发病率为9.2/10万人，死亡率为6.1。尽管通过国际财团的努力，精密肿瘤学取得了相当大的进展，了解不同种族群体的基因组特征及其对抗癌治疗有效性的影响仍然至关重要.方法：我们的研究旨在通过进行集成的计算机分析来确定胃癌驱动基因中可行的基因组改变来满足这一需求。使用有害性评分评估它们的影响，并确定九个全球人群的等位基因频率：欧洲芬兰语，欧洲非芬兰语,拉丁裔,东亚,南亚,非洲,中东,阿什肯纳齐犹太人，还有阿米什人.此外，我们的目标是根据药物基因组学临床指南优先考虑有针对性的治疗策略，在硅药物处方，和临床试验数据。结果：我们的综合分析检查了来自730,947个外显子组序列和76,215个来自无关个体的全基因组序列的60个胃癌驱动基因中的275,634个变异，鉴定13542个注释和预测的致癌变体。我们优先考虑最普遍和有害的致癌变体，用于随后的药物基因组学测试。此外,我们在ARID1A中发现了可行的基因组改变，ATM,BCOR,ERBB2,ERBB3,CDKN2A,KIT,PIK3CA,PTEN,NTRK3，TP53和CDKN2A基因可以增强抗癌疗法的功效，正如计算机药物处方分析所建议的那样，当前药物基因组学临床指南的综述，以及针对胃癌驱动蛋白的III期和IV期临床试验的评估。讨论:这些调查结果强调了巩固努力制定有效预防措施的紧迫性，投资于代表性不足的人群的基因组分析，并确保将少数民族纳入发达国家未来的临床试验和癌症研究。
