PO.MCB08.03 · 分子与细胞生物学
利用胆道癌全基因组分析进行基因分析及其与临床因素的关联
Gene profiling using whole genome analysis of bile tract cancer and its association with clinical factors
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：胆道癌（BTC）是一种预后不良的恶性肿瘤。BTC的遗传背景和分子特征仍知之甚少。目的：利用全基因组分析阐明BTC的遗传多样性，并鉴定作为新型诊断和治疗方法靶点的基因突变。
方法：使用来自本机构接受手术的7例BTC患者的配对肿瘤和正常组织样本进行全基因组测序。使用snpEff检测和注释体细胞突变。Oncoplot分析可视化了突变累积模式，以及与临床因素（包括淋巴结转移、血管侵犯、神经侵犯、门静脉侵犯和IPNB）的关联。
结果：对检测到的体细胞突变进行分类后，注释显示基因间区突变（均值：31,085，范围：26,588-39,135）最为频繁。移码变异（均值：16.7，范围：11-25）、剪接供体/受体变异（均值：34.3，范围：17-45）和终止获得突变（均值：7.4，范围：2-10）被鉴定为重要的功能性突变。此外，还鉴定出错义变异（均值：529.4，范围：363-647）。关于非同义突变，错义突变在变异分类中最为常见，SNP（单核苷酸多态性）在变异类型中最为频繁。在SNV类别中，T到G和C到T转换的检出率较高。包括MUC16和MUC6在内的30个基因在7例中的3例或以上被鉴定出突变。对这些基因的Oncoplot分析提示，在无血管侵犯的样本中突变累积更为广泛，并与肿瘤突变负荷（TMB）相关。相反，未观察到与淋巴结转移、神经侵犯、门静脉侵犯或IPNB相关的突变累积模式。在癌症基因组图谱（TCGA）胆管癌数据库中登记的基因（331个突变，321个基因）中，我们的研究鉴定出MUC16、OBSCN和TP53。然而，未观察到它们突变的重叠。这提示BTC存在极高的遗传异质性。
结论：BTC以高突变负荷和遗传多样性为特征。提示血管侵犯状态与突变累积之间存在关联。基因分析被认为对个体化医疗很重要，所鉴定的基因突变可能作为新型诊断和治疗方法的潜在靶点。
查看英文原文 English abstract
Background: Bile tract cancer (BTC) is a malignant tumor with poor prognosis. The genetic background and molecular profiles of BTC remain poorly understood. Objective: To clarify the genetic diversity of BTC using whole-genome analysis and identify gene mutations as targets for novel diagnostic and therapeutic approaches.
Methods: Whole-genome sequencing was performed using paired tumor and normal tissue samples from 7 patients with BTC who underwent surgery at our institution. Somatic mutations were detected and annotated using snpEff. Oncoplot analysis visualized mutation accumulation patterns, and associations with clinical factors including lymph node metastasis, vascular invasion, neural invasion, portal vein invasion, and IPNB.
Results: On classification of detected somatic mutations, annotation revealed that intergenic region mutations (mean: 31,085, range: 26,588-39,135) were most frequent. Frameshift variants (mean: 16.7, range: 11-25), splice donor/acceptor variants (mean: 34.3, range: 17-45), and stop gained mutations (mean: 7.4, range: 2-10) were identified as important functional mutations. In addition, missense variants (mean: 529.4, range: 363-647) were also identified. Regarding nonsynonymous mutations, missense mutations were most common in variant classification, and SNPs (single nucleotide polymorphisms) were most frequent in variant type. Among SNV classes, T to G and C to T transitions were highly identified. Thirty genes, including MUC16 and MUC6, were identified with mutations in 3 or more of the 7 cases. Oncoplot analysis of these genes suggested that mutations accumulated more extensively and were associated with tumor mutation burden (TMB) in samples without vascular invasion. In contrast, no accumulation patterns of mutations were observed concerning lymph node metastasis, neural invasion, portal vein invasion, or IPNB. Among the genes (331 mutations, 321 genes) registered in The Cancer Genome Atlas (TCGA) bile duct cancer database, our study identified MUC16, OBSCN, and TP53. However, no overlap in their mutations was observed. It suggests extremely high genetic heterogeneity in BTC.
Conclusion: BTC is characterized by a high mutational burden and genetic diversity. An association between vascular invasion status and mutation accumulation was suggested. Gene profiling is considered important for personalized medicine, and the identified gene mutations may serve as potential targets for novel diagnostic and therapeutic approaches.
利益披露 Disclosure
T. Kokuryo, None..
M. Sunagawa, None..
J. Yamaguchi, None..
T. Baba, None..
T. Mizuno, None..
S. Onoe, None..
N. Watanabe, None..
M. Yamada, None..
S. Kawakatsu, None..
T. Ebata, None.