全外显子组测序揭示了原发性硬化性胆管炎胆道癌的新型癌基因和可行靶点

IF 5.6 2区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Hepatology Communications Pub Date : 2024-07-05 eCollection Date: 2024-07-01 DOI:10.1097/HC9.0000000000000461
Marit M Grimsrud, Michael Forster, Benjamin Goeppert, Georg Hemmrich-Stanisak, Irmi Sax, Krzysztof Grzyb, Peder R Braadland, Alphonse Charbel, Carmen Metzger, Thomas Albrecht, Tim Alexander Steiert, Matthias Schlesner, Michael P Manns, Arndt Vogel, Sheraz Yaqub, Tom H Karlsen, Peter Schirmacher, Kirsten M Boberg, Andre Franke, Stephanie Roessler, Trine Folseraas
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引用次数: 0

摘要

背景:原发性硬化性胆管炎(PSC)患者一生中患胆道癌(BTC)的风险为20%。通过全外显子组测序,我们确定了伴有原发性硬化性胆管炎的 BTC 组织样本的基因组变化特征:我们从 52 例 PSC 和 BTC 患者的切除或活检标本中提取了福尔马林固定、石蜡包埋的肿瘤和配对非肿瘤组织的 DNA,并进行了全外显子组测序。在进行拷贝数分析、变异调用和筛选后,通过通路分析评估了推定的 PSC-BTC 相关基因,并将其注释为癌症靶向疗法:我们发现了53个候选癌症基因,在2个或更多样本中,共有123个非同义变异通过了筛选阈值。在已发现的基因中,19%的基因以前未与 BTC 发生过关联,包括 CNGA3、KRT28 和 EFCAB5。另一个子集包括以前与肝胰胆管癌有关联的基因,如 ARID2、ELF3 和 PTPRD。最后,我们发现了与多种癌症有关联的基因子集,如肿瘤抑制基因 TP53、CDKN2A、SMAD4 和 RNF43 以及致癌基因 KRAS、ERBB2 和 BRAF。在 51.9% 的样本中发现了病灶拷贝数变异。发现了ERBB2、MDM2和FGFR3等潜在可操作基因的改变,RTK/RAS(p = 0.036)、TP53(p = 0.04)和PI3K(p = 0.043)通路的改变与总生存率降低显著相关:在这一与PSC相关的BTC外显子组特征描述中,我们发现了PSC特异性基因和通用癌基因。我们的发现为更好地了解 PSC 中 BTC 的发展提供了机会,并可作为开发个性化治疗方法的平台。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Whole-exome sequencing reveals novel cancer genes and actionable targets in biliary tract cancers in primary sclerosing cholangitis.

Background: People with primary sclerosing cholangitis (PSC) have a 20% lifetime risk of biliary tract cancer (BTC). Using whole-exome sequencing, we characterized genomic alterations in tissue samples from BTC with underlying PSC.

Methods: We extracted DNA from formalin-fixed, paraffin-embedded tumor and paired nontumor tissue from 52 resection or biopsy specimens from patients with PSC and BTC and performed whole-exome sequencing. Following copy number analysis, variant calling, and filtering, putative PSC-BTC-associated genes were assessed by pathway analyses and annotated to targeted cancer therapies.

Results: We identified 53 candidate cancer genes with a total of 123 nonsynonymous alterations passing filtering thresholds in 2 or more samples. Of the identified genes, 19% had not previously been implicated in BTC, including CNGA3, KRT28, and EFCAB5. Another subset comprised genes previously implicated in hepato-pancreato-biliary cancer, such as ARID2, ELF3, and PTPRD. Finally, we identified a subset of genes implicated in a wide range of cancers such as the tumor suppressor genes TP53, CDKN2A, SMAD4, and RNF43 and the oncogenes KRAS, ERBB2, and BRAF. Focal copy number variations were found in 51.9% of the samples. Alterations in potential actionable genes, including ERBB2, MDM2, and FGFR3 were identified and alterations in the RTK/RAS (p = 0.036), TP53 (p = 0.04), and PI3K (p = 0.043) pathways were significantly associated with reduced overall survival.

Conclusions: In this exome-wide characterization of PSC-associated BTC, we delineated both PSC-specific and universal cancer genes. Our findings provide opportunities for a better understanding of the development of BTC in PSC and could be used as a platform to develop personalized treatment approaches.

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来源期刊
Hepatology Communications
Hepatology Communications GASTROENTEROLOGY & HEPATOLOGY-
CiteScore
8.00
自引率
2.00%
发文量
248
审稿时长
8 weeks
期刊介绍: Hepatology Communications is a peer-reviewed, online-only, open access journal for fast dissemination of high quality basic, translational, and clinical research in hepatology. Hepatology Communications maintains high standard and rigorous peer review. Because of its open access nature, authors retain the copyright to their works, all articles are immediately available and free to read and share, and it is fully compliant with funder and institutional mandates. The journal is committed to fast publication and author satisfaction. ​
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