PDF(Pubmed)
Abstract：
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.
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.
摘要：
背景：患有原发性硬化性胆管炎（PSC）的人一生中患胆道癌（BTC）的风险为20％。使用全外显子组测序，我们表征了来自具有潜在PSC的BTC的组织样本中的基因组改变。
方法：我们从福尔马林固定的，来自PSC和BTC患者的52例切除或活检标本的石蜡包埋肿瘤和配对非肿瘤组织，并进行了全外显子组测序。在拷贝数分析之后，变体调用，和过滤，通过通路分析评估了推定的PSC-BTC相关基因,并将其注释为靶向癌症治疗.
结果：我们在2个或更多样本中鉴定了53个候选癌症基因，共有123个非同义改变通过过滤阈值。在确定的基因中，19%以前没有与BTC有牵连，包括CNGA3、KRT28和EFCAB5。另一个子集包含先前与肝胰胆管癌有关的基因，如ARID2、ELF3和PTPRD。最后,我们确定了与多种癌症有关的基因子集，例如肿瘤抑制基因TP53，CDKN2A，SMAD4和RNF43以及癌基因KRAS，ERBB2和BRAF。在51.9%的样品中发现了焦点拷贝数变异。潜在可操作基因的改变，包括ERBB2，MDM2和FGFR3被识别和RTK/RAS的改变（p=0.036），TP53（p=0.04），和PI3K(p=0.043)通路与总生存率降低显著相关。
结论：在PSC相关BTC的整个外显子组表征中，我们描述了PSC特异性和普遍癌基因.我们的发现为更好地了解PSC中BTC的发展提供了机会，并可用作开发个性化治疗方法的平台。
方法：我们从福尔马林固定的，来自PSC和BTC患者的52例切除或活检标本的石蜡包埋肿瘤和配对非肿瘤组织，并进行了全外显子组测序。在拷贝数分析之后，变体调用，和过滤，通过通路分析评估了推定的PSC-BTC相关基因,并将其注释为靶向癌症治疗.
结果：我们在2个或更多样本中鉴定了53个候选癌症基因，共有123个非同义改变通过过滤阈值。在确定的基因中，19%以前没有与BTC有牵连，包括CNGA3、KRT28和EFCAB5。另一个子集包含先前与肝胰胆管癌有关的基因，如ARID2、ELF3和PTPRD。最后,我们确定了与多种癌症有关的基因子集，例如肿瘤抑制基因TP53，CDKN2A，SMAD4和RNF43以及癌基因KRAS，ERBB2和BRAF。在51.9%的样品中发现了焦点拷贝数变异。潜在可操作基因的改变，包括ERBB2，MDM2和FGFR3被识别和RTK/RAS的改变（p=0.036），TP53（p=0.04），和PI3K(p=0.043)通路与总生存率降低显著相关。
结论：在PSC相关BTC的整个外显子组表征中，我们描述了PSC特异性和普遍癌基因.我们的发现为更好地了解PSC中BTC的发展提供了机会，并可用作开发个性化治疗方法的平台。
