Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Norwegian PSC Research Center, Oslo University Hospital Rikshospitalet, Oslo, Norway.
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Hepatol Commun. 2024 Jul 5;8(7). doi: 10.1097/HC9.0000000000000461. eCollection 2024 Jul 1.
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.
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.
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.
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.
原发性硬化性胆管炎 (PSC) 患者有 20%的终生胆道癌 (BTC) 风险。通过全外显子组测序，我们对 PSC 相关 BTC 的组织样本中的基因组改变进行了特征描述。
我们从 52 例 PSC 和 BTC 患者的切除或活检标本中提取福尔马林固定、石蜡包埋的肿瘤和配对非肿瘤组织的 DNA，并进行全外显子组测序。在进行拷贝数分析、变异调用和过滤后，通过通路分析和注释靶向癌症治疗方法来评估疑似 PSC-BTC 相关基因。
我们鉴定了 53 个候选癌症基因，在 2 个或更多样本中总共发现了 123 个非同义改变通过过滤阈值。在所鉴定的基因中，19%以前与 BTC 无关，包括 CNGA3、KRT28 和 EFCAB5。另一部分包括以前与肝胆胰癌症相关的基因，如 ARID2、ELF3 和 PTPRD。最后，我们还鉴定了一组与广泛癌症相关的基因，如抑癌基因 TP53、CDKN2A、SMAD4 和 RNF43 以及致癌基因 KRAS、ERBB2 和 BRAF。在 51.9%的样本中发现了局灶性拷贝数变异。鉴定出潜在可操作基因的改变，包括 ERBB2、MDM2 和 FGFR3，以及 RTK/RAS（p=0.036）、TP53（p=0.04）和 PI3K（p=0.043）通路的改变与总生存时间减少显著相关。
在这项对 PSC 相关 BTC 的全外显子组特征描述中，我们描绘了 PSC 特异性和普遍性癌症基因。我们的研究结果为更好地了解 PSC 中 BTC 的发生提供了机会，并可作为开发个性化治疗方法的平台。
