原发性硬化性胆管炎相关胆管癌表现出高肿瘤间和肿瘤内异质性。

Primary Sclerosing Cholangitis-Associated Cholangiocarcinoma Demonstrates High Intertumor and Intratumor Heterogeneity.

机构信息

Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, the Netherlands.

Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, the Netherlands.

出版信息

Clin Transl Gastroenterol. 2021 Oct 5;12(10):e00410. doi: 10.14309/ctg.0000000000000410.

DOI:10.14309/ctg.0000000000000410

PMID:34608877

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8500610/

Abstract

INTRODUCTION

Intertumor and intratumor heterogeneity may explain the diagnostic challenge and limited efficacy of chemotherapy for primary sclerosing cholangitis-associated cholangiocarcinoma (PSC-CCA). In this study, tumor heterogeneity was assessed through p53 and p16 protein expression analysis and next-generation sequencing (NGS) of TP53 and CDKN2A genetic alterations in PSC-associated CCA.

METHODS

Formalin-fixed paraffin-embedded tissue samples from resection material of patients with PSC-CCA or patients with PSC diagnosed with biliary dysplasia were selected. Sections with CCA and foci with dysplastic epithelium were identified by 2 independent gastrointestinal pathologists. Immunohistochemical evaluation of p53 and p16 protein expression and NGS of TP53 and CDKN2A genetic alterations were performed.

RESULTS

A total of 49 CCA and 21 dysplasia samples were identified in the resection specimens of 26 patients. P53 protein expression showed loss of expression, wild type, and overexpression in 14%, 63%, and 23% CCA and in 19%, 62%, and 19% dysplasia samples, respectively. P16 protein expression showed negative, heterogeneous, and positive results in 31%, 57%, and 12% CCA and in 33%, 53%, and 14% dysplasia samples, respectively. NGS showed high intertumor and intratumor heterogeneity of TP53 mutations and CDKN2A loss. Nearly 70% of the samples with a TP53 missense mutation demonstrated p53 overexpression, whereas all samples with a TP53 nonsense mutation demonstrated loss of p53 protein expression.

DISCUSSION

PSC-associated CCA is characterized by high intertumor and intratumor heterogeneity of both p53/p16 protein expression and genetic alterations in TP53/CDKN2A, indicating that these tumors consist of multiple subclones with substantially different genetic makeup. The high intertumor and intratumor heterogeneity in PSC-CCA should be acknowledged during the development of diagnostic and therapeutic strategies.

摘要

简介

肿瘤内和肿瘤间异质性可能解释原发性硬化性胆管炎相关胆管癌（PSC-CCA）的诊断挑战和化疗疗效有限的原因。在这项研究中，通过 p53 和 p16 蛋白表达分析以及 TP53 和 CDKN2A 基因突变的下一代测序（NGS），评估了 PSC 相关 CCA 的肿瘤异质性。

方法

选择 PSC-CCA 患者或经诊断患有胆管发育不良的 PSC 患者的手术切除标本中的福尔马林固定石蜡包埋组织样本。由 2 位独立的胃肠病理学家识别 CCA 切片和发育不良上皮的病灶。进行 p53 和 p16 蛋白表达的免疫组织化学评估以及 TP53 和 CDKN2A 基因突变的 NGS。

结果

在 26 名患者的手术标本中总共确定了 49 例 CCA 和 21 例发育不良样本。p53 蛋白表达在 14%、63%和 23%的 CCA 以及 19%、62%和 19%的发育不良样本中分别显示缺失表达、野生型和过表达。p16 蛋白表达在 31%、57%和 12%的 CCA 以及 33%、53%和 14%的发育不良样本中分别显示阴性、异质性和阳性结果。NGS 显示 TP53 突变和 CDKN2A 缺失的肿瘤间和肿瘤内异质性很高。近 70%的 TP53 错义突变样本显示 p53 过表达，而所有 TP53 无义突变样本均显示 p53 蛋白表达缺失。