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

Authors :
Annemarie C. de Vries
Winand N.M. Dinjens
Michail Doukas
Maikel P. Peppelenbosch
Eline J. C. A. Kamp
Cyriel Y. Ponsioen
Marco J. Bruno
Ronald van Marion
Bas Groot Koerkamp
Joanne Verheij
Gastroenterology & Hepatology
Pathology
Surgery
SmartPort@Erasmus
Gastroenterology and Hepatology
AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
Source :
Clinical and Translational Gastroenterology, Clinical and Translational Gastroenterology, 12(10). Nature Publishing Group, Clinical and translational gastroenterology, 12(10). Nature Publishing Group
Publication Year :
2021

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.

Details

Language :
English
ISSN :
2155384X
Volume :
12
Issue :
10
Database :
OpenAIRE
Journal :
Clinical and Translational Gastroenterology
Accession number :
edsair.doi.dedup.....3c92655807a66571f0bab30b98385e42