Primary Sclerosing Cholangitis-Associated Cholangiocarcinoma Demonstrates High Intertumor and Intratumor Heterogeneity
Clinical and Translational Gastroenterology , Volume 12 - Issue 10 p. e00410
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.
|Clinical and Translational Gastroenterology|
|Organisation||Erasmus MC: University Medical Center Rotterdam|
E.J.C.A. (Eline) Kamp, M.P. (Maikel) Peppelenbosch, M. (Michail) Doukas, Joanne Verheij, Cyriel Y. Ponsioen, R. (Ronald) van Marion, … A.C. (Annemarie) de Vries. (2021). Primary Sclerosing Cholangitis-Associated Cholangiocarcinoma Demonstrates High Intertumor and Intratumor Heterogeneity. Clinical and Translational Gastroenterology, 12(10). doi:10.14309/ctg.0000000000000410