Genetic alterations during the neoplastic cascade towards cholangiocarcinoma in primary sclerosing cholangitis. Issue 3 (6th September 2022)

• Record Type: Journal Article
• Authors: Kamp, Eline JCA; Dinjens, Winand NM; Doukas, Michail; van Marion, Ronald; Verheij, Joanne; Ponsioen, Cyriel Y; Bruno, Marco J; Groot Koerkamp, Bas; Trivedi, Palak J; Peppelenbosch, Maikel P; de Vries, Annemarie C
• Is Part Of: Journal of pathology. Volume 258:Issue 3(2022)
• Page Start: 227
• Page End: 235
• Publication Date: 2022-09-06
• Subjects: genomic imbalance -- molecular diagnostics -- mutation -- fluorescence in situ hybridization; Pathology -- Periodicals; 616.07
• DOI: 10.1002/path.5994
• Languages: English
• ISSNs: 0022-3417

Abstract

Abstract: Carcinogenesis of primary sclerosing cholangitis (PSC)‐associated cholangiocarcinoma (CCA) is largely unexplored. Improved understanding of the molecular events involved may guide development of novel avenues for rational clinical management. We aimed to assess the genetic alterations during progression of the neoplastic cascade from biliary dysplasia towards CCA in PSC. Forty‐four resection specimens or biopsies of PSC patients with biliary dysplasia ( n = 2) and/or CCA ( n = 42) were included. DNA was extracted from sections of formalin‐fixed paraffin‐embedded tissue blocks with dysplasia ( n = 23), CCA ( n = 69), and nonneoplastic tissue ( n = 28). A custom‐made next‐generation sequencing (NGS) panel of 28 genes was used for mutation and copy number variation (CNV) detection. In addition, CNVs of CDKN2A, EGFR, MCL1, and MYC were examined by fluorescence in situ hybridization. Alterations in 16 low‐grade dysplasia samples included loss of FGFR1 (19%), CDKN2A (13%), and SMAD4 (6%), amplification of FGFR3 (6%), EGFR (6%), and ERBB2 (6%), and mutations in SMAD4 (13%). High‐grade dysplasia ( n = 7) is characterized by MYC amplification (43%), and mutations in ERBB2 (71%) and TP53 (86%). TP53 mutations are the most common aberrations in PSC‐CCA (30%), whereas mutations in KRAS (16%), GNAS (14%), and PIK3CA (9%) are also common. In conclusion, PSC‐CCA exhibits a variety of genetic alterations during progression of the neoplastic cascade, with mainly CNVs being present early, whereas mutations in ERBB2, TP53, and KRAS appear later in the development of CCA. These findings are promising for the development of NGS‐guided diagnostic strategies in PSC‐CCA. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.