TY - JOUR
T1 - Genetic alterations during the neoplastic cascade towards cholangiocarcinoma in primary sclerosing cholangitis
AU - Kamp, Eline J. CA
AU - Dinjens, Winand N. M.
AU - Doukas, Michail
AU - van Marion, Ronald
AU - Verheij, Joanne
AU - Ponsioen, Cyriel Y.
AU - Bruno, Marco J.
AU - Groot Koerkamp, Bas
AU - Trivedi, Palak J.
AU - Peppelenbosch, Maikel P.
AU - de Vries, Annemarie C.
N1 - Funding Information: Conflict of interest statement: CYP has served as a speaker for Takeda, Tillotts and Roche. He has served as advisor for Takeda, Pliant, and Shire. He has received grant support from Takeda. Publisher Copyright: © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
PY - 2022/11
Y1 - 2022/11
N2 - 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.
AB - 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.
KW - Bile Duct Neoplasms/pathology
KW - Bile Ducts, Intrahepatic/pathology
KW - Cholangiocarcinoma/pathology
KW - Cholangitis, Sclerosing/genetics
KW - Class I Phosphatidylinositol 3-Kinases/genetics
KW - DNA Copy Number Variations
KW - ErbB Receptors/genetics
KW - Humans
KW - In Situ Hybridization, Fluorescence
KW - Mutation
KW - Myeloid Cell Leukemia Sequence 1 Protein/genetics
KW - Proto-Oncogene Proteins p21(ras)/genetics
KW - fluorescence in situ hybridization
KW - genomic imbalance
KW - molecular diagnostics
UR - http://www.scopus.com/inward/record.url?scp=85137566106&partnerID=8YFLogxK
U2 - 10.1002/path.5994
DO - 10.1002/path.5994
M3 - Article
C2 - 35897137
SN - 0022-3417
VL - 258
SP - 227
EP - 235
JO - Journal of pathology
JF - Journal of pathology
IS - 3
ER -