Abstract
Lymph node metastases (LNM) are an important prognostic factor for patients with intrahepatic cholangiocarcinoma, but underlying genetic alterations are poorly understood. Whole genome array comparative genomic hybridization (aCGH) was performed in 37 tumors and 14 matched LNM. Genomic analyses of tumors confirmed known and identified new (gains in 19q) copy number alterations (CNA). Tumors with LNM (N1) had more alterations and exclusive gains (3p, 4q, 5p, 13q) and losses (17p and 20p). LNM shared most alterations with their matched tumors (86%), but 79% acquired new isolated gains [12q14 (36%); 1p13, 2p23, 7p22, 7q11, 11q12, 13q13 and 14q12 (>20%)]. Unsupervised clustering revealed a poor prognosis subclass with increased alterations significantly associated to tumor differentiation and survival. TP53 and KRAS mutations occurred in 19% of tumors and 6% of metastases. Pathway analyses revealed association to cancer-associated pathways. Advanced tumor stage, microvascular/perineural invasion, and microscopic positive resection margin (R1) were significantly correlated to metastases, while N1-status, R1-resection, and poor tumor differentiation were significantly correlated to survival. ACGH identified clear differences between N0 (no LNM) and N1 tumors, while N1 tumors and matched LNM displayed high clonality with exclusive gains in the metastases. A novel subclass with increased CNAs and poor tumor differentiation was significantly correlated to survival.
Highlights
Cholangiocarcinoma is the second most common liver malignancy worldwide and accounts for nearly 3% of all gastrointestinal cancers[1,2]
Lymph node metastases (LNM) have been identified as an important prognostic factor we aimed to analyze copy number alterations in primary tumors along with their matched LNM and together with important clinical factors
ACGH of all primary tumors confirmed known chromosomal aberrations for iCCA18, and detected frequent novel gains in 19q not previously described. 19q holds the growth factor TGFB1 and several genes involved in cancer associated pathways[19]
Summary
Cholangiocarcinoma is the second most common liver malignancy worldwide and accounts for nearly 3% of all gastrointestinal cancers[1,2]. Intrahepatic cholangiocarcinoma (iCCA) accounts only for 10% of all primary liver malignancies, its incidence and mortality rate is increasing worldwide[3,4]. Several studies recently performed comprehensive genetic analyses of primary iCCA, a clear understanding of how LNM develop and how advanced tumor stages could be treated is still not available. Analyses of grouped pairs of primary tumors and matched metastases have recently been used in pancreatic cancer and melanoma to assess the polyclonality and genetic heterogeneity, but are still not reported for intrahepatic cholangiocarcinomas[13,14,15]. The aim of our study was (1) to analyze copy number alterations in intrahepatic cholangiocarcinomas and their corresponding lymph node metastases and (2) to analyze and correlate clinical and histopathological factors
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