Exome analysis of the evolutionary path of hepatocellular adenoma-carcinoma transition, vascular invasion and brain dissemination.
Hepatocellular adenoma (HCA) is a rare benign liver tumor, predominantly seen in young women. Its major complications are malignant transformation, spontaneous hemorrhage, and rupture. We describe a case of a young female with no underlying liver disease who presented with acute abdominal pain and was found to have a 17cm heterogeneous mass in the left lobe of the liver. She underwent left hepatectomy and pathology revealed a 14cm moderately differentiated hepatocellular carcinoma (HCC) arising in a shell of a HCA. At that time, vascular invasion was already present. She rapidly developed recurrent multifocal hepatic lesions and subsequent spread to the brain, leading to her death 18months after surgery. To investigate the underlying genetic events occurring during hepatocellular adenoma-carcinoma transition and extra-hepatic dissemination, we performed whole exome sequencing of DNA isolated from peripheral blood leucocytes, HCA, HCC, tumor thrombus and brain metastasis. Our data show a step-wise addition of somatic mutations and copy number variations with disease progression, suggesting a linear tumor evolution, which is supported by clonality analysis. Specifically, using a model based clustering of somatic mutations, one single founding clone arising in the HCA, which included catenin beta 1 (CTNNB1) and IL6ST driver mutations, was identified and displayed an increasing clonality rate in HCC, tumor thrombus and brain metastasis. Our data highlight the feasibility of performing whole exome capture, sequencing and analysis using formalin-fixed paraffin-embedded (FFPE) samples, and we describe the first genomic longitudinal study of hepatocellular adenoma-carcinoma transition, vascular invasion and brain metastasis with detailed clinicopathologic annotation.
Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA; Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA. Electronic address: silvia.vilarinho@yale.edu.
Sílvia
S
Vilarinho
Department of Neurosurgery, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA.
E Zeynep
EZ
Erson-Omay
Department of Pathology, Greenwich Hospital, Greenwich, CT, USA.
Kisha
K
Mitchell-Richards
Department of Surgery, Yale School of Medicine, New Haven, CT, USA; VA Connecticut Healthcare System, West Haven, CT, USA.
Charles
C
Cha
Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA.
Carol
C
Nelson-Williams
Department of Neurosurgery, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA.
Akdes Serin
AS
Harmancı
Department of Neurosurgery, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA.
Katsuhito
K
Yasuno
Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA; Department of Neurosurgery, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA.
Murat
M
Günel
Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA; VA Connecticut Healthcare System, West Haven, CT, USA.
Tamar H
TH
Taddei
D000236:Adenoma / Q000473:pathology*; D000328:Adult; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D056915:DNA Copy Number Variations; D059472:Exome; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D009154:Mutation; D009361:Neoplasm Invasiveness
Brain metastasis; FFPE tissue molecular analysis; Hepatocellular adenoma; Hepatocellular adenoma-carcinoma transition; Hepatocellular carcinoma; Whole exome sequencing