Clonal Origin of Multifocal Hepatocellular Carcinoma
KB Hodges, OW Cummings, R Saxena, M Wang, S Zhang, A Lopez-Beltran, R Montironi, H Nour, L Cheng. Indiana University School of Medicine, Indianapolis, IN; Cordoba University, Cordoba, Spain; Polytechnic University of the Marche Region (Ancona), United Hospitals, Ancona, Italy
Background: Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver. Patients frequently have multiple histologically similar, but anatomically separate tumors. The clonal origin of multiple hepatocellular carcinomas is uncertain.
Design: We analyzed 31 tumors from 12 different patients (11 female, 1 male), who had multiple hepatocellular carcinomas involving one or both lobes. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissue using laser capture microdissection. DNA was analyzed for: loss of heterozygosity (LOH) using four highly polymorphic microsatellite loci including 9p21 (D9S161), 11q13 (D11S970), 9p21 (IFNA, D9S171), and 17p13.1 (TP53); X-chromosome inactivation status; and, TP53 gene mutations in exons 5, 7 and 8.
Results: All patients had synchronous tumors. Chronic liver disease was present in 10/12 (83%) patients, and 6 (60%) of these patients had cirrhosis. HCV infection was the main cause of chronic liver disease. All of the separate tumors from an individual patient had similar histology and grade. Ten of the 12 (83%) cases had vascular invasion. Pathologic stages were as follows: pT2 in 2 cases (16%), pT3 in 5 cases (42%), and pT4 in 5 (42%) cases. Ten of the 11 (91%) informative cases showed LOH at one or more of the analyzed microsatellite markers. Eight of the 10 (80%) cases demonstrated identical allelic loss patterns indicating common clonal origin. The remaining two (20%) informative cases had discordant patterns indicating independent clonal origin. Nine of the 10 (90%) informative female patients demonstrated a concordant pattern of non-random X-chromosome inactivation. The remaining case demonstrated a discordant non-random pattern of X-chromosome inactivation suggesting independent clonal origin. TP53 mutations were identified in 8 of 12 (67%) patients. Tumors in 7 of these 8 (88%) patients showed different point mutations. Normal tissue did not harbor any TP53 mutations in these exons.
Conclusions: In summary, our findings suggest that the majority of patients with multifocal hepatocellular carcinomas have common clonal origin. A better understanding of the genetic relationships between multiple tumors may be clinically important in assessing prognosis, and selecting therapeutic options in these patients.
Category: Liver & Pancreas
Tuesday, March 23, 2010 9:30 AM
Poster Session III # 228, Tuesday Morning