Molecular changes in hepatocellular dysplastic nodules on microdissected liver biopsies

The genetic profile of dysplastic hepatocellular nodules arising in cirrhos is is poorly understood. We assessed loss of heterozygosity (LOH) and micro satellite instability (MI) in 10 dysplastic nodules (4 low-grade and 6 high -grade) with surrounding cirrhosis and in 10 hepatocellular carcinomas (HCC ). Six microsatellite loci were selected and investigated on microdissected needle biopsies. Twenty-four (24.4%) informative loci showed allelic loss, while MI was seen in 3 loci only (3%). The most involved sites were locate d on chromosomes 4q (54.5%) and 8p (50%), LOH was documented in 16.6%, cirr hotic, 50% low-grade dysplastic nodules (LGDN), 83% high-grade dysplastic n odules (HGDN), and 70% malignant nodules. LOH at multiple loci was increasi ngly seen from cirrhotic to HGDN, but not from the latter to HCC. The fract ional allelic loss (FAL) was significantly increased in dysplastic and neop lastic nodules as compared with cirrhosis (P <.01). The progressive accumul ation of genetic changes in cirrhotic, dysplastic, and malignant hepatocell ular nodules is in keeping with a multistep process of carcinogenesis; with in this spectrum, HGDN can be considered advanced precursors of HCC.