ALLELIC-EXPRESSION IMBALANCE OF THE INSULIN-LIKE GROWTH-FACTOR-2 GENEIN HEPATOCELLULAR CARCINOMAS AND UNDERLYING DISEASE

It has been well documented that the liver is an exceptional organ in which the monoallelic expression of insulin-like growth factor 2 (IGF2 ) due to genomic imprinting is relaxed during the postnatal period, re sulting in biallelic expression thereafter. In the present study, chan ges in the status of genomic imprinting were examined in 15 hepatocell ular carcinomas (HCCs) as well as in 29 liver biopsies of chronic hepa titis or liver cirrhosis without clinical evidence of HCC, following s creening for heterozygotes with an ApaI polymorphism in IGF2 in 34 HCC s and 80 such non-HCC cases. Extreme allelic-expression imbalance, lea ding to restoration of monoallelic IGF2 expression, was observed in 15 (100%) of 15 informative HCCs for the polymorphism with this monoalle lic IGF2 expression appearing to be non-random from the paternal allel e. Interestingly, the same allelic-expression imbalance was also prese nt in a significant fraction of noncancerous liver specimens of patien ts with underlying disease known to be associated with HCC development . In contrast, the status of genomic imprinting of H19, another gene c losely mapped at 11p15 under opposite imprinting, was strictly maintai ned in seven (100%) of seven cases informative for an RsaI polymorphis m of H19. Together with the previous reports on altered genomic imprin ting of IGF2 and H19 in embryonal lesions such as Wilms tumors as well as in lung cancers, the results suggest that perturbations of imprint ing status occur as locus and tumor-type specific events in the develo pment of human cancers.