HIGH-INCIDENCE OF LOSS OF HETEROZYGOSITY AND ABNORMAL IMPRINTING OF H19 AND IGF2 GENES IN INVASIVE CERVICAL CARCINOMAS - UNCOUPLING OF H19 AND IGF2 EXPRESSION AND BIALLELIC HYPOMETHYLATION OF H19

The few imprinted genes characterized so far include the insulin-like growth factor-2 gene (IGF2) coding for a foetal growth factor and the H19 gene whose normal function is unknown but which is likely to act a s an RNA with an antitumour effect, IGF2 is expressed by the paternal allele and H19 by the maternal allele. This reciprocal expression is q uite interesting because both H19 and IGF2 genes are located close to each other on chromosome 11p15.5 in a region subject to loss of hetero zygosity (LOH), Moreover, loss of imprinting (LOI) or biallelic expres sion has been proposed as an epigenetic mechanism for tumorigenesis in a variety of human cancers including Wilms' tumour, In this study we report the LOH, LOI and methylation status of H19 and IGF2 genes in 29 invasive cervical carcinomas of different clinical stages, Fourteen ( 48%) and 13 (45%) tumours were heterozygous for H19 and IGF2 respectiv ely, LOH for H19 and IGF2 genes were found in 2 of 14 (14%) and 3 of 1 3 (23%) informative tumours, respectively, LOI of H19 and IGF2 was det ected in 2 of 12 (17%) and 5 of 10 (50%) tumours with no LOH, respecti vely, More interestingly, monoallelic expression of the otherwise sile nt H19 allele (allele switch) was observed in 2 of 12 (17%) tumours an d biallelic expression of IGF2 was detected in one specimen of normal cervix adjacent to the tumour, The expressing H19 allele, and to a low er degree also the silent allele, were hypomethylated in tumours sugge sting that demethylation of both H19 alleles may be associated with an early step of imprinting alteration. In cervical cancer H19 and IGF2 expressions could be independently regulated, In conclusion, our data suggest that H19 and IGF2 genes, via deletions and/or abnormal imprint ing, could play a crucial role in a large proportion (58%) of cervical cancers where they may be associated with disease progression.