Distinct patterns of alteration of myc genes associated with integration of human papillomavirus type 16 or type 45 DNA in two genital tumours

We previously described two genital carcinomas (IC2, IC4) containing human papillomavirus type 16 (HPV-16)- or HPV-18-related sequences integrated in chromosomal bands containing the c-myc (8q24) or N-myc (2p24) gene, respect ively. The c-myc gene was rearranged and amplified in IC2 cells without evi dence of overexpression. The N-myc gene was amplified and highly transcribe d in IC4 cells, Here, the sequence of an 8039 bp IC4 DNA fragment containin g the integrated viral sequences and the cellular junctions is reported. A 3948 bp segment of the genome of HPV-45 encompassing the upstream regulator y region and the E6 and E7 ORFs was integrated into the untranslated part o f N-myc exon 3, upstream of the N-myc polyadenylation signal. Both N-myc an d HPV-45 sequences were amplified 10- to 20-fold. The 3' ends of the major N-myc transcript were mapped upstream of the 5' junction. A minor N-myc/HPV -45 fusion transcript was also identified, as well as two abundant transcri pts from the HPV-45 E6-E7 region. Large amounts of N-myc protein were detec ted in IC4 cells. A major alteration of c-myc sequences in IC2 cells involv ed the insertion of a non-coding sequence into the second intron and their co-amplification with the third exon, without any evidence for the integrat ion of HPV-16 sequences within or close to the gene. Different patterns of myc gene alterations may thus be associated with integration of HPV DNA in genital tumours, including the activation of the protooncogene via a mechan ism of insertional mutagenesis and/or gene amplification.