The Alu repetitive elements, which constitute 10% of human genome, may serve as bridges for genomic recombination. However, their roles in
tumorigenesis remain to be elucidated.
Caspase-activated DNase (CAD), whose gene (hCAD) is mapped at chromosome 1p36, a region frequently displaying hemizygote deletion in many human
cancers, is the key
enzyme for
nucleosome fragmentation during apoptosis. Recently, we detected many aberrant mRNAs for hCAD in many human
hepatoma cells. To elucidate the genetic basis leading to the
mRNA aberration, we used PCR-based chromosome walking to clone the corresponding genomic
DNA identifying a novel Alu/Alu homologous recombination/deletion within hCAD in HepG2 and Hep3B cells. We then detected similar recombination events in 13 out of the 20
hepatoma tissues and in eight of the para-cancerous cirrhotic livers. The recombination was inclined to occur in males (P=0.031) and had marginal association with high-grade
hepatoma (P=0.070) and
tumor recurrence (P=0.070). The recombination caused exon-3 deletion, which in turn led to exon-3 skipping or replacement with a partial Alu-sequence, and consequential C-truncation of CAD. Our findings of high frequency of Alu-mediated hCAD deletion in human
hepatoma not only underscore the implication of hCAD in hepatocarcinogenesis, but also highlight the potential roles of human repetitive sequences in mediating
genome instability in human
cancers.