High-frequency Alu-mediated genomic recombination/deletion within the caspase-activated DNase gene in human hepatoma.
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.
Hsieh
Sen-Yung
SY
Liver Research Unit, Chang Gung Memorial Hospital, No 5, Fu-Hsin Road, Kwei-San, Tao-Yuan 333, Taiwan. siming@adm.cgmh.org.tw
Chen
Wai-Ying
WY
Yeh
Ta-Sen
TS
Sheen
I-Shyan
IS
Huang
Shiu-Feng
SF
D020087:Alu Elements; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D003851:Deoxyribonucleases / Q000235:genetics* / Q000378:metabolism; D005787:Gene Frequency; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D008969:Molecular Sequence Data; D011995:Recombination, Genetic; D017384:Sequence Deletion
D003851:Deoxyribonucleases; C109663:caspase-activated deoxyribonuclease