Peculiar structure and location of 9p21 homozygous deletion breakpoints in human cancer cells.
The CDKN2A tumor-suppressor gene in chromosome band 9p21 encoding CDKN2A (also known as p16, INK4A), a negative regulator of cyclin-dependent kinases, and p14(ARF1), an activator of TP53, is inactivated in many human cancers by point mutations, promoter hypermethylation, or deletions. Homozygous deletions predominate in certain cancer types (e.g., bladder cancers). To understand why deletions are unusually prevalent at this locus, deletions in bladder and renal cancer cell lines were mapped in detail and several deletion breakpoints cloned. Deletions were interstitial and encompassed 0.1 to >30 Mb. Most deletion breakpoints were located in or close to LINE-1 retrotransposon clusters. Therefore, deletions of CDKN2A may be facilitated by the presence of LINE-1 clusters that flank the locus. All cloned junctions were products of non-homologous recombination and consistently contained exact 2-bp microhomologies. Microhomologies are otherwise hallmarks of DNA double-strand break repair by non-homologous end joining, but the consistent size found at the CDKN2A deletion junctions is difficult to reconcile with the known properties of this process. Therefore, an unknown mechanism appears to be involved in the generation of CDKN2A deletions during carcinogenesis.
Florl
Andrea R
AR
Urologische Klinik, Heinrich-Heine-Universität, Düsseldorf, Germany.
Schulz
Wolfgang A
WA
D001483:Base Sequence / Q000235:genetics; D019457:Chromosome Breakage / Q000235:genetics*; D002872:Chromosome Deletion; D002874:Chromosome Mapping / Q000379:methods*; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D004273:DNA, Neoplasm / Q000032:analysis / Q000737:chemistry*; D019942:Genes, p16; D006720:Homozygote; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D018895:Microsatellite Repeats / Q000235:genetics; D008969:Molecular Sequence Data; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology
D004273:DNA, Neoplasm