A deletion polymorphism due to alu-alu recombination in intron 2 of the retinoblastoma gene: Association with human gliomas

Abstract

The retinoblastoma gene (RB) encodes a tumor suppressor that is inactivated in a number of different types of cancer. We searched for gross alterations of this gene in tumors of the central nervous system by using Southern blot hybridization. A common alteration was found in several tumors and was mapped to the region around exon 2. Nucleotide sequencing showed that the alteration was caused by a 799-bp deletion in intron 2 of the RB gene and was probably due to homologous recombination between two Alu repeats. Deletions of this type have not been found previously in the RB gene. The deletion turned out to be a polymorphism with an allele frequency estimated at 2.2% in 185 patients without cancer. The deletion was found in five of 48 patients with brain tumors (allele frequency of 5.2%). This difference is not statistically significant (P = 0.149, Fisher's exact test). Confining the analysis only to glioma brain tumors revealed a statistically significant difference compared with the cancer-free patient controls (P = 0.027, Fisher's exact test). Further study is needed to determine if the deletion is a weak brain cancer-predisposing mutation or a harmless polymorphism. Finding this mutation in a tumor and the germline DNA of a retinoblastoma patient could lead to incorrect estimation of the heritability of a tumor.

DNA methylation in cancer: too much, but also too little

“…Of even higher copy number than the LINE-1 repeats in the human genome are the Alu repeats (size, *0.3 kb; copy number, 410 6 ), which also can be mobilized, thus leading occasionally to cancer-associated gene insertions (Rothberg et al, 1997;Schichman et al, 1994). These repeats constitute 410% of the genome.…”

More epigenetic hits than meets the eye: microRNAs and genes associated with the tumorigenesis of retinoblastoma

“…One case is a 799-bp deletion in the intron 2 of RB1 . It was identified in a group of brain tumors and probably emerges due to a homologous recombination between two Alu repeats (Rothberg et al, 1997). Figures 3C,D show LINE1 and ALU repeats distribution in the RB1 gene.…”

An alternative approach to medical genetics based on modern evolutionary biology. Part 4: HERVs in cancer

“…Fukuuchi and colleagues have reported an Alu-linked germline deletion of the MEN1 flanked by Alu sequences in a family where, again, the deletion would have been undetectable by conventional sequencing analysis. 70 Alu repeats have also been associated with familial colorectal cancer, 71,72 breast and ovarian cancer, 73,74 Ewing's sarcoma 75 and glioma, 76 meanwhile it seems likely that this list of associations will increase as the database grows.…”