Breakpoint junctions of chromosome 9p deletions in two human glioma cell lines.

Pomykala, Helen; Bohlander, SK; Broeker, P L; Olopade, Olufunmilayo I.; Dı́az, Manuel O.

doi:10.1128/mcb.14.11.7604

Cited by 33 publications

(35 citation statements)

References 33 publications

(48 reference statements)

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“…To date, to the best of our knowledge, 15 solid tumor cases or cell lines carrying homozygous deletions have been sequenced and reported (Canning and Dryja, 1989;Tadokoro et al, 1992;Murata et al, 1994;Pomykala et al, 1994;Kohno et al, 1996;Inoue et al, 1997;Sekido et al, 1998;Nishioka et al, 2000;Shigemitsu et al, 2001;Tamura et al, 2002). As a result, short direct repeats were found at the breakpoints in seven cases, while repetitive sequences such as long interspersed nuclear elements (LINEs) and Alu sequences appeared to be involved in five cases.…”

Section: Discussionmentioning

confidence: 99%

Detailed characterization of a homozygously deleted region corresponding to a candidate tumor suppressor locus at distal 17p13.3 in human lung cancer

et al. 2003

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17p13.3 is one of the chromosomal regions most frequently affected by allelic loss in a variety of human neoplasms including lung cancer. A number of loss of heterozygosity (LOH) analyses have suggested the existence of a tumor suppressor gene at 17p13.3, distal to the p53 locus at 17p13.1. In the present study, we characterized a homozygous deletion at 17p13.3 in a small cell lung cancer cell line by constructing a bacterial artificial chromosome (BAC) contig and a restriction map surrounding the region, as well as by utilizing publicly available draft sequences. We defined the breakpoint, assigned and analysed two known genes, 14-3-3e and CRK, and a novel gene LOST1 within or at the end of the homozygous deletion of about 170 kb in size. Marked reduction of LOST1 expression was detected in 69% (11/ 16) of lung cancer specimens by quantitative real-time RT-PCR, while significant DNA hypermethylation was observed at the 5 0 end of the LOST1 gene in four of six lung cancer cell lines with negligible LOST1 expression. We also show here that a polymorphic marker D17S1174, which resides within the homozygous deletion, was apparently located in the middle of the minimum LOH region, providing further supportive evidence for the presence of a tumor suppressor gene(s) in this region.

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Section: Discussionmentioning

confidence: 99%

Detailed characterization of a homozygously deleted region corresponding to a candidate tumor suppressor locus at distal 17p13.3 in human lung cancer

et al. 2003

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“…Retrotransposition of LINE-1 sequences results in a highly unstable branched DNA structure prone to undergoing recombination with accessible elements located nearby or even elsewhere in the genome (Feng et al, 1996). Chromosome deletions and translocations probably caused by retrotransposition events have indeed been observed in several human cancers (Morse et al, 1988;Nagarajan et al, 1990;Miki et al, 1992;Pomykala et al, 1994;Liu et al, 1997). The decrease in promoter methylation in urothelial tumour cells and the occurrence of full-length LINE-1 transcripts in two bladder carcinoma cell lines with hypomethylated DNA (Figure 6) raises the possibility of retrotransposition occurring in urothelial carcinoma.…”

Section: Discussionmentioning

confidence: 99%

“…Disruption of genes by insertion of LINE-1 elements has been found in human cancer and genetic disease (Morse et al, 1988;Miki et al, 1992;Dombroski et al, 1993;Holmes et al, 1994). In addition, DNA methylation and expression of LINE-1 and HERV-K provirus sequences in urothelial and renal cell carcinomas LINE-1 sequences have been identified at or near chromosomal translocation sites (Nagarajan et al, 1990;Pomykala et al, 1994;Liu et al, 1997). Presumably to prevent such accidents, most elements are highly methylated in normal adult tissues (Alves et al, 1996;Jürgens et al, 1996;Woodcock et al, 1997).…”

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DNA methylation and expression of LINE-1 and HERV-K provirus sequences in urothelial and renal cell carcinomas

et al. 1999

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Summary Since DNA methylation is considered an important mechanism for silencing of retroelements in the mammalian genome, hypomethylation in human tumours may lead to their reactivation. The methylation status of LINE-1 retroposons was determined in 73 samples of urinary bladder cancers, 34 specimens of renal cell carcinoma and in the corresponding normal tissues by Southern blot analysis. LINE-1 sequences were strongly methylated in normal tissues and were significantly hypomethylated in 69 (95%) urothelial carcinomas, but in none of the renal carcinomas. Hypomethylation in bladder cancers was independent of stage and tended to increase with grade. The methylation status of HERV-K proviral DNA in normal and transformed urothelial cells paralleled that of LINE-1 sequences (r 2 = 0.87). It was shown by ligation-mediated polymerase chain reaction that hypomethylation also extended to the LINE-1 promoter sequence located at the 5′-ends of full-length elements which is repressed by methylation in somatic tissues. Accordingly, full-length LINE-1 transcripts were detected by Northern blot analysis in two urothelial carcinoma cell lines. In contrast, transcripts from HERV-K proviruses were restricted to teratocarcinoma cell lines. Our data indicate that genome-wide DNA hypomethylation is an early change in urothelial carcinoma, but is absent from renal cell carcinoma. The coordinate changes of LINE-1 and HERV-K DNA methylation suggest that hypomethylation in urothelial cancer affects a variety of different retroelements to similar extents. We speculate that decreased methylation of LINE-1 retroelements, in particular, may contribute to genomic instability in specific human tumours such as urothelial carcinoma by rendering these normally repressed sequences competent for transcription and recombination.

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“…To our knowledge, there is only one report focusing on the structure of breakpoints for 9p21 deletions in nonlymphocytic malignancies (Pomykala et al, 1994). Pomykala et al characterized breakpoints for the interstitial deletions removing the interferon gene cluster, which are located approximately 400 kb distal to the CDKN2A locus, in two cases of glioma.…”

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Molecular processes of chromosome 9p21 deletions in human cancers

Sasaki¹,

Kitagawa

Sekido

et al. 2003

Oncogene

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Interstitial deletions of the chromosome 9p21 segment encoding the p16/CDKN2A tumor suppressor gene (i.e., 9p21 deletions) are frequently observed in a variety of human cancers. A majority of these deletions in lymphoid leukemia have been indicated to be mediated by illegitimate V(D)J recombination. In the present study, to elucidate the molecular processes of 9p21 deletions in nonlymphocytic malignancies, breakpoints for these deletions were analysed in 21 lung cancer cell lines and 32 nonlymphocytic cancer cell lines of nine other histological types. In all, 32 breakpoints in 21 lung cancer cell lines and 56 breakpoints in 32 nonlung cancer cell lines were mapped in a 450-kb segment encompassing the CDKN2A locus with a 10-kb resolution. The largest number of breakpoints (i.e., seven breakpoints in lung cancer and 12 breakpoints in nonlung cancers) was mapped in a 10-kb region containing the CDKN2A gene. More precise mapping of these seven and 12 breakpoints revealed that none of these breakpoints were located within 50-bp intervals to each other in this 10 kb region. Cloning and sequencing of breakpoints in 18 representative cell lines (six lung and 12 nonlung cancers) further revealed that there were no significant homologies among breakpoints in these 18 cell lines. In 11 (61%) cell lines, 1-5-bp nucleotides were overlapped at breakpoint junctions. These results indicate that DNA double-strand breaks triggering 9p21 deletions do not occur at specific DNA sequences, although they preferentially occur in or near the CDKN2A locus. It was also indicated that two broken DNA ends are rejoined by nonhomologous end-joining repair, preferentially utilizing microhomologies of DNA ends, in the occurrence of 9p21 deletions. Oncogene (2003) 22, 3792-3798. doi:10.1038/sj.onc.1206589Keywords: 9p21 deletion; p16/CDKN2A; lung cancer; DNA double-strand break; nonhomologous end joining Chromosome 9p deletions frequently occur in a variety of human cancers including lymphoid leukemia, lung cancer, esophageal cancer, glioma and melanoma, and the 9p21 segment including the p16/CDKN2A, p14/ARF and p15/CDKN2B loci has been defined as a common region for the deletions (Kamb et al., 1994;Nobori et al., 1994;Ohnishi et al., 1995;Tanaka et al., 1997;Drexler, 1998;Hamada et al., 1998Hamada et al., , 2000Park et al., 2002). The CDKN2A tumor suppressor gene and two other related genes, ARF and CDKN2B, encode critical regulators of cell cycle and/or apoptosis (Sherr, 2000). Thus, deletion of the 9p21 segment is a causative generic alteration inactivating the CDKN2A, ARF and/or CDKN2B genes, and is thought to play an important role in the development and/or progression of human cancers. Elucidation of the mechanism(s) for the deletions of the 9p21 segment is, therefore, indispensable in understanding the molecular pathways of multistage human carcinogenesis.Structural analyses of breakpoints for interstitial deletions of the 9p21 segment (i.e., 9p21 deletions) have been performed in lymphoid leukemia to predict the molecular processes of th...

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Breakpoint junctions of chromosome 9p deletions in two human glioma cell lines.

Cited by 33 publications

References 33 publications

Detailed characterization of a homozygously deleted region corresponding to a candidate tumor suppressor locus at distal 17p13.3 in human lung cancer

Detailed characterization of a homozygously deleted region corresponding to a candidate tumor suppressor locus at distal 17p13.3 in human lung cancer

DNA methylation and expression of LINE-1 and HERV-K provirus sequences in urothelial and renal cell carcinomas

Molecular processes of chromosome 9p21 deletions in human cancers

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