Association ofCDKN2A (p16)/CDKN2B (p15) alterations and homozygous chromosome arm 9p deletions in human lung carcinoma

Hamada, Kunihiro; Kohno, Takashi; Kawanishi, Masashi; Ohwada, Susumu; Yokota, Jun

doi:10.1002/(sici)1098-2264(199807)22:3<232::aid-gcc9>3.0.co;2-x

Cited by 51 publications

(48 citation statements)

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“…At present, the molecular mechanisms for the di erential SEZ6L expression in lung cancer cells are unclear. Loss or reduction of SEZ6L expression could be caused by epigenetic changes, such as hypermethylation of the CpG island, as in the cases of the VHL and p16 genes (Herman et al, 1994;Merlo et al, 1995;Hamada et al, 1998), or genetic alterations in the promoter region and intron sequences. We preliminarily examined the e ect of 5-aza-2' deoxycytidine on SEZ6L expression in lung cancer cell lines without SEZ6L expression, however, re-expression of the SEZ6L gene was not observed in these cell lines (data not shown).…”

Section: Discussionmentioning

confidence: 97%

“…The 14 SCLC cell lines were NCI-H69, NCI-H82, NCI-H209, NCI-H526, NCI-H774, NCI-H841, N417, RERF-LCMA, Lu24, Lu134, Lu135, Lu139, SBC-5, and MS18, while the 32 NSCLCs consisted of 20 adenocarcinomas (A427, A549, PC3, PC7, PC9, PC14, RERF-LCOK, VMRC-LCD, ABC1, LCMS, NCI-H23, NCI-H322, NCI-H441, Ma1, Ma10, MA12, Ma17, Ma24, Ma26 and Ma29), ®ve squamous cell carcinomas (PC10, LC1-Sq, EBC1, NCI-H157 and NCI-H520), six large cell carcinomas (PC13, Lu99, Lu65, NCI-H1155, Ma2 and Ma25), one adenosquamous cell carcinoma (NCI-H596) (Hamada et al, 1998). Forty-six surgical specimens (16 SCLCs and 30 NSCLCs) of lung tumors and adjacent noncancerous tissues were obtained from patients with NSCLC and SCLC who were treated at the National Cancer Center Hospital, Tokyo.…”

Section: Samplesmentioning

confidence: 99%

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Identification of a 428-kb homozygously deleted region disrupting the SEZ6L gene at 22q12.1 in a lung cancer cell line

Nishioka

Kohno²,

Takahashi³

et al. 2000

Oncogene

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Frequent allelic losses on chromosome 22q in small cell lung carcinomas (SCLCs) and advanced non-small cell lung carcinomas indicate the presence of tumor suppressor gene(s) on this chromosome arm. We detected a homozygous deletion at 22q12.1 in a SCLC cell line, Lu24. Cloning of the breakpoints of the Lu24 deletion revealed that the deletion was interstitial and 428, 131 bp in size. The deleted region contained the SEZ6L (Seizure 6-like) gene, whose structure had been partially determined by the chromosome 22 sequencing project. We determined the full length cDNA sequence for the SEZ6L gene based on the genomic sequence for the SEZ6L locus using the GENSCAN program and the RT ± PCR method. The deduced SEZ6L protein was a transmembrane protein of 1024 amino acids with multiple domains involved in protein ± protein interaction and signal transduction. SEZ6L expression was detected in a variety of human tissues, including lung, while its expression was detected in 14 (30%) of 46 lung cancer cell lines examined. Missense mutations were detected in three (7%) of the 46 cell lines, and a 1 bp deletion in the polypyrimidine tract preceding exon 4 was detected in one (2%) of 46 primary lung cancers. Therefore, it is possible that genetic and/or epigenetic SEZ6L alterations are involved in the development and/or progression in a subset of lung cancer, although functional analysis of the SEZ6L gene as well as molecular analysis of other genes in the homozygously deleted region is necessary to understand the pathogenetic signi®cance of 22q deletions in human lung carcinogenesis. Oncogene (2000) 19, 6251 ± 6260.

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Section: Discussionmentioning

confidence: 97%

Section: Samplesmentioning

confidence: 99%

Identification of a 428-kb homozygously deleted region disrupting the SEZ6L gene at 22q12.1 in a lung cancer cell line

Nishioka

Kohno²,

Takahashi³

et al. 2000

Oncogene

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“…Keywords: 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).…”

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confidence: 99%

“…All these cell lines have been shown to have homozygous 9p21 deletions (Kamb et al, 1994;Nobori et al, 1994;Tanaka et al, 1997;Hamada et al, 1998Hamada et al, , 2000Kohno, unpublished data) (Table 1). Lung cancers were analysed because they show frequent 9p21 deletions (Hamada et al, 1998(Hamada et al, , 2000Park et al, 2002). In addition, it has been suggested that chromosome deletions were largely triggered by exogenous factors such as tobacco carcinogens (Wistuba et al, 1997;Sanchez-Cespedes et al, 2001).…”

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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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Expression of p16 and lack of pRB in primary small cell lung cancer

Yuan

Knorr²,

Altmannsberger

et al. 1999

J. Pathol.

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The retinoblastoma protein (pRB), p16, and cyclin D1 are major components of the RB pathway, which controls the G1 checkpoint of the cell cycle. Proper regulation of this pathway is crucial for normal cell proliferation. Abnormal forms of these proteins have been found in various types of malignant tumours. In the present report, immunohistochemical techniques were applied to study the expression of pRB, p16, and cyclin D1 in 161 samples of primary small cell lung cancer (SCLC) and 20 samples of non‐small cell lung cancer (NSCLC). While pRB and cyclin D1 staining was negative in 161 specimens of SCLC, expression of p16 was observed in 153 samples. In contrast to SCLC, 16 out of 20 NSCLC cases exhibited pRB expression and 15 showed cyclin D1 expression, but only very weak p16 staining was found in five samples. These observations could provide additional criteria for the distinction between SCLC and NSCLC. Furthermore, these findings, based on primary tissues, implicate different mechanisms in the tumourigenesis of SCLC and NSCLC. Copyright © 1999 John Wiley & Sons, Ltd.

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Association ofCDKN2A (p16)/CDKN2B (p15) alterations and homozygous chromosome arm 9p deletions in human lung carcinoma

Cited by 51 publications

References 17 publications

Identification of a 428-kb homozygously deleted region disrupting the SEZ6L gene at 22q12.1 in a lung cancer cell line

Identification of a 428-kb homozygously deleted region disrupting the SEZ6L gene at 22q12.1 in a lung cancer cell line

Molecular processes of chromosome 9p21 deletions in human cancers

Expression of p16 and lack of pRB in primary small cell lung cancer

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