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Oncogenomics Oncogene (2003) 22, 1892–1905 & 2003 Nature Publishing Group All rights reserved 0950-9232/03 $25.00 www.nature.com/onc Detailed characterization of a homozygously deleted region corresponding to a candidate tumor suppressor locus at distal 17p13.3 in human lung cancer Hiroyuki Konishi1, Miyabi Sugiyama1, Kotaro Mizuno1, Hiroko Saito1, Yasushi Yatabe2, Toshitada Takahashi3, Hirotaka Osada1 and Takashi Takahashi*,1 1Division of Molecular Oncology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-Ku, Nagoya 464-8681, Japan; 2Department of Anatomic and Molecular Diagnostic Pathology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-Ku, Nagoya 464-8681, Japan; 3Division of Immunology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-Ku, Nagoya 464-8681, Japan 17p13.3 is one of the chromosomal regions most function (Knudson, 1971). Allelic loss is therefore frequently affected by allelic loss in a variety of human considered to be a hallmark of chromosomal regions neoplasms including lung cancer. A number of loss of harboring tumor suppressor genes. Cytogenetic and heterozygosity (LOH) analyses have suggested the molecular analyses of lung cancers have revealed existence of a tumor suppressor gene at 17p13.3, distal frequent occurrence of multiple chromosomal deletions to the p53 locus at 17p13.1. In the present study, we including 3p, 5q, 8p, 9p, 11p, 13q, 17p, 18q and 22q characterized a homozygous deletion at 17p13.3 in a small (Minna et al., 1997). cell lung cancer cell line by constructing a bacterial It has been shown that 17p is among the most artificial chromosome (BAC) contig and a restriction map frequently affected chromosomal regions in lung cancer surrounding the region, as well as by utilizing publicly (Yokota et al., 1987). We and others have clearly available draft sequences. We defined the breakpoint, provided evidence indicating that the p53 gene at assigned and analysed two known genes, 14-3-3e and 17p13.1 is a genuine molecular target for the frequent CRK, and a novel gene LOST1 within or at the end of the 17p deletions in lung cancer (Takahashi et al., 1989, homozygous deletion of about 170 kb in size. Marked 1992). Interestingly, however, our detailed deletion reduction of LOST1 expression was detected in 69% (11/ mapping analysis of 17p with special reference to the 16) of lung cancer specimens by quantitative real-time p53 gene status revealed the presence of an independent, RT–PCR, while significant DNA hypermethylation was commonly deleted region(s)at 17p13.3, suggesting the observed at the 50 end of the LOST1 gene in four of six existence of an additional tumor suppressor gene(s) lung cancer cell lines with negligible LOST1 expression. distal to the p53 gene (Konishi et al., 1998). Frequent We also show here that a polymorphic marker D17S1174, allelic loss at 17p13.3 independent of the p53 locus has which resides within the homozygous deletion, was also been reported to be common in a variety of other apparently located in the middle of the minimum LOH human malignancies including breast, ovarian and region, providing further supportive evidence for the hepatocellular carcinomas as well as neural tumors presence of a tumor suppressor gene(s) in this region. (Coles et al., 1990; Fujimori et al., 1991; Biegel et al., Oncogene (2003) 22, 1892–1905. doi:10.1038/sj.onc.1206304 1992; Cogen et al., 1992; Saxena et al., 1992; Phillips et al., 1996; Schultz et al., 1996). Keywords: homozygous deletion; 17p13.3; tumor sup- Our subsequent search for a clue to the isolation of a pressor gene; lung cancer; LOST1 tumor suppressor gene from this region resulted in the identification of homozygous deletion of the 14-3-3e gene in two small cell lung cancer (SCLC)cell lines, ONCOGENOMICS Introduction which had been established from distinct metastatic sites of the same patient at different treatment periods Accumulating evidence suggests that a series of genetic (Konishi et al., 2002). Consistent with the notion that alterations such as activation of oncogenes and inactiva- the 14-3-3 family proteins play a role in imposing G2 tion of tumor suppressor genes are involved in the arrest in response to DNA damage through cdc2 pathogenesis of lung cancer (Minna et al., 1997). inactivation, we were able to show that introduction of According to Knudson’s two-hit theory, tumor sup- 14-3-3e into the lung cancer cell line with 14-3-3e pressor genes are inactivated by a recessive mutation in homozygous deletion significantly restored G2 check- one allele and loss of the other allele retaining wild-type point impairment. Together with prevalent perturbation of the G1 and M phase checkpoints in lung cancers *Correspondence: T Takahashi (Takahashi et al., 1989, 1999; Nomoto et al., 1999), the Received 9 September 2002; revised 4 December 2002; accepted 6 involvement of the 14-3-3e gene within the homozygous December 2002 deletions was of interest. However, the possibility that a Homozygous deletion at 17p13.3 in lung cancer H Konishi el al 1893 systematic, detailed investigation of the homozygously the databases. These two BACs widely overlapped each deleted region may yield an additional gene that plays a other, while 818O24 harbored the CRK gene as well as crucial role in the pathogenesis of lung cancer was not 14-3-3e. Further investigation of these BACs using precluded. public databases, however, showed uncertainty with In the present study, we constructed a bacterial regard to their chromosomal location, that is, the artificial chromosome (BAC)contig and a restriction assignment of these two BACs had been repeatedly map surrounding the homozygously deleted region, and changed through revisions to the public databases. defined the breakpoints. One novel and two known Although 14-3-3e and CRK had originally been assigned genes were found within the homozygous deletion and centromeric to ABR in 17p13.3, data from NCBI built analysed in detail. We also provide further supportive 28 mapped these BACs and genes at 17q21.32, whereas evidence for the presence of a tumor suppressor gene(s) according to NCBI built 29 they were located at close in this region as well as in a more centromeric region proximity to the distal end of 17p. A large physical map between D17S5 and D17S379. of 17p13.3 by McHale et al. (2000)spanned the frequent LOH region at 17p13.3 but did not contain 14-3-3e and CRK. To define precisely the genomic context surrounding Results the homozygous deletion, we constructed our own Construction and characterization of a contig covering the genomic contig covering the homozygous deletion. homozygous deletion at 17p13.3 Polymerase chain reaction (PCR)screening for yeast artificial chromosome (YAC)/BAC DNA pool libraries We previously screened 65 lung cancer cell lines with the were performed using three STS markers including 14-3- aid of nine markers mapped within the commonly 3e exon 1, CRK exon 3 and D17S1174, which yielded deleted region at 17p13.3, and found that a sequence- five YAC and three BAC clones mapped at the tagged site (STS)corresponding to the 14-3-3e gene was homozygously deleted region. The insert end sequences involved in a homozygously deleted region in two SCLC for each YAC/BAC clone were determined and utilized cell lines (Konishi et al., 2002). The two cell lines, ACC- to generate STS markers. All five YAC clones were LC-48 and ACC-LC-52, were originated from distinct apparently chimeric, but they were nevertheless useful to metastatic sites of the same patient at the different align BAC clones as shown in Figure 1a. BLAST search treatment periods, suggesting the occurrence of the for each marker on this contig revealed that 818O24 and homozygous deletion before metastasis in vivo.We 241L15, sources of the NCBI sequence information, initiated this study by carrying out the BLAST search were just next to the previously unconnected three against the National Center for Biotechnology Informa- BACs, that is, 407I21 (AF322450.1), RPCI-11-107N19 tion (NCBI)Nucleotide Sequence Databases using (AC006405.1)and RPCI-11-433M14 (AC068936.2) complementary DNA (cDNA)sequence of 14-3-3e. This (Figure 1a). These three BACs harbored MYO1C, in silico screening resulted in the identification of two SKIP, PITPN, SREC, RILP and PRP8, all of which BAC clones, RPCI-11-818O24 (818O24; AC032044.9) had consistently been assigned to 17p13.3. In addition, and RPCI-11-241L15 (241L15; AC025071.3)via the YAC/BAC end markers on our contig were surveyed by high throughput genomic sequences (HTGS)section of PCR using the Human Chromosome 17 Regional Figure 1 STS-based map of the homozygous deletion region at 17p13.3. (a)The STS markers used for mapping are shown at the top. YACs and BACs (closed boxes), identified by PCR screening as well as BACs (open boxes) whose draft sequences are available in the NCBI database as collections of unordered pieces, are indicated in relation to the STS markers. The extent of the homozygous deletion is shown at the bottom. The map is not drawn to scale. (b)Duplex PCR analysis showing no amplification of CRK exon 3 or D17S1174 despite robust amplification of p53 in ACC-LC-48 and ACC-LC-52 Oncogene Homozygous deletion at 17p13.3 in lung cancer H Konishi el al 1894 Mapping Panel, confirming their localization at 17p13.3 these predicted exons as probes yielded no cDNA (data not shown). clones. To further define the extent of the homozygous We also searched for UniGene clusters, which reside deletion, we carried out PCR examinations for all of on the BAC 818O24 draft sequence, using the NCBI the STS markers on our contig map using genomic MapViewer program. One of seven UniGene clusters on DNAs (gDNAs)from ACC-LC-48 and ACC-LC-52 as 818O24, Hs.
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