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Physical and Transcript Map of the Region Between D6S264 and D6S149 on Chromosome 6Q27, the Minimal Region of Allele Loss in Sporadic Epithelial Ovarian Cancer

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Physical and Transcript Map of the Region Between D6S264 and D6S149 on Chromosome 6Q27, the Minimal Region of Allele Loss in Sporadic Epithelial Ovarian Cancer Oncogene (2002) 21, 387 ± 399 ã 2002 Nature Publishing Group All rights reserved 0950 ± 9232/02 $25.00 www.nature.com/onc Physical and transcript map of the region between D6S264 and D6S149 on chromosome 6q27, the minimal region of allele loss in sporadic epithelial ovarian cancer Ying Liu1, Gracy Emilion1, Andrew J Mungall2, Ian Dunham2, Stephan Beck2, Valerie G Le Meuth-Metzinger3, Andrew N Shelling4, Francis ML Charnock2 and Trivadi S Ganesan*,1 1ICRF Molecular Oncology Laboratories, John Radclie Hospital, Headington, Oxford, OX3 9DS, UK; 2Sanger Centre, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK; 3INRA-UMR Genetique Animale, 65 Rue de Saint Brieuc, 35042 Rennes CEDEX, France; 4Research Centre in Reproductive Medicine, Department of Obstetrics and Gynaecology, National Women's Hospital, Auckland, New Zealand We have previously shown a high frequency of allele loss chromosomal arm 6q initially de®ned the minimal region at D6S193 (62%) on chromosomal arm 6q27 in ovarian of allele loss between D6S149 and D6S193 (1.9 cM) in tumours and mapped the minimal region of allele loss one tumour (Figure 1) (Saito et al., 1992, 1996). between D6S297 and D6S264 (3 cM). We isolated and Subsequent studies have shown increased frequency of mapped a single non-chimaeric YAC (17IA12, 260 ± allele loss on 6q around the same region, although a 280 kb) containing D6S193 and D6S297. A further minimal region was not de®ned (Orphanos et al., 1995; extended bacterial contig (between D6S264 and D6S149) Wan et al., 1994). Based on the analysis of 56 malignant has been established using PACs and BACs and a ovarian tumours we showed previously that the minimal transcript map has been established. We have mapped region of allele loss on 6q27 is between D6S297 and six new markers to the YAC; three of them are ESTs D6S264 (3 cM) (Figure 1) (Chenevix-Trench et al., 1997; (WI-15078, WI-8751, and TCP10). We have isolated Cooke et al., 1996b). The allele loss was observed in all three cDNA clones of EST WI-15078 and one clone types of epithelial ovarian cancer. The maximal contains a complete open reading frame. The sequence frequency of allele loss occurred at D6S193 (62%) and shows homology to a new member of the ribonuclease D6S297 (52%). Three tumours showed loss of D6S193 family. The other two clones are splice variants of this only, while retaining ¯anking markers thus suggesting new gene. The gene is expressed ubiquitously in normal that the putative tumour suppressor gene was close to tissues. It is expressed in 4/8 ovarian cancer cell lines by D6S193. Thus the extended region of allele loss taking Northern analysis. The gene encodes for a 40 kDa the two previous studies into account suggests that the protein. Direct sequencing of the gene in all the eight putative gene lies within D6S264 ± D6S149 (approxi- ovarian cancer cell lines did not identify any mutations. mately 7.4 cM). Clonogenic assays were performed by transfecting the Further evidence that there might be a putative full-length gene in to ovarian cancer cell lines and no tumour suppressor gene around D6S193 is provided by suppression of growth was observed. FISH studies using YACs on direct metaphase spreads Oncogene (2002) 21, 387 ± 399 DOI: 10.1038/sj/onc/ from fresh ovarian tumours which suggested that this 1205067 change might be important even in early ovarian tumours (Tibiletti et al., 1996, 1998). It has also been Keywords: ovarian cancer chromosome 6q27 shown that the same region is implicated in a subset of lymphomas and breast cancer (Gaidano et al., 1992; Menasce et al., 1994; Rodriguez et al., 2000; Tibiletti et al., 2000). Introduction To identify the gene on chromosomal band 6q27 implicated in the pathogenesis of ovarian cancer, we Chromosome 6 has been implicated to contain a putative undertook a positional cloning approach involving tumour suppressor gene important in the pathogenesis of isolation of yeast arti®cial chromosomes (YACs), P1 ovarian cancer, both by karyotypic analysis and allele derived arti®cial chromosomes (PACs), bacterial arti- loss studies (Shelling et al., 1995). The analysis of 70 ®cial chromosomes (BACs) and construction of a malignant ovarian tumours using cosmids mapping to physical and transcript map around the key poly- morphic markers. We have identi®ed seven genes in the interval between D6S264 and D6S149. We present the detailed analysis of a gene located telomeric to D6S193 *Correspondence: TS Ganesan; E-mail: [email protected] Received 26 March 2001; revised 5 October 2001; accepted 12 and D6S297, a member of the ribonuclease family October 2001 (RNASE6PL). Chromosome 6q27 ovarian cancer tumour suppressor gene Y Liu et al 388 Figure 1 Combined genetic, physical and transcript map. The genetic map shown is as previously published (Cooke et al., 1996a). The Genethon map is indicated above with the integrated map below. The integrated map is shown with more markers than that on the Genethon map. The distance between markers is shown in centrimorgans (cM). The YAC corresponds to 17IA12 (260 ± 280 kb). Restriction enzymes are as shown. The STS markers D6S193, D6S297, D6S1585 and D6S133 were present in the YAC. The entire bacterial contig from D6S264 until D6S149 is shown with a gap between BAC 178P20 and PAC 431P23. The direction of the arrows of the PAC correspond to orientation. The sequence BAC 178P20 is incomplete although there is overlap with PAC 366N23. The orientation of PAC 431P23 has not yet been determined in relation to the contig. The key STS markers are shown in the bacterial contig. The genes identi®ed within the region are drawn to scale in relation to the bacterial contig and shown below the contig. TCP10 is shown twice as exons 8 and 9 are present in an antisense orientation in the PAC 366N23. The AF-6 gene is present in part in PAC 431P23 were evaluated by PCR and three ESTs (WI-8751, WI- Results 15078 and TCP10) were identi®ed to be located in the YAC, in addition to the STS markers D6S193 and Genetic and physical mapping D6S297. We had previously constructed an integrated genetic Simultaneously, PACs and BACs were isolated from map of chromosome 6q24 ± 6q27 using the Genethon whole genome libraries (Ioannou et al., 1994; Shizuya map as a backbone (Figure 1) (Cooke et al., 1996a). et al., 1992) for all the markers in this region and were This map improved the number and order of markers assembled into a contig by STS content and within 6q24 ± 6q27 compared to the Genethon map. ®ngerprinting (Mungall et al., 1997). The orientation We initially screened the ICRF, CEPH and ICI YAC of the minimal overlapping set of bacterial clones in libraries by hybridization and PCR with markers from relation to the genetic map and YAC map is shown in this region. Several YACs were isolated and character- Figure 1. The PAC RP1-167A14 contained STSs ized for sequence tagged site (STS) content, size and stSG11162, stSG17631 that were not present in the integrity using FISH. Three YACs were identi®ed YAC 17IA12. This suggested that there was an internal which contained the relevant markers D6S193 and deletion in the YAC corresponding to these markers. D6S297 from the ICI YAC library. One non-chimaeric The bacterial contig is not yet complete as there is still YAC 17IA12 (ICI YAC library) was shown to contain a gap between RP11-178P20 and the PAC that D6S193, D6S297, D6S1585 and D6S133. A detailed contains the marker D6S149 and part of the gene long-range restriction map of this YAC (260 ± 280 kb) AF6 (RP3-431P23). was constructed and an overlapping contig of cosmids In order to facilitate the identi®cation of genes was made. Thirty ESTs/STS mapping in the region within this region between D6S264 ± D6S149, sequen- Oncogene Chromosome 6q27 ovarian cancer tumour suppressor gene Y Liu et al 389 cing of the entire contig was undertaken. Except for testis (data not shown) we did not characterize this the BAC RP11-178P20, which has not yet been gene further in ovarian cancer (Islam et al., 1993). sequenced to completion, linear overlapping sequence is available from PAC RP4-655C5 until the PAC RP3- WI-15078 The third EST which was identi®ed and 366N23. mapped to the YAC (WI-15078, IMAGE clone 174311, size 1049 bp) was sequenced in its entirety. We used this clone as a probe and isolated two larger partial Transcript map cDNA clones (IMAGE clones 199297 1332 bp, 246630 Several methods were used to identify coding sequences 1195 bp) after screening of cDNA libraries. The three within the region. They included homology search of clones were completely sequenced in both strands. the GenBank/EMBL databases using BLAST algo- Comparison and analysis of the cDNA sequences of all rithms and a suite of exon prediction programme to the three clones suggested that there was an open identify genes (Altschul et al., 1990). In addition, reading frame in clone 246630 of 242 amino acids that experiments were also performed to assess ESTs encoded for a protein of 29 kDa. A search of the mapped within the interval between D6S264 ± D6S149 database showed that the sequence was homologous to and so far none have yielded new bona ®de genes. The the family of ribonucleases (Hime et al., 1995). This order of genes identi®ed so far is D6S264 ± p90Rsk-3 ± family is characterized by two conserved motifs RNASE6PL ± FOP ± CCR6 ± GPR31 ± TCP10 ± HUnc93 ± `IHGWLP' and `KHGTC' that span the active site of D6S149 ± AF6. the enzyme (Kurihara et al., 1996). This gene is the human equivalent and was the ®rst reported member of this family (Trubia et al., 1997).
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