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<body topmargin=0 leftmargin=0 marginheight=0 marginwidth=0> <table cellpadding=0 cellspacing=0 border=0><tr> <td valign="top" colspan=2 height=22 BGCOLOR="#FFFFFF" TEXT="#080000" bgproperties="fixed" background="041000d2egerdp.gif"> <div> </div> </td> </tr><tr> <td valign="top" width=145 BGCOLOR="#333399" TEXT="#080000" background="040a2c00erkjzj.gif"> <div> <IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="BOTTOM" HSPACE="0" VSPACE="0" WIDTH="30"></div> <div> <IMG BORDER="0" SRC="1x1.gif" HEIGHT="14" ALIGN="BOTTOM" HSPACE="0" VSPACE="0" WIDTH="40"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="14" ALIGN="BOTTOM" HSPACE="0" VSPACE="0" WIDTH="40"></div> <div> <IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="BOTTOM" HSPACE="0" VSPACE="0" WIDTH="30"></div> <bR> </td> <td valign="top" height=458 BGCOLOR="#FFFFFF" TEXT="#080000"> <div> <FONT SIZE="5" COLOR="#336600" FACE="Times New Roman" ><I>TUMORS</I></FONT><FONT SIZE="1" COLOR="#663399" FACE="Times New Roman" >    </FONT> |    <B> </B><FONT SIZE="2" COLOR="#0000BF" FACE="Times New Roman" ><A HREF="index.htm" TARGET="_top" TITLE="TUMORS"><U><B>home</B></U></A></FONT></div> <div> <IMG SRC="04207040.gif" border=0 width="263" height="4" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></div> <div> <B>TO READ</B></div> <bR> <DIV ALIGN="LEFT"></DIV> <div> <A HREF="http://linkage.rockefeller.edu/chr1/workshops/workshop98/report/neoplasia.shtml" TARGET="_top" TITLE="http://linkage.rockefeller.edu/chr1/work"><U>http://linkage.rockefeller.edu/chr1/workshops/workshop98/report/neoplasia.shtml</U></A></div> <bR> <div> Chromosome 1 abnormalities in human neoplasia</div> <div> <B>(Prepared by Richard Wooster)</B></div> <bR> <div> There are multiple lines of evidence that implicate regions of chromosome 1 in the development and progression of cancer. These include regions of the chromosome that are duplicated or lost in tumours, translocations between chromosome 1 and other regions of the genome, genetic linkage studies in familial cancer syndromes, the analysis of candidate genes and functional rescue of tumourigenicity by chromosome transfer. Abnormalities have been identified in a wide range of solid tumours and haematopoietic malignancies however very few of the genes that are the targets of these alterations have been cloned. In many cases this is due to the relatively large critical interval sometimes covering many megabases of DNA. Presentations during the workshop included work towards refining these intervals and identifying the genes at the heart of the aberrations. </div> <div> Previous chromosome 1 workshop reports provide an eloquent review of abnormalities in human neoplasia for this chromosome (see <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>Vance et al.</U></FONT> 1997 and references therein). This report will concentrate on developments that were presented during this workshop or published between this and the <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>last workshop</U></FONT> in 1997. Specific sections are present for frequently studied tumour types with a general review for tumour types that are either rare or less frequently associated with chromosome 1.</div> <div> <I>Chromosome 1 abnormalities in cancer</I></div> <div> The distal portion of 1p continues to be the region of chromosome 1 thought to contain genes involved in cancer. Vortmeyer and colleagues (1998) found loss of heterozygosity (LOH) of 1p35-p36 in 7 out of 10 Merkel cell carcinomas while Williamson and co-workers (1997) detected loss of the same cytogenetic interval in 27% of 39 parathyroid adenomas and <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>T. Martinsson</U></FONT> (this report) observed LOH in this region in germ cell tumours. Proximally, 1p34-p36 was deleted in 5 of 11 informative pheochrmocytomas (Vargas et al., 1997). Amplification of 1q was reported in 43% (6 out of 14) and 73% (11 out of 15) of endometrial cancers analysed by comparative genomic hybridisation (Sonoda et al. 1997 and Suzuki et al. 1997 respectively) while amplification of 1q23 was observed in adenocarcinoma of the lung (Petersen et al., 1997). Almeida and colleagues (1998) identified a me Mer of the leucine-rich repeat superfamily, GAC1, that is amplified and over expressed in malignant gliomas. Loss of heterozygosity on 1q occurs less frequently than on 1p, for example Pietsch and colleagues (1997) found LOH between 1q31 and q32 in 36% of 30 medulloblastomas.</div> <div> <I>Breast and ovarian cancer</I></div> <div> Multiple regions of chromosome 1 have been implicated in breast and ovarian cancer. <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>Y. Hey</U></FONT> (this report) reported considerable progress on the characterisation of a 200 Kb region on 1p31.1, an interval frequently lost in breast cancer. Sequencing of the critical interval is nearly complete and the analysis of the sequence is underway. Additional experiments to find genes in the region are in progress. Deletion of a proximal interval, 1p22-p31, has been implicated in local progression and metastasis (Tsukamoto et al. , 1998). Functional studies with the melanoma metastasis suppressor gene, KiSS 1, which maps to 1q32-q41, suggest it may suppress metastasis in some breast tumours (Lee et al. 1997) and co-inside with 1q deletions in late stage breast carcinomas. However the picture is clouded by the amplification of the MUC1 mucin gene at 1q21-q24 in breast tumours (as shown by Southern analysis, Bieche and Lidereau 1997). This demonstrates the heterogeneity of gains and losses of chromosome 1 in breast cancers. Thompson and colleagues (1997) confirmed the observation of 1p36 deletions in ovarian tumours and reported consistent translocations between 1p36 and chromosome 17 in 3 out of 11 cases. These suggestions suggested that this region is important in some sporadic ovarian cancers.</div> <div> <I>Colorectal cancer</I></div> <div> A significant correlation has been reported between 1p deletions and aneuploidy in colorectal tumors. These observations suggest that loss of genes in this region may be implicated in chromosome instability (Di Vinci et al., 1998). More specifically, a comparison of disease free interval, survival and LOH at 5 microsatellite makers on 1p32 and 1p36 showed that allelic loss was an independent predictor of poor prognosis (Ogunbiyi et al., 1997).</div> <div> <I>Neuroblastoma</I></div> <div> Many recent publications, and presentations at this workshop, indicate that investigation has continued into the involvement of chromosome 1 in neuroblastma. The number of different minimal regions that have been suggested may be due to experimental variation or could be biased by the collection method and phenotypes of the different tumour sets. Recent mapping data locates neuroblastoma genes in 1p36 (<FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>Martinsson et al</U></FONT>., this report), 1p36 and 1p31-32 (Avigad et al. 1997) and 5 locations between 1p34-pter (<FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>Kageyama et al</U></FONT>., this report). While these findings complement previous work, no specific genes have been identified by these methods. A limited study of familial neuroblastomas identified LOH of 1p in tumours from three patients (Tonini et al. 1997) however linkage studies in three large neuroblastoma kindreds excluded 1p36.2-36.3 as the location of a familial neuroblastoma gene (Maris et al., 1997). An alternative mapping approach identified two genes, Alx3 and p73, that were altered in neuroblastomas and map to 1p13-21 and 1p36 respectively (<FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>Zhu et al</U></FONT>., this report). While a candidate gene approach has excluded CDC2L1 (Martinsson et al., 1997) and phospholipase A2 (Haluska et al., 1997) which are both located on 1p36. One possible route to reduce and clarify the minimal region thought to contain the neuroblastoma gene is to compare the minimal regions identified in different tumour types in the hope that only one gene is the target of the deletions. To this end <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>Martinsson et al</U></FONT>. (this report) have identified a common interval of 5 cM that is lost in both neuroblastomas and germ cell tumours.</div> <div> <I>Prostate cancer</I></div> <div> The genetic analysis of prostate cancer families has continued with particular interest on chromosome 1. Cooney and co-workers (1997) confirmed that 1q24-q25 is likely to contain the prostate cancer gene called HPC1 (Smith et al. 1996) while Eeles and colleagues (1998) found no evidence of linkage in their prostate cancer families. A detailed analysis of the data from Smith and co-workers (1996) indicated that only 34% of familial prostate cancer may be linked to HPC1. Furthermore, linkage to this gene was found in large kindreds (with five or more members affected) with the disease diagnosed at an early age, suggesting that HPC1 is not the only familial prostate cancer gene (Gronberg et al., 1997). Indeed, Berthon and colleagues (1998) have identified a second familial prostate cancer locus on 1q42.2-q43 that is distinct from HPC1. Approximately 50% of the families in this European study were linked to this new locus. So far, neither of these familial prostate cancer genes have been cloned.</div> <div> <I>Sarcomas</I></div> <div> Interest has continued on possible regions of amplification in sarcomas (see <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>Forus et al</U></FONT>. and <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>Meza-Zepeda et al</U></FONT>., this report). 1q21-q24 is amplified in liposarcomas but not in lipomas (Szymanska et al., 1997). A similar interval, 1q21-q22, was found to be amplified in the sarcomas studied by <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>Meza-Zepeda and colleagues</U></FONT> (this report). It would be easy to speculate that a single gene is the target of these aberrations in both studies. However Meza-Zepeda has refined the original amplicon to the extent that it may be two separate amplified regions indicating the presence of two genes. Gains of 1q were also observed in alveolar soft part sarcomas, although the size of the amplicon and significance of the event is unclear (Kiuru Kuhlefelt et al., 1998).</div> <DIV ALIGN="LEFT"></DIV> <div> Physical maps on chromosome 1p</div> <div> <B>(Prepared by Simon Gregory)</B></div> <bR> <div> <I>Genetic Localisation</I> </div> <div> The position of 27 chromosome 1p genes have either been refined or established in the period following the last chromosome workshop (<FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>Table 1</U></FONT>). Approximately half of the localizations were within 1p35-1pter, the region of 1p believed to contain genes responsible for various neoplasias. A few genetic localizations of note are discussed below.</div> <div> DFFA, believed to involved in cellular apoptosis by chromatin cleavage, has been localized by FISH to 1p36.2-p36.3 by Leek and colleagues. Human DR3, which encodes a tumor necrosis factor and is also believed to be involved in apoptosis, is reported to be tandemly duplicated in 1p36.2-p36.3 and deleted or translocated in neuroblastoma cell lines. CD137, another member of the tumor necrosis family, has been localized by PCR and Southern blot analysis to 1p36 by Schwarz and colleagues. In an attempt to identify putative tumor suppressors in 1p36, Onyango and co-workers have identified two new genes, C1orf1 and XBX1; two new members of known gene families, PTPRZ2 and FRAP2; and ENO1L1, which shares coding sequence with ENO1 and MBP-1, differing only in its 5’ UTR. The previously reported human cDNA, B120, has been localized to 1p35-p36, and is believed to have a role in lipid metabolism and a possible association with Schnyder crystalline corneal dystrophy. Van Camp and colleagues have established linkage of DFNA2, one of thirteen genes thought to be responsible for autosomal dominant hearing loss, to 1p34 between D1S432 and MYCL1. Hereditary isolated congenital ptosis, an autosomal dominant disorder characterized by dropping of the upper eyelids, has been positioned in 1p32-p34 by Engle and co-workers using FISH. SSCP, mutation analysis and physical mapping by Van Hul and colleagues has excluded CSF-1 as the gene responsible for causing Albers-Schonberg disease in 1p21.</div> <div> <I>Physical Mapping</I></div> <div> Significant progress has been made towards the generation of a sequence ready bacterial clone map of 1p since the last workshop. Contributions towards this target have been made by 10 localized projects (<FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>Table 2</U></FONT>), six of which were reported at this workshop, and by the whole chromosome mapping project.</div> <div> Three new physical maps have been generated within 1p36, a region of the chromosome prone to deletion or rearrangements in several human malignancies. White and colleagues have mapped CA6 and ENO1 to a 1.3 Mb contig and have reassigned SLC2A5 from 1p31 to 1p36.2 by somatic hybrid and RH typing. Tao and co-workers have provided anecdotal evidence to confirm the difficulty of obtaining faithful YAC coverage in telomeric regions of the chromosome. In their attempt to identify the CMT2A gene they have reported that all but 1 of 45 YACs isolated for the region to be chimeric. Contigs from the Sanger Centre are now being amalgamated with PAC clones isolated using markers chosen from RH and genetic maps. A YAC contig covering the GLC3A critical region is being used as an anchor by Stoilov and colleagues to establish bacterial clone coverage. Bacterial clones, which map within the critical region, are currently being used to identify candidate genes.</div> <div> In an attempt to isolate the gene responsible for Choreoathetosis/Spasticity, episodic (CSE) Hofele and colleagues have constructed an 8 cM YAC contig comprising 50 YACs covering a region of 1p33. Previously identified loci as well as 15 new STSs, generated from YAC ends, and 13 ESTs have been assigned to the contig.</div> <div> Loss of heterozygosity in breast cancer is frequent in 1p31. Two contigs have been generated in the period following the last workshop. Brintnell and colleagues have constructed a 7 Mb contig comprising CEPH and Zeneca YACs and BACs. Two overlapping BACs spanning the region of loss have been sequenced and are being used for gene detection. Baptista and co-workers are using YACs across a 10 Mb interval as probes to generate a cosmid pocket map and to identify additional PACs from the region. Roberts and colleagues are characterizing a neuroblastoma breakpoint in 1p22 by constructing a 6 Mb YAC contig. The contig contains 6 STSs and 3 newly assigned ESTs.</div> <div> A 2 Mb YAC contig in 1p13.3 is being constructed by Flomen and co-workers. YACs from this gene rich region, defined by the genes MCSF (distal) and YKL39 (proximal), are being used in conjunction with STSs/ESTs and YAC ends to isolate PAC clones. Overlaps between bacterial clones will be identified by EcoRI fingerprinting. Two physical maps of the GSTM cluster have been constructed. The partial map of the 4 GSTM genes generated by Xu and colleagues has been used to localise the end points of a polymorphic GSTM1 deletion. Mayau and co-workers have constructed a YAC map across the same region of 1p13 and were able to determine the order of 12 genes, whilst reassigning AMPD2 from 1p21-p34 to 1p13.</div> <div> In the past 18 months substantial progress has been made by the <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>Sanger Centre’s</U></FONT> chromosome 1 <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>mapping and sequencing project</U></FONT>. The short arm has been the initial focus of large scale PAC isolation and fingerprinting. The current <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>RH map</U></FONT> of 1p contains 2819 STSs, 2329 of which have been used to screen gridded bacterial clone arrays. Restriction fingerprinting (Gregory et al., 1997) of a proportion of the positive clones, and parallel assignment of individual STSs, has yielded 25 Mb of contigs with established STS content. Another 110 Mb of bacterial clone contigs are awaiting individual STS assignment. (For more details see <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>below</U></FONT>).</div> <div> <I>Gene Structures</I></div> <div> The genomic structures of 11 genes have been resolved in the period following the last workshop (<FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>Table 3</U></FONT>). Of note is the characterisation of mutations within ABCR, the gene associated with autosomal recessive Stargardt disease (STGD), retinitis pigmentosa (RP19), and cone rod dystrophy (CRD).</div> <bR> <bR> </td> </tr></table></body>