Deletion mapping of chromosome 19 in human gliomas

There is evidence that a putative glioma tumor suppressor locus resides on the long arm of chromosome 19. We present data on 161 gliomas from IS6 patients, which were studied by microsatellite analysis for loss of heterozygosity (LOH) on chromosome 19. Eight loci on the long arm and 2 loci on the short arm of chromosome IV were examined. LOH on I9qwas observed in 3/19 astrocytomas (WHO grade II), 12/27 anaplastic astrocytomas (WHO grade III), 16/76 cases of glioblastoma multiforme WHO (grade IV), 4/9 oligodendrogliomas (WHO grade II), 3/5 anaplastic oligodendrogliomas (WHO grade III), 5/9 mixed oligo-astrocytomas (WHO grade II) and 8/10 anaplastic oligo-astrocytomas (WHO grade III). While 31 of the tumors with LOH on chromosomal arm I9q exhibited allelic loss at every informative locus, 20 tumors showed terminal or interstitial deletions. In contrast to astrocytomas and glioblastomas, tumors with an oligodendroglial component had predominantly lost the entire long arm of chromosome 19. The common region of overlap in gliomas was located on 19q 13.2-q 13.4 between the markers D 19S 178 and D 19S 180. Our data confirm the involvement of a putative tumor suppressor gene on chromosomal arm 19q in gliomas and assign this gene to 19q 13.2-q 13.4.     

Fine mapping of chromosome 3 in uveal melanoma: identification of a minimal region of deletion on chromosomal arm 3p25.1-p25.2

To identify minimal common areas of allelic loss on chromosome 3, we have mapped both arms of the chromosome in 21 uveal melanomas that did not show monosomy 3 in our previous allelotype study. DNA was isolated from microdissected paraffin sections and amplified by PCR. In an initial screening, 14 microsatellite markers on chromosomal arm 3p and 13 on chromosomal arm 3q were used. Loss of heterozygosity for at least one marker was found in 9 of 21 tumors (43%) on 3p and 8 of 21 tumors (38%) on 3q. The initial analysis defined two common regions of allelic loss on 3p, a 7.3-Mb region between markers D3S1263 and D3S3510 spanning 3p25.3-24.3 and a larger region between markers D3S1578 and D3S1284. The two common regions of allelic loss were further mapped with an additional 14 microsatellite markers. A 1.4-Mb minimal region of allelic loss was identified between microsatellite markers D3S3610 and D3S1554 on 3p25.1-3p25.2. A total of 10 tumors had allelic loss in this region; 2 of these tumors had corresponding putative homozygous deletions. These homozygous deletions may further narrow the region of interest to 0.1 Mb. This 1.4-Mb minimum region of deletion includes several genes that might be involved in the carcinogenesis of uveal melanoma as well as other important tumor types.     

Fine deletion mapping of chromosome 8p in non-small-cell lung carcinoma.

Several somatic genetic alterations have been described in non-small-cell lung carcinomas (NSCLC). Recurrent chromosomal deletions have suggested the presence of tumor-suppressor genes specifically involved in lung carcinogenesis. For one of these, 2 non-overlapping regions have been proposed on the short arm of chromosome 8, encompassing the LPL and NEFL genes. The LPL region has been extensively studied in NSCLC and other cancer types. Two genes, N33 and PRLTS, have been identified, but the small number of mutations excludes their involvement in the vast majority of tumors. In order to delineate a reliable region of deletional overlap on chromosome 8p in NSCLC, a series of 77 NSCLC was studied for 34 microsatellite polymorphisms distributed on chromosome 8p, using multiplex-PCR amplification. After purification of tumor nuclei by flow cytometry based on either the abnormal DNA index or the presence of a high expression of cytokeratin, allelic losses on chromosome 8p were observed in 39% of cases. Measurement of DNA index showed that 62% of tumors were hyperploid; allelic losses were more frequent in hyperploid than in diploid tumors (54% vs. 14%; p < 10(-4)). Deletions of part of the short arm were observed in 7 instances. Our data allow definition of an interval of common deletion, flanked by the loci D8S511 and D8S1992, where the putative tumor-suppressor gene might be localized.     

Molecular abnormalities of chromosome-19 in malignant gliomas - preferential involvement of the 19q13.2-q13.4 region

A deletion mapping analysis of chromosome 19 was performed on a series of 101 samples derived from malignant gliomas. A total of 35 tumors displayed different deletions for the loci studied (D19S21, D19S11, D19S74, D19S7, D19S8, CKM, and D19S22). In most instances, losses involving the long arm markers of chromosome 19 were observed, and only four samples were characterized by losses on the short arm. No tumor was found displaying loss of both short and long arm markers. The higher frequency of deletions was detected in tumors with a major oligodendroglial component: 76% of samples included in this group displayed losses at 19q. Among the astrocytic tumors, the frequency of 19q alterations varied as follows: 11% in pilocytic astrocytomas, 17% in astrocytomas grade II, 10% in anaplastic astrocytomas and 21% in glioblastoma multiforme. No ependymoma was found displaying allele loss on chromosome 19. The common region of overlap for the 19q deletions observed involves primarily the distal portion of the long arm, 19q13.2-q13.4. In agreement with previous reports, these data suggest the non-random involvement of a tumor suppressor gene located at 19q13 in the genesis or progression of malignant gliomas.     

Localization of a tumor suppressor gene associated with the progression of human breast carcinoma within a 1-cM interval of 8p22-p23.1

BACKGROUND: Frequent allelic losses on the short arm of chromosome 8 in several types of human cancers, and deletion maps of this region in tumor DNAs, have suggested that 8p harbors one or more genes that are important for suppressing tumorigenesis in the tissues in question. METHODS: To define the locations of potential tumor suppressor genes involved in breast carcinoma, the authors examined 144 primary breast carcinomas for loss of heterozygosity at 18 highly polymorphic microsatellite loci on 8p. They also sought correlations between allelic loss on 8p and several clinicopathologic parameters. RESULTS: Allelic loss was observed in 74 of the 144 sporadic breast carcinomas examined. Whereas more than half of the informative tumors showed loss of an allele at every locus on the short arm, 32 showed partial or interstitial deletions. Deletion mapping in this panel of tumors identified two distinct commonly deleted regions, one in a 1-cM interval flanked by D8S511 and D8S1991 at 8p22-p23.1, and the other in a 16-cM interval flanked by D8S136 and D8S1477 at 8p22-p21. Allelic losses in both of these regions were observed more frequently in tumors of the solid-tubular or scirrhous type than in less aggressive histologic types. Furthermore, allelic loss in either region occurred more frequently in larger and infiltrative tumors (T1 < T2 < T3). CONCLUSIONS: The association of allelic losses on 8p with advanced tumor stage and aggressive histologic type implies that loss or inactivation of one of at least two putative tumor suppressor genes on 8p may contribute to the progression of breast carcinoma.     

Detailed deletion mapping on the short arm of chromosome-3 in nasopharyngeal carcinomas

Allelic loss on the short arm of chromosome 3 is one of the most consistent molecular genetic alterations observed in primary nasopharyngeal carcinoma (NPC). Detailed mapping of the region of common deletion on chromosome 3p will help to locate the site of candidate tumor suppressor gene(s) involved in the pathogenesis of NPC. We have examined allelic deletion in 27 primary undifferentiated NPC at 11 chromosomal loci (spanning from 3p13-3p25) using microsatellite polymorphic markers. Allelic loss was observed in 18 of 27 primary tumors (67%) when comparing tumor DNA with normal constitutional DNA of the same patient. Among these 18 cases, 10 showed allelic loss in all informative loci of chromosome 3p and 8 showed partial or interstitial deletion, The highest frequency of allelic loss was found in three loci, D3S1038 (52%), D3S1228 (50%) and D3S659 (50%). In 5 of the 8 cases with partial deletion of chromosome 3p, a common deletion region within 3p13 to 3p14.3, flanked by two loci, D3S1079 (3p13) proximally and D3S1228 (3p14.1-14.3) distally, was identified. These results suggest strongly the presence of tumor suppressor gene(s) within the 3p13 to 3p14.3 region, the deletion of which represent a critical event in the development of NPC. In the remaining 3 cases with partial chromosomal deletion, the pattern of allelic loss suggests the presence of two other regions of deletion distal to the commonly deleted region (3p13-14.3) identified. The presence of multiple deleted regions on chromosome 3p in NPC suggests that more than one tumor suppressor gene on 3p may be involved in the development of NPC.     

Allelic loss of chromosome 2 in human oral squamous cell carcinoma: correlation with lymph node metastasis

To evaluate the role of chromosome 2 deletions in human oral squamous cell carcinoma (SCC) progression and to define the precise location of putative tumor suppressor genes, we examined 40 primary tumors and seven lymph node metastatic tumors from 40 patients with oral SCC by the polymerase chain reaction (PCR)-loss of heterozygosity (LOH) assay, using 10 different polymorphic loci on the long arm of chromosome 2. LOH was observed in 67.5% of the patients at one or more loci on the chromosome 2q. Two commonly deleted regions with high frequency of LOH, D2S1327 region at 2q32-35 (31.6%) and D2S206 region at 2q36 (36.7%), were identified by the deletion mapping of chromosome 2q, suggesting the presence of putative tumor suppressor genes associated with oral SCC. Examination of seven metastatic tumors also revealed four commonly deleted regions, D2S436, D2S1327, D2S155, and D2S164. Of these four regions D2S1327 region has no significant increase in the frequency of LOH between in primary tumors and in metastatic tumors. However, at other three regions the frequencies were much increased in metastatic tumors, comparing the results in primary tumors. Especially, very high frequencies of LOH in metastatic tumors were detected at two regions on 2q35, 100.0% at D2S155 and 57.1% at D2S164, suggesting the significant relationship between lymph node metastasis and LOH at these two regions. Our results indicate that LOH on chromosome 2q is a common event in oncogenesis and/or progression of oral SCC, and also suggest that the LOH at 2q35 play a significant role in the lymph node metastasis.     

Frequent allelic loss/imbalance on the long arm of chromosome 21 in oral cancer: evidence for three discrete tumor suppressor gene loci.

Frequent allelic imbalances including loss of heterozygosity (LOH) and microsatellite instability (MI) on the long arm of chromosome 21 (21q) have been found in several types of human cancer. This study was designed to identify tumor suppressor locus (or loci) associated with oral squamous cell carcinoma (SCC) on 21q. Among 38 patients with oral SCC tested, 15 (44%) of 34 informative cases showed LOH at one or more loci. Deletion mapping of these 15 tumors revealed three discrete commonly deleted regions on the chromosome arm. A minimal region with frequent LOH was found at the marker D21S236 mapped on 21q11.1. Another region of frequent deletion was identified between markers D21S11 and D21S1436 on 21q21, and a further commonly deleted region was found at D21S1254 on 21q22.1. In addition, we have detected MI on the chromosome arm in our oral SCC samples with significant correlation with tumor stage. Thus, our results strongly suggest that allelic imbalances on 21q may be involved in the development of oral SCC; and that at least three different putative tumor suppressor genes contributing to the pathogenesis of this disease are present on 21q.     

Loss of heterozygosity of 1p in uveal melanomas with monosomy 3

Gains and losses of chromosomes 1, 3, 6 and 8 are nonrandom chromosomal aberrations in uveal melanoma. Monosomy 3 is the most frequent abnormality and is associated with poor prognosis. To identify regions of allelic loss on the short arm of chromosome 1 and to investigate if these alterations contribute to uveal melanoma progression, we performed microsatellite analysis of 10 loci in 70 uveal melanomas. A total of 51 tumors were obtained from patients with clinical follow-up data, 19 tumors were from recent patients without follow-up. Loss of heterozygosity (LOH) of at least 1 marker was more frequent in tumors with monosomy 3 (40%) than in tumors with disomy 3 (10%). In particular, loss of the entire short arm of chromosome 1 was only observed in tumors with monosomy 3 (p = 0.0001). By comparing the extent of 1p LOH in all tumors with monosomy 3, we were able to define a smallest region of overlap (SRO) of approximately 55 Mb, which is flanked by markers D1S507 and D1S198. On the basis of our data and published cytogenetic data, we propose that 1p31 harbors genes involved in the progression of uveal melanoma with monosomy 3.     

Allelic loss on chromosome 17 in human ovarian cancer

In order to identify a common region of deletion on chromosome 17 potentially containing a tumor-suppressor gene, 27 ovarian carcinomas and 3 ovarian tumors of low malignant potential (LMP) were examined for loss of heterozygosity (LOH) at 6 p arm and 10 q arm loci. Ninety percent of all tumors had deletions at one or more loci. On the p arm, there was a single near-common region of deletion on 17p 13.3 (D/7S30/ pYNZ22.1; 86% LOH), an intervening locus with a low LOH rate, and a more proximal locus on 17p11.2 (D/7S58/pEW301; 82% LOH) with a high LOH rate. In less aggressive tumors, LOH at Df 7S30 was not accompanied by LOH at p53. The q arm had a common region of deletion for high-stage carcinoma at D/7S579 (Mfd 188; 74% LOH) on q21, a locus tightly linked to the familial breast-ovarian-cancer syndrome (BRCAI) locus. D/7S579 was lost in all informative high-stage carcinomas and retained in all low-stage carcinomas and tumors of LMP. There may be at least 2 tumor-suppressor genes, an early-acting gene on the p arm and a gene on the q arm involved in tumor progression and metastasis.     

Evidence for two distinct tumor-suppressor gene loci on the long arm of chromosome 11 in human oral cancer

Loss of heterozygosity (LOH) on human chromosome 11 has been reported in a variety of human cancers. To search for the existence of tumor-suppressor gene(s) associated with oral squamous cell carcinoma (SCC) on chromosome 11, we have performed high-resolution deletion mapping in 31 patients with oral SCC using 22 microsatellite markers for this chromosomal region. LOH was observed in 14 of 25 cases (56.0%) that were informative with at least one locus. Most allelic deletions detected in our study were specific to the long arm of the chromosome. Furthermore, the data presented here show 2 distinct, commonly deleted regions. The first region, with frequent LOH, was restricted between markers D11S939 and D11S924 separated by 3 centimorgans (cM) on chromosome 11q23. The second region of common deletion was identified between markers D115912 and D11S910, separated by 7 cM at 11q25. Our results suggest that at least 2 tumor-suppressor genes involved in the development of oral SCC are present on the long arm of chromosome II. © 1996 Wiley-Liss, Inc.     

Allelotyping defines minimal imbalance at chromosomal region 17q25 in non-serous epithelial ovarian cancers

Allelic deletions of multiple chromosome 17q loci in sporadic ovarian cancer of epithelial origin suggest that inactivation of tumor suppressor gene(s) in these regions may be important for ovarian tumorigenesis. To further define the pattern of allelic imbalance in epithelial ovarian tumors of different histologies, a PCR-based assay was used to assess loss of heterozygosity (LOH) of polymorphic markers representative of TP53, BRCA1, NME1 and GH1, and region 17q23-25. LOH was observed for at least one marker in 68% of malignant tumors (n=60) and in 18% tumors of borderline malignancy (n=11), but not in benign tumors (n=5). The highest frequency of LOH in malignant tumors (64%) was observed with D17S801 on 17q25. Ten of 39 malignant ovarian tumors displaying LOH of at least one 17q marker, displayed a LOH pattern enabling the determination of a minimal region of overlapping deletion defined by D17S795 and D17S801. One borderline tumor also displayed an interstitial LOH pattern that overlapped this 17q25 minimal region of deletion. The histologies of malignant tumors displaying a pattern indicative of interstitial 17q deletions were of the endometrioid, clear cell and mucinous epithelial types. As the minimal region of overlap defined by these tumors overlap regions deleted in malignant tumors of all histologic types, and in a tumor of borderline malignancy, the 17q25-tumor suppressor may be implicated in the development of all types of epithelial ovarian tumors.     

Deletion mapping on chromosome 1p in well-differentiated gastric cancer.

To define the region on the short arm of chromosome 1 that is thought to include one or more tumour-suppressor genes for gastric cancers, we carried out loss of heterozygosity (LOH) studies in 26 gastric adenocarcinomas, using three restriction fragment length polymorphism (RFLP) markers and nine microsatellite markers. All tumours were informative with at least one locus; three revealed replication errors (RERs) at multiple microsatellite loci, and interstitial or telomeric allelic deletions were observed in 12 cases. Deletion mapping of these tumours defined a commonly deleted region between two loci, D1S201 and D1S197, that are 13 cM apart. As two loci within the commonly deleted region, D1S57 (pYNZ2) and D1S62 (pTHI54), were mapped respectively to 1p35 and 1p34.3 by fluorescence in situ hybridisation, we conclude that a locus likely to contain a tumour-suppressor gene for gastric cancer is located within a 13 cM region encompassing two chromosomal bands.     

Identification of two distinct regions of allelic imbalance on chromosome 18Q in metastatic prostate cancer

Like most cancers, prostate cancer (CaP) is believed to be the result of the accumulation of genetic alterations within cells. Previous studies have implicated numerous chromosomal regions with elevated rates of allelic imbalance (AI), using mostly primary CaPs with an unknown disease outcome. These regions of AI are proposed sites for tumor suppressor genes. One of the regions previously implicated as coding for at least one tumor suppressor gene is the long arm of chromosome 18 (18q). To confirm this observation, as well as to narrow the critical region for this putative tumor suppressor, we analyzed 32 metastatic CaP specimens for AI on chromosome 18q. Thirty-one of these 32 specimens (96.8%) exhibited AI at one or more loci on chromosome 18q. Our analysis using 17 polymorphic markers revealed statistically significant AI on chromosome 18q at 3 markers, D18S35, D18S64 and D18S461. Using these markers as a guide, we have been able to identify 2 distinct minimum regions of AI on 18q. The first region is between the genetic markers D18S1119 and D18S64. The second region lies more distal on the long arm of the chromosome and is between the genetic markers D18S848 and D18S58. To determine if 18q loss is a late event in the progression of CaP, we also examined prostatic intraepithelial neoplasia (PIN) and primary prostate tumors from 17 patients for AI with a subset of 18q markers. We found significantly higher AI in the metastatic samples. Our results are consistent with 18q losses occurring late in CaP progression.     

Fine-scale deletion mapping of the distal long arm of chromosome 6 in 70 human ovarian cancers.

To define a small region on chromosome 6q containing a putative tumor suppressor gene for ovarian cancer, we examined loss of heterozygosity in 70 ovarian tumors of three histological types with nine restriction fragment length polymorphism markers located at 6q24-27. Among 33 cancers of serous type that were informative at one or more loci, 17 showed allelic loss at a few or all loci examined, whereas only 1 of 15 mucinous-type tumors and 2 of 12 clear-cell tumors revealed loss of heterozygosity. This result supported our earlier suggestion that alteration of a gene on chromosome 6q may play an important role during development of serous ovarian tumors (Sato et al., Cancer Res., 51: 5118-5122, 1991). Frequent losses were observed between loci defined by CI6-119 (D6S195) at 6q26 and CI6-49 (D6S161) at 6q27. A detailed deletion map indicated a commonly deleted region between loci defined by CI6-111 (D6S193) and CI6-24 (D6S149); these two markers are estimated to be 1.9 cM apart on the basis of linkage analysis. Our results further define a region containing a tumor suppressor gene involved in ovarian carcinoma within an approximately 2-megabase-long segment of chromosome 6q.     

Frequent loss of heterozygosity on chromosomes 6q, 11, and 17 in human ovarian carcinomas

Recently, tumor-specific allele loss has been shown to be an important characteristic of some tumors. When such loss includes one or more growth-regulatory genes, it may allow the expression of tumorigenicity. Using Southern blots, we analyzed normal and tumor DNA samples from 19 ovarian cancer patients, using a series of polymorphic DNA probes that map to a variety of chromosomal loci. Of 14 informative cases, tumor-specific allelic loss was observed in nine (64%) at the estrogen receptor (ESR) gene locus on chromosome 6q. On chromosome 17p at the D17S28 and D17S30 loci, allelic losses were also detected in 6 of 8 (75%) and 9 of 14 (64%) cases, respectively. Allelic loss at the HRAS1 gene locus on chromosome 11p occurred in 5 of 11 (46%) informative cases. The relatively high incidence of these allelic losses observed on chromosome 6q represents the first implication by molecular genetic analysis of this chromosomal region in a human malignancy, and it thus appears to be a genetic change specific to ovarian carcinoma. DNA sequence losses on 11p and 17p, also reported for other cancers, may reflect the presence of tumor- or growth-suppressor genes on these chromosomes that are important in the genesis of many tumor types, including ovarian malignancies.     

Detailed genetic and physical mapping of tumor suppressor loci on chromosome 3p in ovarian cancer.

Hemizygosity and homozygosity mapping studies show that many common sporadic cancers including lung, breast, kidney, cervical, ovarian, and head and neck cancer display deletions on the short arm of chromosome 3. For ovarian cancer, monochromosomal transfer suppression studies have identified three candidate regions for chromosome 3p ovarian cancer tumor suppressor genes (OCTSGs). To accurately map OCTSG candidate regions, we analyzed 70 ovarian tumors for loss of heterozygosity (LOH) at 20 loci on chromosome 3p that were selected to target those regions proposed to contain tumor suppressor genes for common sporadic cancers. All samples were informative for at least five markers. In 33 (52%) tumors without microsatellite instability, LOH was observed for at least one 3p marker. Analysis of 27 ovarian tumors demonstrating both loss and retention of 3p markers enabled us to define four nonoverlapping minimal deletion regions (OCLOHRs): (a) OCLOHR-1 mapped distal to D3S3591 at 3p25-26; (b) OCLOHR-2 mapped between D3S1317 and D3S1259 at 3p24-25; (c) OCLOHR-3 mapped between D3S1300 and D3S1284, an area that includes the FHIT locus at 3p14.2; and (d) OCLOHR-4 mapped between D3S1284 and D3S1274 at 3p12-13, a region known to contain overlapping homozygous deletions in lung and breast tumor cell lines. However, microsatellite markers from the chromosome 3p21.3 interval homozygously deleted in lung cancer cell lines did not identify a distinct OCLOHR. The frequency and extent of 3p LOH correlated with tumor stage such that LOH at two or more OCLOHRs was present in 53% (16 of 30) of stage III tumors but only 26% (5 of 19) of stage I/II tumors (P = 0.08). To determine the relationship between the OCLOHRs and the three candidate ovarian cancer suppression regions (OCSRs) identified previously by monochromosome transfer studies, we performed detailed genetic and physical mapping studies to define the extent of the three candidate OCSRs and to establish YAC contigs covering each region. OCSR-A at 3p25-26 and OCSR-B at 3p24 were shown to overlap with OCLOHR-1 and OCLOHR-2, respectively, providing further evidence for OCTSGs in these regions. We also show that OCSR-C overlaps with a locus at 3p21.3 previously implicated in lung and breast cancer.     

Frequent Allelic Loss at 7p14-15 Associated with Aggressive Histologic Types of Breast Cancer

We examined 142 primary human breast cancers to determine their patterns of loss of heterozygosity (LOH) at 19 microsatellite markers over the entire length of chromosome 7. Allelic loss at one or more loci on the short arm of chromosome 7 was observed in 37 of the tumors (26%). We found a new target region of allelic loss on 7p between D7S1802 and D7S817 at 7p14-15. LOH on 7p was found more frequently in tumors of the invasive solid tubular and scirrhous type (31 of 87; 36%) than in other less aggressive types (2 of 27; 7%) ( P =0.0047). The results suggest that inactivation of putative tumor suppressor gene(s) located at 7p14-15 may play a role in the development and/or progression of primary breast cancers, particularly those of the invasive solid tubular and scirrhous type. Allelic loss was also found in 56 of 142 tumors on the long arm, and a commonly deleted region was defined between D7S522 and D7S1801 at 7q31.     

Mapping of Target Regions of Allelic Loss in Primary Breast Cancers to 1-cM Intervals on Genomic Contigs at 6q21 and 6q25.3

Allelic losses on the long arm of human chromosome 6 are frequently observed in cancers of the ovary, prostate, and breast. To identify the locations of putative tumor suppressor genes on 6q, we examined 192 primary breast cancers for patterns of allelic loss at 16 polymorphic microsatellite loci distributed along this chromosome arm. Allelic losses at one or more loci were observed in 105 (55%) of the tumors examined. Detailed deletion mapping with appropriate yeast artificial chromosome (YAC) contigs identified two distinct commonly deleted regions; one was confined to a 1-cM interval at 6q21 flanked by D6S1040 and D6S262 and the other to a 1-cM interval at 6q25.3 flanked by D6S305 and D6S411. Allelic losses at 6q21 were more frequent in invasive solid tubular and scirrhous carcinomas than in tumors of less aggressive histologic types ( P =0.0006). Allelic loss at 6q25.3 was associated with loss of progesterone receptor ( P =0.0256). Our results suggest the presence of two tumor suppressor genes for breast cancer on 6q that are likely to be associated with tumor progression and/or loss of hormonal dependency.     

Mapping of target regions of allelic loss in primary breast cancers to 1-cM intervals on genomic contigs at 6q21 and 6q25.3.

Allelic losses on the long arm of human chromosome 6 are frequently observed in cancers of the ovary, prostate, and breast. To identify the locations of putative tumor suppressor genes on 6q, we examined 192 primary breast cancers for patterns of allelic loss at 16 polymorphic microsatellite loci distributed along this chromosome arm. Allelic losses at one or more loci were observed in 105 (55%) of the tumors examined. Detailed deletion mapping with appropriate yeast artificial chromosome (YAC) contigs identified two distinct commonly deleted regions; one was confined to a 1-cM interval at 6q21 flanked by D6S1040 and D6S262 and the other to a 1-cM interval at 6q25.3 flanked by D6S305 and D6S411. Allelic losses at 6q21 were more frequent in invasive solid tubular and scirrhous carcinomas than in tumors of less aggressive histologic types (P = 0.0006). Allelic loss at 6q25.3 was associated with loss of progesterone receptor (P = 0.0256). Our results suggest the presence of two tumor suppressor genes for breast cancer on 6q that are likely to be associated with tumor progression and / or loss of hormonal dependency.