Refinement of the LOH region 1 at 11q23.1 deleted in human breast carcinomas and sublocalization of 11 expressed sequence tags within the refined region

Loss of constitutive heterozygosity at 11q23 has been detected in various human solid tumors. Here, we described the analysis of a series of normal and tumor pairs from 110 breast carcinomas for the presence of loss of heterozygosity at 11q23 loci. The overall frequency of LOH was 48%, confirming the importance of deletions at 11q23 in breast tumorigenesis. Previously, we have identified two independent regions of LOH at 11q23, the LOH region 1 at 11q23.1 and the LOH region 2 at 11q23.3. The most telomeric region was recently refined between loci D11S1345 and D11S1316, a region of about 1 Mb. However, the LOH region 1, most centromeric, was still not finely refined: the boundaries were defined by loci D11S2000 and D11S897, separated by about 8 Mb. Here, we refined its boundaries between loci D11S1347 and D11S927, a region of about 2 Mb. We have mapped 11 expressed sequence tags (ESTs) within this region and excluded another 20. This study represents a further step toward the identification of the putative tumor suppressor gene found within the LOH region 1 at 11q23.1.     

Microsatellite analysis at 1p36.3 in malignant melanoma of the skin: fine mapping in search of a possible tumour suppressor gene region

Deletions in 1p36 in malignant melanoma have been found in high percentages in nodular melanomas and melanoma metastases. Despite many efforts, no candidate tumour suppressor gene associated with malignant melanoma has so far been found in this region. To further determine a possible tumour suppressor gene locus, we carried out a deletion mapping of chromosome 1p36 at nine microsatellite loci in 74 malignant melanomas. Loss of heterozygosity (LOH) in this region was found in 77% of nodular melanomas (NMs), 86% of metastatic melanomas, but only 20% of superficial spreading melanomas (SSMs). Regarding the allelic losses, the nodular and metastatic melanoma samples could be divided into three groups: one showing LOH at the more telomeric loci D1S243 and D1S468 (1p36.33), one displaying allelic loss at the more centromeric loci D1S214 and D1S253 (1p36.32-31) and one with LOH over all informative loci between D1S243 and D1S160. We did not find any significant correlation between a deletion in any of the investigated loci and the survival data of the patients. However, our results confine the deleted region in malignant melanoma to a very small area around 1p36.32, thus facilitating the search for the tumour suppressor gene with importance in malignant melanoma.     

Loss of two new loci on chromosome 8 (8p23 and 8q12-13) in human prostate cancer

Inactivation of tumor suppressor genes due to allelic loss is thought to be an important mechanism of gene alterations in prostatic carcinogenesis. Loss of sequences on the short arm of chromosome 8 (8p) has been reported in human cancers, especially of 8p22 and 8p12-21 in prostate cancer. By using PCR analysis of polymorphic microsatellite repeat markers at four 8p loci and three 8q loci in 60 tumors, we observed deletion of sequences at two other deletion domains (8p23, and 8q12-13). There was loss in 51 of 60 cases (85%) with at least one marker. Four distinct regions of loss detected were: i) at 8p23, at locus D8S262; ii) at 8p22, on locus D8S259; iii) at 8p12, on loci D8S255 and D8S285; iv) at 8q12-13, on loci between D8S260 and D8S528. We found that 29% of the tumors showed LOH at 8p23; 19% LOH on 8p22; 54% had LOH at 8p12; and 48% had LOH at 8q12-13. There was higher frequency of LOH at 3 or more loci in samples of T3 stage (62%) as compared to T2 stage (13.3%) which suggests higher incidence of LOH in advanced stage of prostate cancer. We report deletion of two novel loci at 8p23 and 8q12-13, these regions may contain putative tumor suppressor genes in prostate cancer.     

Frequent loss of heterozygosity of the long arm of chromosome 7 is closely associated with progression of human gastric carcinomas

Loss of heterozygosity (LOH) on the long arm of chromosome 7 was examined using 5 polymorphic marker probes on 98 gastric carcinomas to elucidate a novel locus for development and progression of the tumors. Twenty-six (32%) of 82 informative cases showed LOH on 7q on at least one locus of 5 loci. Among 5 loci, LOH at D7S95 locus was most frequent, the incidence being 53% in well-differentiated gastric carcinomas and 33% in poorly differentiated and scirrhous gastric carcinomas respectively. At 3 loci, c-met, D7S63 and D7S22, the incidence of LOH was about 30% and 10% in well-differentiated and poorly differentiated gastric carcinoma cases respectively. In contrast, LOH at D7S64 was not detected in any gastric-carcinoma cases. Deletion mapping of 7q revealed that D7S95 locus was the essential region of LOH. Eight (62%) of 13 cases with LOH at D7S95 locus belonged to the most advanced stage grouping. Furthermore, 6 (75%) of 8 cases with abdominal dissemination showed LOH at D7S95. Therefore, cases with LOH at D7S95 showed significantly worse prognosis than the cases without the LOH in the stage-III and stage-IV groups. These findings overall suggest that D7S95 locus on 7q may contain a candidate suppressor gene for the progression of gastric carcinoma.     

High frequency of deletion on chromosome 9p21 may harbor several tumor-suppressor genes in human prostate cancer.

Chromosome 9p has been reported to be a critical region of loss in various cancers. Our present study was designed to determine the frequency of deletions at different loci of chromosome 9p in microdissected samples of normal prostatic epithelium and carcinoma from the same patients. For this purpose, DNA was extracted from the microdissected sections of normal and tumor cells of 40 prostate specimens, amplified by PCR and analyzed for loss of heterozygosity (LOH) on chromosome 9p using 15 microsatellite markers. Only 6 of 15 microsatellite markers exhibited LOH in prostate cancer specimens (D9S162, D9S1748, D9S171, D9S270, D9S273 and D9S153). LOH on chromosome 9p was identified in 29 of 40 cases (72.5%) with at least 1 marker. The main deletion was found on 9p21, at loci D9S1748 (50%), D9S171 (51.4%) and D9S270 (21.8%). There was also a deletion on 9p22 at locus D9S162 (8.3%), on 9p13 at locus D9S273 (13.8%) and on 9p11 at locus D9S153 (7.7%). LOH data were correlated with stage of prostate cancer and revealed a high frequency of LOH at 3 or more loci in samples with stage T(3)N(0)M(0) (46%) compared with stage T(2)N(0)M(0) (15%), which suggests a higher incidence of LOH in the advanced stage of prostate cancer. One of the candidate target tumor-suppressor genes, p16 (MTS-1/CDKN2), has been identified within the 9p21 deleted region in tumor cell lines. Expression of P16 protein was either absent or very low in prostate cancer samples, suggesting that loss of the p16 gene may be involved in prostatic carcinogenesis.     

Allelic loss on the short arm of chromosome 8 in oral squamous cell carcinoma.

Allelic deletions on the short arm of chromosome 8 (8p) are frequent events in many different types of malignant tumors, including head and neck tumors and oropharyngeal cancers. These regions are thought to harbor tumor suppressor genes. However, there has been no detailed analysis of loss of heterozygosity (LOH) on the chromosome arm 8p in oral squamous cell carcinoma (SCC). In order to estimate details of 8p loci involved in oral SCC, 32 patients with oral SCCs were examined for the LOH state 8p by PCR-LOH assay using 14 microsatellite markers. Based on our results a detailed deletion map of 8p showed LOH in at least one of the loci tested in 62.5% (20 of 32) of patients; and microsatellite instability (MI) was observed in 50% (16 of 32). The frequent LOH on this chromosome arm was identified at D8S87 and D8S258, mapped on 8p12 and 8p22, respectively. Fisher's exact test revealed no significant statistical correlation between the incidence of LOH or MI and clinicopathological features. Our observations indicate that the short arm of chromosome 8 may play a role in the pathogenesis of oral SCC; and that the two loci identified in this study may be tumor suppressor gene loci on 8p.     

中国人胃癌组织微卫星DNA的杂合性缺失研究

目的从多位点筛选中国人胃癌的杂合性缺失（ＬＯＨ）频率,以初步确定与胃癌的致病基因连锁最密切的ＭＳｍａｒｋｅｒ。方法选择了３０个多态微卫星标记,采用ＰＣＲ、聚丙烯酰胺凝胶电泳及银染技术,对４２例胃癌组织进行了ＬＯＨ分析。结果在２９个位点上检测到总的ＬＯＨ频率为２７．７％。高频率的ＬＯＨ主要集中在Ｄ３Ｓ１５７７、Ｄ３Ｓ１０６７、Ｄ６Ｓ４３０、Ｄ１５Ｓ２０５、Ｄ１７Ｓ９４５等位点。ＬＯＨ频率均在４０％以上。其次是Ｄ５Ｓ４０７、Ｄ２Ｓ１３６、Ｄ２Ｓ１４７、Ｄ１３Ｓ１７５、Ｄ１４Ｓ６８、Ｄ８Ｓ２７９,其ＬＯＨ频率均在３０％以上。不同病理分型的胃癌,ＬＯＨ频率存在明显差异。印戒细胞癌的ＬＯＨ明显高于低分化胃癌（Ｐ＜０．０１）;低分化胃癌的ＬＯＨ频率亦明显高于高分化胃癌（Ｐ＜０．０１）。４例高分化胃癌均未发现ＬＯＨ。结论高频率的ＬＯＨ位点附近,除了已克隆的癌基因、抑癌基因外,可能还含有未知的胃癌易感基因。这一结果表明,恶性程度高的胃癌涉及更多的等位基因丢失     

Deletion mapping on the short arm of chromosome 1 in Merkel cell carcinoma

Twenty-two Merkel cell carcinoma (MCC) biopsies and six cell lines from 24 patients were examined for loss of heterozygosity (LOH) at 11 loci on 1p and one on 1q, to determine LOH regions on chromosome 1p. Sixteen (73%) tumors had LOH for at least one locus; 14 demonstrated LOH at more than one locus, and 7 (29%) samples had more than one region of loss, with 4 of these having loss at all informative loci on 1p. Three common regions of loss (SRO) were defined by LOH in multiple tumors. Eight samples demonstrated LOH between D1S214 and D1S160 (1p36), seven between D1S234 and D1S186 (1p35), and 11 for the region centromeric of D1S211 and D1S220 (1p32-1p33). Seven samples (29%) demonstrated more than one region of loss. LOH on 1p occurs frequently in MCC and more than one tumor suppressor gene on 1p is likely to play a role in the development of this tumor type.     

Two distinct regions of deletion on chromosome 13q in primary nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is rare in most parts of the world, but prevalent in Southern China. Although this disease poses a serious health problem in our population, the genetic alterations that lead to the development of NPC have yet to be defined. In a comparative genomic hybridization (CGH) study on NPC by our group, loss of the long arm of chromosome 13 has been identified as a frequent event. To investigate further the involvement of this genetic alteration in NPC tumorigenesis, we examined 31 primary NPC tumours by LOH analysis with a panel of 13 microsatellite polymorphic markers distributed along the long arm of chromosome 13. It was found that 19/31 tumours (60%) showed LOH for markers on chromosome 13q. The highest frequency of LOH was found at loci D13S133 (53.6%) on 13q14.3 and D13S796 (38.5%) on 13q32-34. Two distinct smallest deletion regions were delineated: the first region between D13S133 and D13S119 at 13q14.3-22, and the second region between D13S317 and D13S285 at 13q31-34. Our findings show that LOH of 13q is a common event in NPC and that at least 2 putative tumour-suppressor loci may be present on 13q. Mapping of the critical regions of these loci suggests that some candidate tumour-suppressor genes on 13q, other than Rb and BRCA2, may be involved in the development of NPC.     

Loss of heterozygosity of microsatellite loci on chromosome 9p in astrocytic tumors and its prognostic implications

Summary We analyzed 19 samples of various astrocytic tumors (3 astrocytomas, 5 anaplastic astrocytomas, and 11 glioblastomas) for loss of heterozygosity (LOH) on chromosome 9p at 6 microsatellite loci (D9S54, IFNA, D9S171, D9S104, D9S165, and D9S166). Polymerase chain reaction was performed and the products were electrophoresed on polyacrylamide gel. As many as 16 of the 19 samples (84%) exhibited LOH. Three of the 7 informative loci (43%) showed LOH at D9S54, 7 of 17 (41%) at IFNA, 8 of 14 (57%) at D9S171, 7 of 14 (50%) at D9S104, 4 of 8 (50%) at D9S165, and 2 of 7 (29%) at D9S166. LOH was recognized in 57% of the informative loci in anaplastic astrocytomas and 54% in glioblastomas, while it was seen in only 8% of the astrocytomas. Accumulation of LOH with progression or recurrence of tumor was seen in 2 patients. Although, the survival period of the patients correlated well to the histological types of astrocytic tumors, we could not find any obvious correlations between the presence/absence of LOH and the survival period in these patients. In conclusion, we speculate that LOH on chromosome 9p is involved in malignant progression of astrocytomas, but has no significance in predicting survival period in these patients.     

Genetic heterogeneity of surgically resected prostate carcinomas and their biopsy specimens is related to their histologic differentiation

BACKGROUND: In human prostate carcinogenesis, many genetic analyses including conventional loss of heterozygosity (LOH) studies and microsatellite LOH analyses using the polymerase chain reaction method have revealed frequent LOH events at specific regions on chromosomes 3p, 7q, 8p, 10q, 16q, 17q, and 18q. METHODS: Using the laser-captured microdissection method, the authors extracted genomic DNA from 23 cases of prostate carcinomas including 59 different lesions and 8 biopsy specimens. Using (32)P-labeled primers, the authors analyzed six microsatellite loci (D3S647, D3S1228, D7S522, D8S137, NEFL, and D10S190) at which frequent LOH events have been reported. RESULTS: Of 10 cases in which the authors found LOH at any of the loci, 8 cases showed a heterogeneous LOH pattern. In four cases, the authors also found replication error (RER) at some of the loci examined. There was no significant relation between histologic differentiation and frequency of LOH or RER events. The overall LOH rate was found to be significantly lower in foci at classification pT2 (1 of 28 foci, 3%) compared with those at classification pT3 (13 of 44 foci, 30%). In pT3 samples, LOH events in extraglandular foci (9 of 23 foci, 39%) tended to be more frequent compared with those in intraglandular foci (8 of 41 foci, 20%). The patterns of LOH events in biopsy specimens correlated well with those in foci from surgical material showing the same histologic characteristics. CONCLUSIONS: Prostate carcinoma is a genetically multicentric carcinoma, and the genetic heterogeneity is well correlated with histologic differentiation. The frequency of LOH events increased according to the degree of tumor progression.     

Detailed deletion mapping at chromosome 11q23 in colorectal carcinoma

Loss of heterozygosity (LOH) is frequent at the chromosomal region 11q22-q23 in several types of tumours of diverse cell origin. Previous investigations of LOH at this chromosomal region in colorectal carcinoma have been contradictory in their findings, and have only included between 1-4 loci. In order to define any regions of LOH on 11q23, we investigated 16 loci between D11S940 and D11S934 on the long arm of chromosome 11 using microsatellite analysis. Of 57 colorectal carcinomas specimens, 36 (63.2%) demonstrated LOH at one or more marker, with the highest frequencies of LOH at D11S1340 (41.0%), located between 105.13-111.97 Mb from the centromere, and D11S924 (37.1%) and D11S4107 (40.5%), both located approximately 113 Mb from the centromere. No statistically significant associations between LOH and age-of-presentation or Dukes' stage were found. LOH was observed in colorectal tumours of all Dukes' stages, including Dukes' stages A and B, suggesting that the inactivation of a tumour suppressor gene(s) on 11q23 occurs in the early stages of colorectal carcinoma. These results confirm the presence of putative tumour suppressor gene(s) at chromosome 11q23, involved in the carcinogenesis of colorectal carcinoma, and will facilitate future identification of candidate genes.     

Weak linkage at 4p16 to predisposition for human neuroblastoma

The most frequent genetic alterations described in neuroblastoma (NB) are amplification of MYCN oncogene and deletion of chromosome 1p, although somatic deletions have been demonstrated at other chromosomal intervals. Since loss of heterozygosity (LOH) at distal 4p has been observed in about 20-29% of neuroblastomas, we have evaluated deletions in 41 Italian NB samples by LOH analysis at loci mapping to 4p as follows: pter-D4S2936-D4S412-D4S2957-D4S432-D4S3023-D4S431-cen. Our analysis showed allele losses in eight out of 41 samples (19.5%) and allowed the identification of a smallest region of overlapping deletion (SRO) of 3.0 cM, delimited by D4S412 and D4S3023. Two of these tumors with 4p LOH are from patients belonging to a family with recurrent NB. Interestingly the genotyping of this family revealed an identical haplotype that includes the nonrecombinant loci D4S412, D4S2957 and D4S432 shared by all affected children and demonstrated that this haplotype is retained in the two tumors carrying somatic deletions from patients of this family. Furthermore linkage analysis was performed in two NB families and yielded an overall lod-score of 3.0 in the interval including the haplotype. This provides a confirmatory indication that the region delimited by D4S2936 and D4S3023, which also includes the new defined SRO, may harbor NB predisposing gene/s.     

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.     

原发性肝癌8号和16号染色体杂合子丢失的研究

目的:分析人肝细胞肝癌(HCC)组织中染色体8和16部分染色体片段的杂合子丢失及与临床病理关系,初步筛选HCC相关的抑癌基因,为HCC的早期诊断、预后预警提供可能的新分子标记物.方法:应用聚合酶链反应-变性聚丙烯酰胺凝胶-银染法分析45例HCC组织标本中分别位于染色体8和16上的具有高度多态性微卫星位点的杂合性丢失(LOH)状态.结果:发生LOH的总频率为68.89％ (31/45),其中D16S511位点的LOH发生率最高为53.33％ (24/45),其次是D8S261( 39.02％,16/41)和D8S499(34.88％,15/43).结论:染色体16q23、8p22-21.3及8p12区域的LOH发生频率高,可能存在与HCC发生发展相关的新的抑癌基因,特定位点的遗传变异可能与HBV感染、临床病理恶性程度等预后因素相关.     

原发性胃癌染色体7q31的最小共同缺失区域及其意义

背景与目的:先前的研究显示7号染色体长臂(7q)在原发性胃癌有高频缺失;位于7q31的D7S486是7q上最高频的杂合性缺失(lossofheterozygosity,LOH)位点,且该位点的LOH频率与肿瘤的淋巴结转移显著相关;推测D7S486位点附近可能存在胃癌相关的抑癌基因(tumorsuppressorgene,TSG)。为能在更小的区域内找寻胃癌相关的TSGs,本研究通过检测原发性胃癌在7q31区域内微卫星标记位点的LOH情况,确定胃癌的最小共同缺失区域,并分析它们在胃癌发病中的可能作用。方法:以D7S486位点为中心,在位于其上下的7q31区域内选取平均遗传距离约0.5厘摩(centimorgan,cM)的12个微卫星标记。显微切割78例原发性胃癌和相应的正常胃粘膜组织,分别提取DNA;进行多重PCR扩增,聚丙烯酰胺凝胶电泳分离PCR产物,以GeneScan、Genotyper软件分析各微卫星位点的LOH情况。根据LOH结果作图,确定胃癌在7q31内的最小共同缺失区域,并与临床病理指标联系,分析区域缺失在胃癌发病中的可能作用。结果:12个微卫星标记位点均可在原发性胃癌中出现LOH,总的LOH频率为41.7%(40/72)。LOH的最高频位点是D7S486(位于7q31.2),为30.4.%(17/56);次高频位点是D7S650(位于7q31.3),为21.1%(8/38)。原发性胃癌在7q31内有两个最小共同缺失区域,分别为D7S2543～D7S486和D7S480～D7S650(长度均约为90kb)。D7S2543～D7S486区域缺失的频率与胃癌患者的临床分期和淋巴结转移显著相关(P=0.01和P=0.03);D7S480～D7S650区域缺失的频率与胃癌患者的临床分期显著相关(P=0.03),且该区域缺失仅出现于临床Ⅲ/Ⅳ期、T3/T4期或淋巴结转移的患者。结论:原发性胃癌在染色体7q31上存在两个最小共同缺失区域,分别为D7S2543～D7S486和D7S480～D7S650;在这两个区域内可能存在胃癌发展密切相关的抑癌基因。     

Allelic loss of the PTEN region (10q23) in breast carcinomas of poor pathophenotype

Loss of heterozygosity (LOH) in loci of the 10q23 region that harbor the PTEN gene and mutations in the sequence of this gene have been found in several primary human tumors including breast carcinomas, suggesting that this gene could be implicated in their pathogenesis. We investigated allelic losses in microsatellites of the 10q23 region, and their correlations with nine pathologic parameters in 105 breast carcinomas. The LOH analysis was performcd by amplifying DNA by PCR, using five markers of the 10q23 region (D10S1687, D10S541, D10S2491, D10S583 and D10S571). LOH in at least one marker of the PTEN region was found in 29.5% of tumors. The statistical comparison between carcinomas with and without LOH in terms of the pathologic parameters showed significant differences in age (p=0.03), lymph node metastases (p=0.02), and higher histological grade (p=0.02); a trend toward significance was found for progesterone receptors (p=0.05). LOH in an individual marker and statistically significant relationships to tumor characteristics were observed at locus D10S541 for lymph node metastases (p=0.04), at D10S2491 (intragenic to the PTEN gene) for lymph node metastases (p=0.02), and at D10S583 for progesterone receptors (p=0.01) and for high grade (p=0.03). These results suggest the PTEN gene, or other genes of the 10q23 region, could be functionally related to breast cancer, probably influencing the development of histological features associated with poor prognosis.     

Loss of heterozygosity on chromosome 10q23 and mutation of the phosphatase and tensin homolog deleted from chromosome 10 tumor suppressor gene in Korean hepatocellular carcinoma patients

Loss of heterozygosity (LOH) in the 10q23 chromosomal region was analyzed in 18 tissue samples from Korean hepatocellular carcinoma (HCC) patients. LOH at the phosphatase and tensin homolog deleted from chromosome 10 (PTEN) region (D10S215, AFMa086wg9 and D10S541) was found in 8 of the 18 (44.4%) HCCs. LOH (20%) and microsatellite instability (26.7%) were also frequently found at the D10S2177 locus, which is located on the telomere side of the PTEN region. LOH was found in other loci, such as AFM280we1 and D10S2281. The presence of LOH in regions other than the PTEN region on chromosome 10q23 suggested the presence of additional tumor suppressor gene(s). PTEN mutation was found in only a subset of HCCs: A single base insertion at the end of the 5'-end splice signal (AG-GUAAGUU) in intron 5 and a silent mutation in exon 6 (codon 188, CTG-Val to CTA). Our data collectively suggest that the genetic alterations of chromosome 10q23, including the PTEN gene, could be important in hepatocarcinogenesis in the Korean population.     

Deletion mapping and linkage analysis provide strong indication for the involvement of the human chromosome region 8p12-p22 in breast carcinogenesis.

We have identified a high frequency of loss of heterozygosity (LOH) on the human chromosome region 8p12-p22 in a panel of microdissected familial (86% LOH) and sporadic (74% LOH) breast tumours. The two most frequently deleted regions were defined around marker D8S133 and in a broader centromeric region bounded by markers D8S137 and D8S339. We cannot unequivocally characterize the 8p12-p22 loss as an early or a late event in breast carcinogenesis. In parallel, we have performed linkage analysis in four German breast cancer families. A location score greater than 13.67 corresponding to a LOD score of 2.97 at the marker D8S137 has been obtained. Our results considerably strengthen the evidence for a breast cancer susceptibility gene(s) located on the short arm of the chromosome region at 8p12-p22.     

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.