High resolution mapping of chromosome 6 deletions in cervical cancer.

Chromosome 6 is frequently affected in different tumors. However, little information exists on chromosome 6 deletions in cervical cancer. We have studied loss of heterozygosity (LOH) and microsatellite instability (MIN) in 62 invasive squamous cell carcinomas of the cervix (CC) using 19 polymorphic microsatellite markers spanning both arms of chromosome 6 and one marker located at 5p15. We found that LOH at chromosome 6 is a common feature of cervical carcinomas: 90% (56/62) of CC had LOH at least at one locus and about 58% (36/62) had LOH on both arms of chromosome 6. The highest LOH incidence was shown in HLA region (6p21.3-6p21.1) with markers D6S273 and D6S276 in 52.7% and 45.2% of informative cases respectively. Frequent LOH on 6q was found at loci D6S311 (6q24-25. 1), D6S305 (6q26) and D6S281 (6q27-6qter) in 37.8%, 33.3% and 39.0% of informative cases respectively. There was no significant correlation observed between clinical parameters of cervical cancer (age, histologic grade, clinical stages and progression) and LOH frequency. Microsatellite instability was found in 3 out of 62 cases (4.8%) at three and more loci out of 20 tested. The study shows that several regions on 6p and 6q may harbour potential tumor-suppressor genes important for cervical cancer progression.     

Loss of heterozygosity at the short arm of chromosome 3 in microdissected cervical intraepithelial neoplasia

Loss of heterozygosity (LOH) is a common genetic finding in many human neoplasms, including cervical cancer. The detection of LOH at specific loci in the precursor of cervical cancer, cervical intraepithelial neoplasia (CIN) may help in elucidating the evolution of this cancer, which has a clearly defined histological premalignant phase. However, molecular genetic investigation of CIN is difficult because many of the lesions are very small and sometimes ill defined topographically. In this study we analyzed eighteen polymorphic microsatellite repeats on chromosome 3p in CINs using a method of primer extension pre-amplification (PEP) for whole genome amplification combined with microdissection. These markers encompass chromosome region 3pter-3p12. LOH at one or more loci was detected in five (33%) out of the 15 informative cases with low grade CIN (CIN 1), while 22 (92%) out of 24 cases with high grade CIN (CIN 2 and 3) (P<0.01). The highest incidence (41%) of LOH was detected at locus D3S1038 (3p26.1-3p25.2). Frequent LOH (more than 20%) was also found at other loci including D3S1110 (3p25.3-3p25.1) (31%), D3S656 (3p25.1) (24%), D3S1076 (3p21.2-3p21.1) (29%), D3S1300 (3p21.1-3p14.2) (24%), D3S1600 (3p14.2-3p14.1) (24%), and D3S1079 (3p13) (25%). The results from this study taken together with others indicate that the genetic alterations on chromosome 3p are common in high grade of CIN and are probably early events in cervical carcinogenesis. Tumor suppressor gene(s) that play a role in cervical neoplasm may be located on the short arm of chromosome 3, likely at or near 3p26.1-25.1, 3p21.2-21.1, and 3p14.2-13.     

Multiple regions with allelic loss at chromosome 3 in superficial multifocal bladder tumors

We have examined six patients with multiple low grade, low stage superficial multifocal bladder tumors with surrounding tissues for loss of heterozygosity (LOH) and microsatellite instability at chromosome 3, totaling 76 samples. The majority (4/5) of the patients had LOH at or close to the fragile histidine triad (FHIT) gene (3p14.2; D3S1300), which is a candidate tumor suppressor gene for many cancer types. One patient showed a consistent LOH with four adjacent markers around FHIT region in all the tumors whereas in the corresponding surrounding tissues the heterozygosity was retained. In addition to the region near FHIT, two other regions had frequent allelic losses - one near the p telomere (3p25-26; D3S3050) and another near the q telomere (3q27; D3S2418). The largest numbers of LOH in the surrounding tissues were found at these regions (3/5 at D3S3050 and 2/5 at D3S2418). The D3S3050 marker is located at 3p26-3p25, near the Von Hippel-Lindau (VHL) tumor suppressor gene locus. LOH that were more random were found at 3q21.3-25.2 (D3S1744) and at 3p12-3p11 (D3S2465). Taken together, at least three regions at chromosome 3p25-26, 3p14.2 and 3q27 seem to have frequent loss of heterozygosity in multifocal superficial bladder tumors. We also performed a phylogenetic-type analysis to find out common changes and the degree of heterogeneity. The overall heterogeneity was low within a given patient: in all cases the majority of the tumor samples arranged in a single branch with a common origin. This point of origin varied from patient to patient, which is compatible with the earlier studies demonstrating the heterogeneity of the single primary bladder tumors. However, the phylogenetic-type analysis suggests that the FHIT region contains often the very first alterations at chromosome 3.     

Investigation of allelic imbalances on chromosome 3p in nasopharyngeal carcinoma in Tunisia: high frequency of microsatellite instability in patients with early-onset of the disease

Tunisia is one of the world's intermediate risk areas for nasopharyngeal carcinoma (NPC). Loss of heterozygosity (LOH) on the short arm of chromosome 3 (3p) is the most frequent genetic change reported in NPC from endemic areas. In the present study, we investigate the incidence of LOH and microsatellite instability (MSI) on chromosome 3p in 49 microdissected primary NPC specimens and corresponding non-cancerous tissues from Tunisian patients using six microsatellite polymorphic markers. LOH at one or more markers was observed in 40 out of 48 informative cases (83.3%). The markers D3S1038 at 3p25.2-26.1 and D3S1076 at 3p21.1-21.2 have showed the highest frequency of LOH (51.3%), followed by D3S1067 at 3p14.3-21.1 (48.7%), D3S1568 at 3p21.3 (47.4%), D3S659 at 3p13 (15.3%), and D3S1228 at 3p14.1-14.2 (11%). Interestingly, MSI at one or more microsatellite markers was observed in 15 cases (31.2%). The highest frequency of MSI was presented by D3S1568 (18.4%), D3S1067 (17.9%), and D3S1038 (12.8%). With regard to clinicopathological features, LOH was found to be less common in young patients (under 25 years) than in adults (p=0.04), whereas MSI was found to be more frequent in patients under 45 years than in older patients (p=0.006). No significant correlation was found between LOH or MSI and the other clinicopathological features investigated including, gender, tumor size, lymph node metastasis, UICC clinical stage, and histological subtype. This study revealed different patterns of allelic imbalance on chromosome 3P in NPC between age groups in Tunisia, and suggests an alteration in the DNA mismatch repair machinery that may be, in part, responsible of the early age onset form of this disease in North African populations. More attention should be given to the mismatch repair system in the juvenile form of this disease in future studies.     

胶质母细胞瘤6号染色体杂合性丢失的初步研究

目的：寻找胶质母细胞瘤（GBM）6号染色体上可能存在肿瘤抑制基因的杂合性丢失（LOH）区域,为发现和定位肿瘤抑制基因（TSG）提供线索和依据。方法：应用聚合酶链反应（PCR）方法,采用荧光标记的引物及377型DNA序列自动分析仪,分析了21例GBM患者6号染色体上20个微卫星多态性标记的LOH。结果：6号染色体总的LOH检出率为47．6％（10／21）,在28．1％（81／288）能提价信息位上检测了LOH。其中,6p和6q的LOH检出率分别是28．6％（6／21）、38．1％（8／21）,在6q^tel上距短臂端粒201．1cM的微卫星位点D6S281检测到较高的LOH率（50％）,6q^16.3上D6S287的LOH率也高达50％,另外,6p^21.1-21.3上D6S276的LOH率也较高（35．3％）。结论：6号染色体分子遗传学异常改变可能在GBM的发生发展中起着重要作用,染色体6q^tel上的D6S281位点,6q^16.3上的D6S287和6p^21.1-21.3的D62S276位点所在的染色体区域可能存在与GBM相关的肿瘤抑制基因。     

Chromosome 3p Alterations in Northeastern Thai Women with Cervical Carcinoma

The purpose of this study was to determine the incidence of the loss of heterozygosity (LOH) among normal ‍cervixes, cervical intraepithelial neoplasias (CINs) and invasive cervical cancers (ICCs). DNA samples (136) were ‍obtained from 31 normal cervixes, 49 CINs and 56 ICCs. Four polymorphic microsatellite markers (D3S1300, ‍D3S1351, D3S1478 and D3S4103) covering the chromosome 3p arm, were employed. LOH at one or more loci were ‍identified in: 9/31 (8.1%) normal cervixes, 17/49 (14.6%) CINs and 26/56 (22.1%) invasive cancers. The incidence of ‍the LOH at 3p varied for each locus and ranged from 5.6% for D3S1351 to the highest rate of 16.6% for D3S1300. ‍We thus found that LOH of chromosome 3p can occur in normal cervixes and that incidences increase in CINs and ‍ICCs. Deletion in the 3p14.2 (D3S1300) and 3p21.2 (D3S1478) regions might be an early event and, in fact, necessary ‍for cervical cancer progression. The loss of function of tumor suppressor genes (TSGs) located in these regions may ‍have a sequential effect in cervical cancer carcinogenesis.     

Instability of chromosome 6 microsatellite repeats in human cervical tumors carrying papillomavirus sequences

Loss of heterozygosity (LOH) in chromosome 6 in human squamous cervical carcinomas was analyzed in the long and short arms of the chromosome using 3 pairs of primers each. In all cases, normal adjacent tissue was used as control. Among 51 cases analyzed, we identified LOH or microsatellite instability in 23% using primer D6S291 (located at position 6p21.3) and in 11% using primers D6S308 (6q16.3–6q27) and D6S270 (6q22.3–6q23.2). On the contrary, no significant LOH or genomic instabilities were detected with primers D6S306 (6p22.3–6p21.2), D6S299 (6p22.3–6p21.3) and D6S287 (6q21–6q23.3). Our results thus suggest the existence of instable loci at 3 regions of chromosome 6. Whether these loci contain putative tumor-suppressor genes or genes involved in cell cycle control remains unknown. © 1996 Wiley-Liss, Inc.     

Deletion Mapping of Chromosome 1p and 22q in Pheochromocytoma

To identify the localization of tumor suppressor genes, 22 pheochromocytomas (9 hereditary and 13 sporadic) were examined for loss of heterozygosity (LOH) on the short arm of chromosome 1 and on the long arm of chromosome 22 by using 11 polymorphic DNA markers on each chromosome arm. LOH on 1p was observed in 12 of 22 informative cases (55%) and on 22q in 8 of 20 informative cases (40%). There was no significant difference in the frequency of LOH on 1p or 22q between hereditary and sporadic cases. We could localize the commonly deleted regions as distal to D1S73 and proximal to D1S63 on 1p and distal to D22S24 and proximal to D22S1 on 22q. In addition, the relationship between LOH on 1p and 22q was studied in 20 pheochromocytomas which were informative for probes on both chromosome arms. Of eight tumors that showed LOH on 22q, allelic loss on 1p was also detected in seven. Thus, LOH on 22q was correlated significantly with LOH on 1p ( P = 0.0249; Fisher's exact test). These results suggest that inactivation of multiple tumor suppressor genes may be required for development and progression of hereditary and non-hereditary pheochromocytoma.     

10号染色体可能含有多个与胶质母细胞瘤相关的肿瘤抑制基因

目的 寻找胶质母细胞瘤（GBM）10号染色体上可能存在肿瘤抑制基因的杂合性丢失（LOH）区域,为发现和定位肿瘤抑制基因（TSG）提供线索和依据。方法 应用聚合酶链反应（PCR）方法,采用荧光标记的引物和先进的377型DNA序列自动分析仪,分析了21例GBM10号染色体上20个微卫星多态性标记的LOH。结果 在85．7％（18／21例）GBM的10号染色体上观察到LOH,在57．7％（162／281）可提供信息位点上存在LOH。10q的LOH率高于10p,分别是81．0％（17／21）、66．7％（14／21）。在下列位点或区域检测到较高的LOH率（＞60％）：10q22.3-23.3上的D10s185-D10s192间区域,10p14-15.1上的D10s591-D10s249间区域,10q24.2-26.3上的D10s1693-D10s212间区域,10p12.2-14上的D10s547位点,10q21.3上的D10537位点。结论 10号染色体可能在GBM的分子水平发病机制中发挥着重要作用,它上面的多个染色体区域可能存在与GBM相关的多个TSG。     

食管鳞状细胞癌染色体13q12-13 杂合性丢失

 目的 分析食管鳞状细胞癌（ESCC）在13号染色体长臂12—13区（13q12—13）上的等位基因杂合性丢失（LOH），以期寻找13q12-13区上可能存在的与ESCC有关肿瘤抑制基因（TSG）的缺失区域。方法 用8个位于13q12—13区的微卫星标志物，对56例ESCC患者进行PCR-LOH分析，56例ESCC患者包括34例有上消化道癌家族史，22例无上消化道癌家族史。结果 56例ESCC患者中，48例（86％）显示一个或更多位点LOH；并发现一个LOH高频率区，位于位点D13s267和D13s219之间，物理距离仅有2．83Mb；在位点D13S1242有上消化道癌家族史组LOH为68％，明显高于无上消化道癌家族史组的18％，（P=0．003）；在位点D13S289有上消化道癌家族史组LOH为82％，明显高于无上消化道癌家族史组的31％（P=0．008），有显著意义。结论 研究提示染色体13q12-13的LOH可能在食管癌发生发展中起重要作用，在染色体13q12-13区上，可能存在一个或多个与ESCC发生发展有关肿瘤抑制基因（TSG）。     

Critical tumor-suppressor gene regions on chromosome 3P in major human epithelial malignancies: allelotyping and quantitative real-time PCR

To ascertain the involvement of human chromosome 3p and its established critical TSG regions in various epithelial malignancies, 21 polymorphic and 2 nonpolymorphic 3p markers were allelotyped in nonpapillary RCC, NSCLC, CC and BC from a total of 184 patients. LOH was observed with high frequency in all types of cancer studied: RCC (52/57, 91%), BC (41/51, 80%), NSCLC (30/40, 75%) and CC (27/36, 75%). Interstitial deletions, believed to signal TSG inactivation, were verified using the "L-allele rule" and real-time quantitative PCR. Significant correlation was observed between DNA copy numbers for 2 nonpolymorphic STS markers and LOH data for adjacent polymorphic loci. Interstitial deletions in 3p were demonstrated for all cancer types studied. However, the distribution of different types of deletion was characteristic for tumors from various locations. Large terminal deletions were predominantly seen in RCC and NSCLC (51% and 40%, respectively), correlating with clear cell RCC and squamous cell carcinomas of the lung. In addition to the LUCA region at 3p21.3 (centromeric), we found that the AP20 region (3p21.3, telomeric) was frequently affected in all 4 cancers, suggesting that this newly defined critical region contains multiple TSGs. Moreover, at least 3 candidate cancer-specific loci were identified. The telomeric 3p26.1-p25.3 region was predominantly deleted in RCC and NSCLC. The D3S1286 and D3S3047 markers (3p25.2-p24.3) were deleted nonrandomly in NSCLC. High-frequency LOH was detected in a segment mapped closely distal to the LUCA site (3p21.3), around the D3S2409 and D3S2456 markers.     

食管鳞状细胞癌染色体13q12-13杂合性丢失

目的分析食管鳞状细胞癌(ESCC)在13号染色体长臂1213区(13q1213)上的等位基因杂合性丢失(LOH),以期寻找13q1213区上可能存在的与ESCC有关肿瘤抑制基因(TSG)的缺失区域。方法用8个位于13q1213区的微卫星标志物,对56例ESCC患者进行PCRLOH分析,56例ESCC患者包括34例有上消化道癌家族史,22例无上消化道癌家族史。结果56例ESCC患者中,48例(86%)显示一个或更多位点LOH;并发现一个LOH高频率区,位于位点D13S267和D13S219之间,物理距离仅有2.83Mb;在位点D13S1242有上消化道癌家族史组LOH为68%,明显高于无上消化道癌家族史组的18%,(P=0.003);在位点D13S289有上消化道癌家族史组LOH为82%,明显高于无上消化道癌家族史组的31%(P=0.008),有显著意义。结论研究提示染色体13q1213的LOH可能在食管癌发生发展中起重要作用,在染色体13q1213区上,可能存在一个或多个与ESCC发生发展有关肿瘤抑制基因(TSG)。     

Frequent epigenetic inactivation of chromosome 3p candidate tumor suppressor genes in gallbladder carcinoma

Gallbladder carcinoma (GBC) is a highly malignant neoplasm that represents the leading cause of death for cancer in Chilean females. There is limited information about the molecular abnormalities involved in its pathogenesis. We have identified a number of molecular changes in GBC, including frequent allelic losses at chromosome 3p regions. Four distinct 3p sites (3p12, 3p14.2, 3p21.3 and 3p22-24) with frequent and early allelic losses in the sequential pathogenesis of this neoplasm have been detected. We investigated epigenetic and genetic abnormalities in GBC affecting 6 candidate tumor suppressor genes (TSG) located in chromosome 3p, including DUTT1 (3p12), FHIT (3p14.2), BLU, RASSF1A, SEMA3B and hMLH1 (3p21.3). DNA extracted from frozen tissue obtained from 50 surgical resected GBCs was examined for gene promoter methylation using MSP (methylation-specific PCR) technique after bisulfite treatment in all 6 genes. In addition, we performed PCR-based mutation examination using SSCP in FHIT and RASSF1A genes and loss of heterozygosity (LOH) analysis using microdissected tissue in a subset of tumors for the 3p21.3 region with 8 microsatellite markers. A very high frequency of GBC methylation was detected in SEMA3B (46/50, 92%) and FHIT (33/50, 66%), intermediate incidences in BLU (13/50, 26%) and DUTT1 (11/50, 22%) and very low frequencies in RASSF1A (4/50, 8%) and hMLH1 (2/50, 4%). Allelic loss at 3p21.3 was found in nearly half of the GBCs examined. We conclude that epigenetic inactivation by abnormal promoter methylation is a frequent event in chromosome 3p candidate TSGs in GBC pathogenesis, especially affecting genes SEMA3B (3p21.3) and FHIT (3p14.2).     

食管鳞癌FHIT基因等位缺失及其表达下调

背景与目的：食管癌3号染色体短臂(3p14)经常发生缺失或易位,脆性组氨酸三联体基因(fragile histidinetriad,FHIT)定位于3p14．2,在许多肿瘤中均发现此基因缺失或表达异常。然而,FHIT基因在食管癌中变化的形式以及FHIT改变在食管癌发生、发展中的作用尚未明确。本研究旨在探讨FHlT基因在食管鳞癌中的变化情况及其意义。方法：用微卫星分析方法观察80例食管鳞癌中FHIT基因的缺失,并用半定量逆转录聚合酶链反应法(reverse transeriptase-polymerase chain reaction,RT-PCR)分析其中20例食管鳞癌FHIT mRNA表达的变化。结果：FHIT基因内标志D3S3356、D3S3378、D3S3361在本系列的标本中为纯合子。FHIT基因旁侧微卫星位点D3S1234和D3S1540在癌旁组织具有较高的杂合度,信息个体中肿瘤组织的杂合性丢失(10ssofhelerozygosily,LOH)频率分别为57．69％(30／52)和67．86％(38／56)。在20例同时获得其RNA的标本中,15(75％)例出现FHIT基因的mRNA表达下调,且多发生于DNA水平伴有LOH的病例。但LOH发生与mRNA表达下调并不完全一致。结论：食管癌中FHIT基因频发异常,LOH是FHIT基因表达失调的主要机制,表观遗传学(epigenetic)变化可能与部分食管癌中FHIT基因的表达下调相关。     

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.     

显微切割鼻咽癌组织16号染色体杂合性缺失的研究

目的：研究鼻咽癌中１６号染色体的缺失情况。方法：采用显微切割的方法获取肿瘤组织,然后用ＰＣＲ的方法以１６号染色体上的８对引物对３８例鼻咽癌进行分析。结果：３８例鼻咽癌组织中所有标本至少有一个位点出现有杂合笥缺失,其中Ｄ１６Ｓ５３３出现杂合性缺失的频率最高,占８６．１％（３１／３３）,此外,杂合性缺失频率超过５０％的有引物Ｄ１６Ｓ３９８、Ｄ１６Ｓ３００和Ｄ１６Ｓ４２０。分别占７８．８％（２６／３３）     

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.     

CHROMOSOME 3 MAY HARBOR MULTIPLE TUMOR SUPPRESSOR GENES ASSOCIATED WITH PRIMARY GLIOBLASTOMA MULTIFORME

Glioblastoma multiforme (GBM), the most malignant type of glioma, is the most common primary brainneoplasm. Although comprehensive therapeutic measures are applied, the prognosis of GBM remains dismal with a median post-treatment survival of less than one year.Modern molecular genetics has demonstrated thatabnormal alterations of tumor suppressor genes (TSGs) and oncogenes are the major mechanisms responsible for the initiation and progression of this malignant tumor.Identifying of related…     

High resolution chromosome 3p allelotyping of human lung cancer and preneoplastic/preinvasive bronchial epithelium reveals multiple, discontinuous sites of 3p allele loss and three regions of frequent breakpoints

Allele loss involving chromosome arm 3p is one of the most frequent and earliest known genetic events in lung cancer pathogenesis and may affect several potential tumor suppressor gene regions. To further study the role of chromosome 3p allele loss in the pathogenesis of lung cancer, we performed high resolution loss of heterozygosity (LOH) studies on 97 lung cancer and 54 preneoplastic/preinvasive microdissected respiratory epithelial samples using a panel of 28 3p markers. Allelic losses of 3p were detected in 96% of the lung cancers and in 78% of the preneoplastic/preinvasive lesions. The allele losses were often multiple and discontinuous, with areas of LOH interspersed with areas of retention of heterozygosity. Most small cell lung carcinomas (91%) and squamous cell carcinomas (95%) demonstrated larger 3p segments of allele loss, whereas most (71%) of the adenocarcinomas and preneoplastic/preinvasive lesions had smaller chromosome areas of 3p allele loss. There was a progressive increase in the frequency and size of 3p allele loss regions with increasing severity of histopathological preneoplastic/preinvasive changes. In analyses of the specific parental allele lost comparing 42 preneoplastic/preinvasive foci with those lost in the lung cancer in the same patient (n = 10), the same parental allele was lost in 88% of 244 comparisons for 28 3p markers (P = 1.2 x 10(-36) for this occurring by chance). This indicates the occurrence of allele-specific loss in these foci similar to that seen in the tumor by a currently unknown mechanism. Analysis of all of the data indicated multiple regions of localized 3p allele loss including telomere-D3S1597, D3S1111-D3S2432, D3S2432-D3S1537, D3S1537, D3S1537-D3S1612, D3S4604/Luca19.1-D3S4622/Luca4.1, D3S4624/Luca2.1, D3S4624/Luca2.1-D3S1582, D3S1766, D3S1234-D3S1300 (FHIT/FRA3B region centered on D3S1300), D3S1284-D3S1577 (U2020/DUTT1 region centered on D3S1274), and D3S1511-centromere. A panel of six markers in the 600-kb 3p21.3 deletion region showed loss in 77% of the lung cancers, 70% of normal or preneoplastic/preinvasive lesions associated with lung cancer, and 49% of 47 normal, mildly abnormal, or preneoplastic/preinvasive lesions found in smokers without lung cancer; however, loss was seen in 0% of 18 epithelial samples from seven never smokers. The 600-kb 3p21.3 region and the 3p14.2 (FHIT/FRA3B) and 3p12 (U2020/DUTT1) regions were common, independent sites of breakpoints (retention of heterozygosity by some markers and LOH by other markers in the immediate region). We conclude that 3p allele loss is nearly universal in lung cancer pathogenesis; involves multiple, discrete, 3p LOH sites that often show a "discontinuous LOH" pattern in individual tumors; occurs in preneoplastic/preinvasive lesions in smokers with and without lung cancer (multiple lesions often lose the same parental allele); frequently involves breakpoints in at least three very small defined genomic regions; and appears to have allele loss and breakpoints first occurring in the 600-kb 3p21.3 region. These findings are consistent with previously reported LOH studies in a variety of tumors showing allele loss occurring by mitotic recombination and induced by oxidative damage.     

Deletion of chromosome 11p15, p12, q22, q23-24 loci in human prostate cancer

Loss of heterozygosity (LOH) on chromosome 11 is frequently altered in various epithelial cancers. The present study was designed to investigate LOH on chromosome 11 in microdissected samples of normal prostatic epithelium and invasive carcinoma from the same patients. For this purpose, DNA was extracted from the microdissected normal and tumor cells of 38 prostate cancers, amplified by polymerase chain reaction PCR and analyzed for LOH on chromosome 11 using 9 different polymorphic DNA markers (D11S1307, D11S989, D11S1313, D11S898, D11S940, D11S1818, D11S924, D11S1336 and D11S912). LOH on chromosome 11 was identified in 30 of 38 cases (78%) with at least one marker. Four distinct regions of loss detected were: 1) at 11p15, at loci between D11S1307 and D11S989; 2) at 11p12, on locus D11S131 (11p12); 3) at 11q22, on loci D11S898, D11S940 and D11S1818; and 4) at 11q23-24, on loci between D11S1336 and D11S912. We found 25% of the tumors with LOH at 11p15; 39% had LOH at 11p12; 66% had LOH at 11q22; and 47% had LOH at 11q23-24. These deletions at 11p15, 11p12, 11q22 and 11q23-24 loci were not related to the stage or grade of the tumor. Int. J. Cancer 72:283–288, 1997. © 1997 Wiley-Liss, Inc.