Two discrete regions of deletion at 7q in uterine leiomyomas

This study further defines the region of consistent deletion of chromosome 7 in uterine leiomyomas. We have examined 74 leiomyomas for allelic loss of markers spanning the 7q22 region defined by markers D7S518 and D7S471. Forty tumors with cytogenetically defined 7q deletions, twenty-nine tumors without cytogenetically visible 7q deletions, and five tumors with no cytogenetic information were examined for allelic loss of D7S518, D7S666, D7S515, D7S658, D7S496, D7S692, and D7S471. Loss of heterozygosity for one or more of these loci was observed in twenty-eight leiomyomas with cytogenetically defined 7q deletions and in three leiomyomas with a normal karyotype. Allelic loss of D7S666 was common and was observed in all twenty-three informative tumors with 7q deletions and in two tumors with normal karyotypes. This study indicates the presence of a tumor suppressor gene in close proximity to the D7S666 locus. Eight tumors followed an unusual pattern of allelic loss. These tumors showed retention of heterozygosity for at least one locus flanked by deleted loci. These results suggest the possibility that two discrete regions of deletion at 7q22 are involved in the development of a subset of leiomyomas. Genes Chromosom. Cancer 19:156–160, 1997. © 1997 Wiley-Liss Inc.     

Defining the region(s) of deletion at 6q16-q22 in human prostate cancer

Deletion of the long arm of chromosome 6 (6q) frequently occurs in many neoplasms, including carcinomas of the prostate and breast and melanoma, suggesting the location of a tumor-suppressor gene or genes at 6q. At present, however, the region of deletion has not been well defined, and the target gene of deletion remains to be identified. In this study, we analyzed 44 primary prostate cancers with 16 polymorphic markers for loss of heterozygosity (LOH) by using PCR-based techniques. We also examined 23 cell lines/xenografts of prostate cancer with 38 markers for LOH by the method of homozygosity mapping of deletion. LOH at 6q16 - q22 was detected in 21 of 44 (48%) primary tumors and in 12 of 23 (52%) cell lines/xenografts. Two regions of LOH were defined. One was 7.5 cM at 6q16 - q21 between markers D6S1716 and D6S1580, and the other was 4.3 cM at 6q22 between D6S261 and D6S1702. Whereas no correlation was found between LOH at 6q16-q22 and patient age at diagnosis or Gleason score, tumors at higher stage appear to have more frequent LOH. These findings suggest that deletion of 6q16 - q22 is a frequent event in prostate cancer, and that the deletion originates from two distinct regions. These results should be useful in identifying the target gene(s) of deletion at 6q.     

An 8-cM interstitial deletion on 4q21-q22 in DNA from an infant with hepatoblastoma overlaps with a commonly deleted region in adult liver cancers

We performed molecular analysis of a germline interstitial deletion of chromosome 4 [del(4)(q21.22q23)], which had been observed in a male infant manifesting early-onset hepatoblastoma (HBL). The chromosomal anomaly in this child was associated with a unique congenital syndrome including HBL, atrial septal defect, ventricular septal defect, patent ductus arteriosus, mental retardation, and seizures. However, the patient did not exhibit a megalencephaly typical of 4q21-22 deletions. His HBL was associated with an increasing serum alpha-fetoprotein level and rapid growth. To define the chromosomal deletion at the molecular level in this child, we analyzed his lymphoblasts with fluorescence in situ hybridization, using as probes a panel of BAC/PAC genomic clones containing STS markers covering the 4q12-27 region. The analysis revealed that the affected chromosome had an 8-cM deletion within 4q21-q22, flanked by markers D4S2964 and D4S2966. This microdeletion overlaps with the commonly deleted region at 4q21-q22 that was recently defined in adult hepatocellular carcinomas.     

Definition of a region of loss of heterozygosity at chromosome 11q in cervical carcinoma.

Chromosomal deletions at segment 11q23-q24 have been identified in a variety of human epithelial tumors, including cervical carcinoma (CC), indicating the presence in this region of at least a tumor suppressor gene (TSG) involved in the development of these neoplasms. To localize the 11q deletion target more precisely, 54 primary cervical carcinomas were examined for loss of heterozygosity (LOH) using a panel of microsatellite DNA markers mapping to 11p.15 and spanning region 11q23-qter. Nineteen tumors were found to have LOH at chromosome 11q. The highest frequency of LOH was observed at locus APOC-3, located in 11q23.1-q23.2, which was deleted in 42% of the informative cases. In contrast, LOH was infrequent at distal 11q in current series of CC. The smallest common region of loss included APOC-3 and was defined distally by marker D11S925 in region 11q23. The present data strongly suggest that the 11q suppressor gene(s) involved in cervical tumorigenesis is likely to be located at chromosome region 11q22-q23.     

Molecular cytogenetic definition of three distinct chromosome arm 14q deletion intervals in gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms characterized by frequent chromosome arm 14q losses. In this study, the 14q changes in a series of 39 histologically and immunohistochemically confirmed GISTs were analyzed in detail by metaphase and/or interphase fluorescence in situ hybridization (FISH) studies using 21 genetically well-characterized, region-specific 14q11-24 YAC clones. By conventional cytogenetic analysis, acquired clonal chromosome aberrations were found in 17 out of 35 tumors. Chromosome 14 was involved in 13 cases; six specimens showed complete chromosome 14 loss, while the remaining seven had structural abnormalities with the breakpoints residing within the intervals 14q11-13 or 14q22-24. Other recurrent chromosome aberrations included frequent deletions of chromosome 1p (11/17), losses of chromosome 22 (7/17), losses or deletions of chromosome arm 13 (6/17) or 15 (4/17), and gains or translocations involving chromosome 17 (4/17). Combining cytogenetic data with double-color FISH analysis, total or partial losses of 14q material were detected in 29 out of 36 tumors (81%). The 14q losses were found in all stages and histological subtypes. Two most frequent common deletion regions flanked by YACs 931B1 and 761D4, and 802E7 and 892C11 at 14q23-24 (25/30 of each; 83%) could be identified. Furthermore, 21 tumors (70%) shared a region of deletion defined by YACs 957H10 and 931E5 at 14q11-12. Our results suggest the presence of at least three distinct critical deletion regions on chromosome 14 in GISTs.     

Split foot and developmental retardation associated with a deletion of three microsatellite markers in 7q21.2-q22.1

A deletion of 7q21.2-q22.1 has been found in a patient with split foot and developmental retardation. Molecular analysis using polymerase chain reaction (PCR) showed deletion of three microsatellite markers, D7S527, D7S479 and D7S554, in the patient's paternal chromosome. These results pinpoint the critical region for an ectrodactyly locus (SHFD1) on chromosome 7.     

Loss of heterozygosity on chromosome 22q in gastrointestinal stromal tumors (GISTs): a study on 50 cases

Mutational activation of KIT or PDGFRA is considered an early step in pathogenesis of gastrointestinal stromal tumors (GISTs); however, other nonrandom genetic changes have also been identified. At least three common regions of deletions on chromosome 22q, which may harbor putative tumor suppressor genes, have been defined. However, mapping of these regions has been inconsistent. It has also been speculated that GI autonomous nerve tumors (GANTs), GISTs with ultrastructural features suggestive of autonomic nerve differentiation, are characterized by a specific deletion involving 22q13 cytogenetic region. This study was undertaken to evaluate loss of heterozygosity (LOH) on chromosome 22q in 50 GISTs, including 10 GANTs. Four tumors were incidental minimal lesions 相似文献   

Delineation of a critical region on chromosome 18 for the del(18)(q12.2q21.1) syndrome

Deletions involving the long arm of chromosome 18 have been reported in many patients. Most of these deletions are localized in the distal half of the long arm (18q21.1 --> qter) and are detectable by standard cytogenetic analysis. However, smaller interstitial deletions leading to a recognizable phenotype and residing in the region around chromosome band 18q12.3 (bands q12-q21) are less common. Here we report on an interstitial deletion of less than 1.8 Mb within chromosomal band 18q12.3. The phenotypic features of the propositus correspond well with those observed in patients with larger cytogenetically detectable deletions encompassing chromosome band 18q12.3. The deletion enabled us to define a critical region for the following features of the del(18)(q12.2q21.1) syndrome: hypotonia, expressive language delay, short stature, and behavioral problems.     

An interstitial deletion of chromosome 7 at band q21: a case report and review

We report on a girl with moderate developmental delay and mild dysmorphic features. Cytogenetic investigations revealed a de novo interstitial deletion at the proximal dark band on the long arm of chromosome 7 (7q21.1-q21.3) in all analyzed G-banded metaphases of lymphocytes and fibroblasts. Fluorescence in situ hybridization (FISH) and molecular studies defined the breakpoints at 7q21.11 and 7q21.3 on the paternal chromosome 7, with the proximal deletion breakpoint between the elastin gene (localized at 7q11.23) and D7S2517, and the distal breakpoint between D7S652 and the COL1A2 gene (localized at 7q21.3-q22.1). Deletions of interstitial segments at the proximal long arm of chromosome 7 at q21 are relatively rare. The karyotype-phenotype correlation of these patients is reviewed and discussed. The clinical findings of patients with a deletion at 7q21 significantly overlap with those of patients with maternal uniparental disomy of chromosome 7 (matUPD(7)) and Silver-Russell syndrome (SRS, OMIM 180860). Therefore, 7q21 might be considered a candidate chromosomal region for matUPD(7) and SRS.     

Expression of the HMGA2-LPP fusion transcript in only 1 of 61 karyotypically normal pulmonary chondroid hamartomas

We present the results of a comparative genomic hybridization (CGH) analysis of three meningeal solitary fibrous tumors (SFT). One case showed loss of chromosome 3 and two tumors had deletions of the region 3p21-p26. Other chromosomal losses included 4p15, 8q22-q24, 10, 11q14-q25, 17q11- q23, 20, and 21 in one case each. In addition, there were gains of 18p11-p13 in one case, and 1p11-p36 and 20q11-q13 in another. To our knowledge, there are no previous CGH or cytogenetic data on meningeal SFT, and loss of material on chromosome 3 has not been described in SFT at other sites. Our findings are discussed in relation to published molecular genetic and cytogenetic data on meningioma and hemangiopericytoma, the two lesions with which meningeal SFT are most likely to be confused.     

Substantial reduction of the gastric carcinoma critical region at 6q16.3-q23.1.

Deletions of the long arm of chromosome 6 are a common event in gastric carcinomas. In a previous study, deletion mapping of 6q identified two smallest regions of overlap (SROs) of heterozygous deletions: one interstitial, spanning 12-16 cM, bordered by D6S268 (6q16.3-q21) and ARG1 (6q22.3-q23.1), and one distal to IFNGR1 (6q23-q24), spanning more than 30 cM. Loss of heterozygosity (LOH) of the interstitial SRO was detected in 50% of informative tumors. We analyzed 60 primary gastric tumors with 19 highly polymorphic markers from 6q16.3-q23.3 to delimit the interstitial SRO further. Of the 50 tumors that were informative for at least one locus, 18 (36%) showed allelic imbalance (AI). The overlap of these cases allowed us to define an SRO of approximately 3 Mb flanked by D6S278 and D6S404. AI or LOH of this region occurs in all histologic types of gastric carcinoma and in early stages of development, indicating that loss of a gene from this region of 6q is a crucial step in a main route of gastric carcinogenesis. For cases with retention of 6q, alternative routes of gastric carcinogenesis may exist. Genes Chromosomes Cancer 26:29-34, 1999.     

High-resolution deletion mapping of chromosome 14 in stromal tumors of the gastrointestinal tract suggests two distinct tumor suppressor loci

DNA copy number losses at chromosome arm 14q are the most frequently occurring aberrations in gastrointestinal stromal tumors (GISTs). To characterize the deletion at 14q, we performed comparative genomic hybridization (CGH) and high-resolution deletion mapping using a panel of 32 polymorphic microsatellite markers in 30 GISTs. The GISTs were classified according to their metastatic potential and mitotic counts into 15 low-risk and 15 high-risk tumors. Losses with a minimal common overlapping region at 14q12-q24 were detected by CGH in 16 tumors (53) (nine low-risk and seven high-risk). Investigation with microsatellite markers was informative in 690 analyses (72%). Loss of heterozygosity (LOH) with at least one marker was detected in 279 analyses in 24 tumors (80%). Deletions were equally frequent in low-risk and high-risk GISTs. Two common deletion regions were identified at 14q11.1-q12 and 14q23-q24.3. The highest frequencies of deletions were seen in regions corresponding to markers D14S283 (20/28, 71%) at 14q11.1-q12 and D14S258 (17/27, 63%) at 14q23-q24, suggesting that these are two tumor suppressor loci.     

Interstitial 1q25.3-q31.3 deletion in a boy with mild manifestations

We describe a 4-year-old boy with an accessory right thumb, short and broad toes, cryptorchidism, micrognathia, abnormally modeled ears, and delayed speech development. The chromosome analysis of patient's peripheral blood lymphocytes by conventional GTG banding demonstrated a small deletion in the long arm of chromosome 1. Confirmation and defined localization of the deleted segment to chromosomal bands 1q25.3-q31.3 was obtained by high resolution prometaphase analysis. Molecular studies, using a set of polymorphic chromosome 1q specific microsatellite markers, localized the deletion between the markers D1S2127 and D1S1727 on the paternally inherited chromosome 1. The maximum physical distance between these markers is approximately 21 Mb. The previously described two patients with 1q25-q31 deletions both had severe clinical manifestations, just as the other 10 patients with the proposed "intermediate 1q deletion syndrome," associated with 1q25-q32 deletions. Distinct from all these patients, the clinical picture of our patient is markedly milder, i.e., without growth retardation, microcephaly, or clear mental retardation.     

Identification of a 7.1-mega base pairs minimal deletion at 14q31.1-32.11 in adenocarcinomas of the gastroesophageal junction

In a recent evaluation by comparative genomic hybridization, we demonstrated chromosome 14q31-32.1 to be frequently deleted in adenocarcinomas of the gastroesophageal junction. This suggests the presence of a tumor suppressor gene in the deleted region. In the present study, we have performed a detailed loss of heterozygosity analysis in 34 gastroesophageal junction adenocarcinomas and 1 tumor-corresponding dysplastic Barrett's epithelium sample with 37 polymorphic microsatellite markers. Thirty-five markers are in the 14q24.3-32.33 region with a mean distance of 800 kilo base pairs. Of 34 tumor samples, 14 (41%) showed loss of 14q markers. We identified a minimal region of allelic loss of 7105440 base pairs between markers D14S1000 and D14S256 at cytogenetic location 14q31.1-32.11. Within this region, markers D14S1035, D14S55, D14S1037, D14S1022, D14S1052, D14S974, D14S73, D14S1033, D14S67, D14S68, and D14S1058 showed loss in all informative tumors with 14q loss. The region between markers D14S1000 and D14S256 contains 7 known genes. The identification of this minimal deletion and the data base information on the genes present in this region facilitate the search for the candidate tumor suppressor gene(s).     

Loss of heterozygosity analysis of a candidate gastric carcinoma tumor suppressor locus at 7q31

Gastric carcinoma is one of the most common malignancies in Asia. Although the allelic deletion of 7q has been reportedly associated with primary gastric carcinoma tumorigenesis, no predisposing genes in this region have been identified so far. Here, we report the results of genotype and loss of heterozygosity (LOH) analysis on 7q in this tumor. A panel of nine microsatellite markers distributed over the whole chromosome 7q was used for genotyping primary gastric carcinomas. Of 72 primary tumors LOH of D7S486 occurred in 24.0% (12/50) of cases. Fine mapping with 12 additional markers flanking D7S486 resulted in LOH of 30.36% (17/56) and defined one minimal deleted region in primary gastric carcinomas, a 90-kilobase region bounded by D7S2543 and D7S486 at 7q31.2. The allelic deletion correlates statistically with clinicopathologic variables. Our data suggest a possible link between putative tumor suppressor genes and gastric carcinoma in the 7q31 region.     

A new case of 2q duplication supports either a locus for orofacial clefting between markers D2S1897 and D2S2023 or a locus for cleft palate only on chromosome 2q13-q21

We report on a pure duplication of the proximal chromosome 2q in a 6.5-year-old boy with V-shaped midline cleft palate and bifid uvula, posteriorly located tongue, and micrognathia (Pierre Robin sequence), celiac disease, failure to thrive, and developmental delay. Cytogenetic and FISH analysis indicated a duplication of chromosome 2q13-q22. In general, pure proximal duplication or triplication of 2q is rare. The clinical features and chromosomal breakpoints of the 10 previously reported patients varied, and no common phenotype or proximal duplication/triplication 2q syndrome could be defined to date. However, based on four previous patients with different orofacial clefts and our case, a locus for orofacial clefting may be located at proximal 2q. The duplication/triplication comprised chromosome 2q13 in all five affected individuals including our patient. Our patient and three previous cases (two with cleft palate only (CPO) and one with cleft lip/palate (CL/P)) showed a cytogenetic breakpoint at 2q13, which could support the presence of a critical dominant gene disrupted by a common breakpoint, however, the fifth case with CPO showed different breakpoints, advocating against the disruption of a critical dominant gene and supporting that the overexpression of a gene(s) on chromosome 2q13-q21 may cause cleft palate only (CPO) and Pierre Robin sequence. Hence, our findings support either the presence of one locus for orofacial clefting (CL/P, CPO, and Pierre Robin sequence) between markers D2S1897 (chromosome 2q12.2) and D2S2023 (chromosome 2q14.2), or alternatively the presence of a locus for CPO and Pierre Robin sequence on chromosome 2q13-q21.     

Identification of two distinct regions of deletion at 6q in gastric carcinoma

Loss of heterozygosity (LOH) affecting the long arm of chromosome 6 has been found repeatedly in human cancers. Recently, our group reported that del(6)(q21-22→qter) was the most consistent structural cytogenetic abnormality in gastric carcinomas. To determine more precisely the deleted region, we studied 51 tumors with 9 polymorphic markers on this chromosome arm. LOH of one or more markers was found in 39% of the tumors. LOH at region 6q22.3 was detected in 50% of informative tumors and at 6q26-q27 in 37% of informative tumors. By comparative analysis of LOH regions, we identified two separate regions of overlapped deletions at 6q, one between 6q16.3-q21 and 6q22.3-q23.1, another distal to 6q23-q24. A comparison of clinicopathologic features of gastric carcinomas with and without LOH at 6q revealed statistically significant or suggestive differences between LOH and young age of the patients and proximal location of the tumors. The two informative early gastric carcinomas both showed LOH at 6q. The occurrence of LOH at 6q was similar in all histological types. We conclude that two distinct regions at 6q appear to be involved in the early stages of gastric carcinogenesis.     

Molecular cytogenetic characterization of del(7q) in two uterine leiomyoma-derived cell lines

Uterine leiomyoma cytogenetically exhibits at least six chromosomally abnormal subgroups. The largest subgroup is characterized by deletions of the long arm of chromosome 7. Few molecular and fluorescence in situ hybridization data are available that have aimed at a better definition of the lesion. Here, we report the results of a partial molecular cytogenetic characterization of two del(7q) chromosomes that were derived from cell lines established from two uterine leiomyomas with del(7)(q22q32). By using a large series of ordered 7q markers, we were able to identify the most proximal and the most distal conserved markers, which delineate the size of the deletion and which allow for a more targeted approach to the nature and function of genes that are possibly relevant for the pathogenesis of the disorder. Genes Chromosom. Cancer 18:155–161, 1997. © 1997 Wiley-Liss, Inc.     

FISH analysis in Prader-Willi and Angelman syndrome patients

We report on a combined high resolution cytogenetic and fluorescent in situ hybridization study (FISH) on 15 Prader-Willi syndrome (PWS) and 14 Angelman syndrome (AS) patients. High resolution banding showed a microdeletion in the 15q11-q13 region in 7 out of 15 PWS patients, and FISH analysis of the D15S11 and SNRPN cosmids demonstrated absence of the critical region in three additional cases. Likewise 8 out of 14 AS patients were found to be deleted with FISH, using the GABRB3 specific cosmid, whereas only 4 of them had a cytogenetically detectable deletion. © 1995 Wiley-Liss, Inc.