Cytogenetic and fluorescence in situ hybridization characterization of clonal chromosomal aberrations and CCND1 amplification in esophageal carcinomas

Cytogenetic analyses of four squamous cell carcinomas (SCC) of the esophagus showed complex numerical and structural abnormalities. Chromosomal bands or regions preferentially involved were 11q13, 8q10, 21q10, 3p10 approximately p11, 1p11 approximately q11, 5p11 approximately q11, and 14p11 approximately q11. For the first time, to our knowledge, recurrent aberrations were identified in esophageal SCC, including homogeneous staining region (hsr), isochromosomes i(3q) and i(21q), and ring chromosome. Losses of chromosomal material dominated over gains. Recurrent imbalances included under-representation of 4p13 approximately pter, 5q14 approximately qter, 9p22 approximately pter, 10p, 11p13 approximately pter, 12p13 approximately pter, 17p10 approximately pter, 18p11 approximately pter, 21p, and 22p, as well as over-representation of 1q25 approximately qter, 3q, 7q, and 8q. Interestingly, hsr at different chromosomal regions occurred in three of four cases. With the application of fluorescence in situ hybridization (FISH) and multicolor combined binary ratio labeling-FISH with specific DNA probes, it could be shown that in two cases the hsr was derived from chromosome 11 material and that the amplicon included CCND1. Our results, together with previous molecular genetic findings, indicate that CCND1might be a prime target in 11q13 amplification, and that amplification of this gene might be crucial in the tumorigenesis of esophageal SCC. These observed chromosomal aberrations and imbalances thus provide important information for further molecular genetic investigation of esophageal SCC.     

Chromosomal imbalances in Korean intrahepatic cholangiocarcinoma by comparative genomic hybridization

Intrahepatic cholangiocarcinoma (ICC) arises from epithelial cells in the intrahepatic bile duct. Until now, only few reports have been available concerning the genetic changes during the progression of ICC. In this study, we analyzed chromosomal aberrations in 19 frozen ICC samples using comparative genomic hybridization. The common chromosomal gains were observed in 8q22 approximately qter (11 cases, 58%), 5p14 approximately pter (32%), 2q33 approximately qter (26%), 7p (26%), 17q21 approximately q22 (26%), 18q12 approximately q21 (26%), and 19q13.1 (26%). DNA amplification was identified in nine tumors (47%). Chromosomal loss was found in Y (60%), 1p34 approximately pter (37%), 4q(32%), 18q21 approximately qter (32%) 19p (32%), X (32%), 5q11 approximately q14 (26%), 8p(26%), 9p (26%), and 17p (26%). Chromosomal aberrations identified in this study provide candidate regions involved in the tumorigenesis and progression of ICC.     

Characterization of gains, losses, and regional amplification in testicular germ cell tumor cell lines by comparative genomic hybridization

We have performed comparative genomic hybridization on 12 testicular germ cell tumor (TGCT) cell lines and one paraffin-embedded surgical specimen to identify and characterize genome-wide gains and losses of chromosomes in these specimens. All specimens demonstrated overrepresentation of 12p. Other significant chromosomal gains, apart from 12p, included the X chromosome and chromosome arms 1q and 20q. Chromosomal losses were observed for chromosomes 4 and 18 and chromosome arms 2q, 9q, and 13q. Genomic differences were observed between an embryonal carcinoma component of a mixed tumor, 833K, and its cisplastin-resistant derivative line, 64CP, including losses of 6q23 approximately qter and 9p22 approximately q21. Five lines also demonstrated gain of 12p and additional 12p12 approximately p13 material. Similarly, two lines demonstrated gain of 12p and additional 12p11.2 approximately p12 material. The data supports the consistent gain of 12p in adult TGCT cell lines and additional regional amplification of 12p in some lines. This regional amplification has been observed in both primary tumor specimens and TGCT cell lines and may support a hypothesis that at least two different regions of 12p, one proximal and one distal, harbor genes important for the pathogenesis of testicular germ cell neoplasia.     

Molecular cytogenetic analysis of oral squamous cell carcinomas by comparative genomic hybridization, spectral karyotyping, and fluorescence in situ hybridization

We investigated relationships between DNA copy number aberrations and chromosomal structural rearrangements in 11 different cell lines derived from oral squamous cell carcinoma (OSCC) by comparative genomic hybridization (CGH), spectral karyotyping (SKY), and fluorescence in situ hybridization (FISH). CGH frequently showed recurrent chromosomal gains of 5p, 20q12, 8q23 approximately qter, 20p11 approximately p12, 7p15, 11p13 approximately p14, and 14q21, as well as losses of 4q, 18q, 4p11 approximately p15, 19p13, 8p21 approximately pter, and 16p11 approximately p12. SKY identified the following recurrent chromosomal abnormalities: i(5)(p10), i(5)(q10), i(8)(q10), der(X;1)(q10;p10), der(3;5)(p10;p10), and der(3;18)(q10;p10). In addition, breakpoints detected by SKY were clustered in 11q13 and around centromeric regions, including 5p10/q10, 3p10/q10, 8p10/q10 14q10, 1p10/1q10, and 16p10/16q10. Cell lines with i(5)(p10) and i(8)(q10) showed gains of the entire chromosome arms of 5p and 8q by CGH. Moreover, breakages near the centromeres of chromosomes 5 and 8 may be associated with 5p gain, 8q gain, and 8p loss in OSCC. FISH with a DNA probe from a BAC clone mapping to 5p15 showed a significant correlation between the average numbers of i(5)(p10) and 5p15 (R(2) = 0.8693, P< 0.01) in these cell lines, indicating that DNA copy number of 5p depends upon isochromosome formation in OSCC.     

Detection of genetic alterations in Korean ovarian carcinomas by degenerate oligonucleotide primed polymerase chain reaction-comparative genomic hybridization

Chromosomal aberrations in 22 Koreans with ovarian carcinomas were investigated by degenerate oligonucleotide primed-polymerase chain reaction comparative genomic hybridization. The common sites of copy number increases were 20q (90%), 17q23 approximately qter (86%), 8q22 approximately qter (68%), 3q25 approximately qter (59%), 6p21 (59%), 11q13 (54%), 16p (40%), 2q31 approximately qter (36%), 7q (36%), 14q31 (36%), 15q24 approximately qter (36%), and 1q32 approximately qter (31%). DNA amplification was identified in 18 carcinomas (82%). The frequent sites of amplification were 20q13.2 approximately qter, 8q24.1, 17q23 approximately qter, 3q25 approximately qter, and 6p21. The most frequent sites of copy number decreases were 4q21 approximately q31 (54%), 5q13 approximately q21 (50%), and 13q14 approximately q21 (45%). The recurrent gains and losses of chromosomal regions identified in this study provide candidate regions that may contain oncogenes or tumor suppressor genes, respectively.     

Characterization of large chromosome markers in a malignant fibrous histiocytoma by spectral karyotyping, comparative genomic hybridization (CGH), and array CGH

In this study, we characterized the chromosomal composition of an intra-abdominal soft tissue sarcoma diagnosed as a malignant fibrous histiocytoma (MFH). By applying a combination of spectral karyotyping, G-banding, and comparative genomic hybridization (CGH), this case was shown to carry large chromosome markers with material mainly from chromosomes 6 and 8. Further characterization of this unique tumor revealed high-level amplifications at the 6q21 approximately q23, 8p21 approximately pter, 8q24 approximately qter, and 12q13 approximately q21 regions. Using array CGH, these amplified regions were found to include MASL1 in 8p, as well s MDM2 and CDK4 in 12q, which have been shown to be amplified in MFH. Similarly, gains of 6q and 8q have also been seen in MFH. In conclusion, our study demonstrates the occurrence of large chromosome markers in MFH and suggests that the regions 6q21 approximately q23, 8p21 approximately pter, 8q24 approximately qter, and 12q13 approximately q21 might harbor oncogenes that could play a role in MFH's tumorigenesis. In addition, gain of 12q13 approximately q21, which is typical of well-differentiated liposarcoma, may also occur in MFH, supporting the previously suggested overlap in genetic etiologies between these two tumor types.     

DNA copy number changes detected by comparative genomic hybridization and their association with clinicopathologic parameters in breast tumors

The purpose of this study was to use comparative genomic hybridization (CGH) to screen breast tumors for copy number changes: 22 ductal, 9 lobular, 7 mixed, 2 micropapillary carcinomas, and 2 ductal carcinoma in situ were studied and various regional genomic imbalances were detected. The majority of the aberrations identified in this study were in line with previous CGH findings. The most frequent DNA sequence copy number changes were 1q, 8q, and 20q gains. The frequency of 16q losses was significantly higher in lobular carcinomas. The nodal involvement was 10 times higher in cases showing losses of 13q than in cases having normal peak profile at this region. Estrogen receptor positivity was significantly higher in cases displaying 20q gains and 16q losses. Unambiguous high-level DNA amplifications have also been detected. These mapped to 4q31, 6q21 approximately q22, 8q21 approximately q24, 8p11.2 approximately p12, 11q13, 15q24 approximately qter, 20q13.1 approximately qter, and 20q12 approximately qter chromosomal locations. Our results highlight several chromosomal regions that may be important in the molecular genetics of distinct clinicopathologic breast cancer subgroups.     

Comparative genomic hybridization analysis of benign and invasive male breast neoplasms

Comparative genomic hybridization (CGH) analysis was performed for the identification of chromosomal imbalances in two benign gynecomastias and one malignant breast carcinoma derived from patients with male breast disease and compared with cytogenetic analysis in two of the three cases. CGH analysis demonstrated overrepresentation of 8q in all three cases. One case of gynecomastia presented gain of 1p34.3 through pter, 11p14 through q12, and 17p11.2 through qter, and loss of 1q41 through qter and 4q33 through qter. The other gynecomastia presented del(1)(q41) as detected by both cytogenetic and CGH analysis. CGH analysis of the invasive ductal carcinoma confirmed a gain of 17p11.2 through qter previously detected by cytogenetic analysis. These regions showed some similarity in their pattern of imbalance to the chromosomal alterations described in female and male breast cancer.     

Stepwise genetic changes associated with progression of nontumorigenic HPV-18 immortalized human prostate cancer-derived cell line to a malignant phenotype

Cytogenetics, fluorescence in situ hybridization (FISH), and comparative genomic hybridization (CGH) were used to identify genes that are involved in the development and progression of prostate cancer. For that purpose, we chose a cell line established in vitro from a prostatic adenocarcinoma which was nontumorigenic in nude mice and followed its progression to a tumorigenic cell line. Stepwise changes were observed in the cell line as it became tumorigenic. The composite karyotype at the nontumorigenic stage (CA-HPV-10) was 68 approximately 77,XXY,-(1, 9, 13, 14, 19, 22),+(4, 5, 11, 18, 20, 21),+(del(1) (q23q31)=M1 (two copies), +der(9)t(1;9)(q24 approximately q31;p23)=M5(two copies), der(14)t(14;?)(q10;?)=M17 in the majority of metaphases. These two derivative chromosomes were also observed a previous study. Our CGH analysis clearly showed that this deleted region in M1 is, in fact, translocated with derivative M5 and, in reality, is amplified. The cell line established from nodule (SCID 5019 p11), showed a number of new changes, as described; however, the most significant change was amplification of the 8q23 approximately qter region, harboring c-myc. This region was translocated with chromosomes 2, 4, and 16 as der(2)t(2;8)(q33;q23)=M12, der(4)t(4;8)(q34;q23)=M11, and der(16)t(8;16)(q24;q21)=M9. We deduce from our study that amplification of c-myc and other genes in the 8q23 approximately qter region were important in progression but did not lead to tumorigenicity. The population that became tumorigenic (SCID 5019 II) showed almost all of the same changes in the karyotype as observed in the nodular cell line; the only significant change was the appearance of der(11)t(4;11)(q32;q22)=M7 and the addition of another copy of t(3q;7p)=M2. These new changes lead to loss of chromosomes 3p, 4pter approximately q34, 6, 7q21 approximately qter, 11q22 approximately qter, and 18q, and gain of 3q, 7p, 8q23 approximately qter, and 11pter approximately q22, before the cell line became tumorigenic. The clonal selection of the population is proven by the presence of a number of the same derivative chromosomes in both the nodular and tumorigenic cell line. As it progressed to tumorigenicity, some of the same changes observed in the original study re-appear at different stages of malignancy, although it was absent in the nontumorigenic cell line. These are: der(16)t(8;16)(q24;q21)=M9 in the nodular cell line and der(11)t(4;11)(q32;q22)=M7 in the tumorigenic cell line. In our system, amplification of c-myc and other genes in der(2)t(2;8)(q33;q23)=M12,der(4) t(4;8)(q34;q23)=M11 together with the presence of der(16)t(8;16)(q24;q21)=M9 and der(11)t(4;11)(q32;q22)=M5 makes the cell line tumorigenic. It is either nontumorigenic, with the presence of a marker equivalent to der(16)=M9 and der(11)=M7 observed in the original study, and only nodular (SCID 5019 p11, present study), with the presence of number of markers with c-myc amplification (M9, M11, and M12). There is accumulation of all the above-mentioned changes in the same cell before it becomes tumorigenic.     

Chromosomal changes associated with clinical outcome in lymph node-negative breast cancer

Breast cancer is the most common malignancy among women and accounts for over one million new cases worldwide per year. Lymph node-negative breast cancer patients are reputed as having a better prognosis than lymph node-positive ones. Around 20% of the lymph node-negative patients die within 10 years after diagnosis. To improve the prognostics of node-negative breast cancer, it is important to understand the underlying biologic mechanisms promoting survival, such as specific genetic changes in the tumor genome. In this study, CGH was applied to analyze 64 tumors from node-negative breast cancer patients to identify DNA copy number changes in chromosomes and chromosome regions that may be correlated to survival. The main findings show gains at 4q, 5q31 approximately qter, 6q12 approximately q16, and 12q14 approximately q22, as well as losses of 17p, 18p, and Xq, which were significantly more recurrent in tumors from deceased patients than in tumors from survivors. The average number of chromosomal changes was higher in the tumors from deceased compared to the survivor tumors. Our findings suggest that tumors with specific chromosomal aberrations at 4q, 5q31 approximately qter, 6q12 approximately q16, 12q14 approximately q22, 17p, 18p, and Xq result in an aggressive form of breast cancer and that these patients are predisposed to succumb to breast cancer.     

易位点在随体的2q37缺失综合征患儿的临床及遗传学分析

目的对1例儿童多动症患儿进行细胞以及分子遗传学检测以明确诊断。方法常规进行外周血细胞培养制片及核型分析,荧光原位杂交(fluorescence in situ hybridization,FISH);常规提取外周血DNA,进行单核苷酸多态性微阵列(single nucleotide polymorphism array,SNP-array)检测。结果患儿具有典型的面部畸形,包括耳位低、耳廓卷曲、眉弓高突、鼻孔凹口、人中短平、上唇薄等。SNP-arry检测显示患儿染色体2q37区存在4.883 Mb的缺失,综合各项检测结果,患儿染色体核型最终被确定为45,XY,der(2;21)(2pter→2q37.3∷21p13→21p10∷20p10→20pter),der(20)(21qter→21q10∷20q10→20qter)。结论报道了1例涉及3条染色体的易位点发生在随体的2q37缺失综合征,综合运用各种细胞及分子遗传学技术对复杂结构染色体异常的诊断十分重要。     

Genetic and epigenetic alterations in sentinel lymph nodes metastatic lesions compared to their corresponding primary breast tumors

The accumulation of genetic and epigenetic changes plays a pivotal role in tumor development and progression. In this study, we investigated these changes using comparative genomic hybridization and bisulfite polymerase chain reaction analysis for CpG island hypermethylation of the following genes: TP16, THBS2, E-Cadherin (ECAD), RARbeta2, MINT1, MINT2, and MINT31 in six paired primary breast tumors and their matched sentinel lymph nodes (SLN). The most frequent chromosomal alterations observed were the following: losses of 6q13 approximately q23 and 13q13 approximately q32 and gains of 9q31 approximately qter, 11p15 approximately q21, 12q23 approximately qter, and 20q12 approximately qter. Gain of 6p21 approximately pter was observed in the SLN but in none of the primary tumors. Overall, 71% (30/42) of the methylation measurements were identical between the primary tumors and the SLN. Of the six cases, two showed no differences between the primary tumors and SLN, one tumor with 4 of 7 genes hypermethylated in the primary tumor showed loss of all four hypermethylation events in the SLN, and the remaining three tumors showed loss of one methylation event and simultaneous gain of one to two methylation changes in the SLN. This is the first study reporting genetic and epigenetic alterations in breast sentinel lymph nodes compared to their corresponding primary tumors. Characterization of such alterations may lead to identification of initial events associated with the metastatic dissemination process.     

Genome-wide semiquantitative microsatellite analysis of human hepatocellular carcinoma: discrete mapping of smallest region of overlap of recurrent chromosomal gains and losses

Recurrent chromosomal gains at 1q, 6p, 8q, and 17q, or losses at 1p, 4q, 6q, 8p, 9p, 13q, 16q, and 17p are common features of human hepatocellular carcinoma (HCC). For precise determination of the shortest region of overlap (SRO), 49 HCC obtained at the time of surgery or autopsy were subjected to comprehensive microsatellite analysis by using 400 markers distributed at almost equal distances throughout the 22 autosomes and X chromosomes. Each allele showing imbalance was subjected to comparative duplex polymerase chain reaction using a retained allele as an internal control to determine whether the imbalance was the result of chromosomal gain or loss. The following SRO of recurrent chromosomal gains and losses were determined: -1p36.22 approximately p36.33, D1S450-D1S2893, 5.0 mega-base pairs (Mbp); +1q23.3 approximately q25.3, D1S2878-D1S2619, 16.9 Mbp; -4q21.2 approximately q24, D4S2964-D4S1572, 23.0 Mbp; -6q23.3 approximately qter, D6S292-qter, 34.7 Mb; -8p22 approximately p23.1, D8S549-D8S550, 4.8 Mbp; +8q12.2 approximately q24.13, D8S260-D8S514, 61.8 Mbp; -13q13.3 approximately q22.1, D13S218-D13S156, 35.6 Mbp; -16q22.1 approximately qter, D16S503-qter, 26.7 Mbp; and -17p12 approximately pter, D17S921-pter, 14.2 Mbp. Contrary to our initial expectations, many HCC showed major deletions or additions of chromosome arms, so that a number of genes were included in the SRO. Although some putative oncogenes or tumor suppressor genes mapped in these SRO may be important, relative copy number changes of numerous other genes may affect pathogenesis of HCC.     

Partial triplication and deletion of 13q: study of a family presenting with bilateral retinoblastomas

This report compares the pathogenetic influences of selective deletion and triplicaton of chromosome 13 derived from a familial 12;13 insertional translocation. In the proband a heritable chromosomal basis for his bilateral retinoblastomas is established [46,XY,del (13) (pter leads to q12.5: :q22.1 leads to qter)mat], and in his sister the relatively modest effects of triplication of the mid-portions of 13q are demonstrated [46,XX,ins(12;13) (12pter leads to 12p11.2: :13q22.1 leads to 13q12.5: :12p11.2 leads to 12qter)mat]. Qualitative and quantitative gene marker studies and chromosomal staining techniques to differentiate timing of DNA replication failed to indicate functional gene changes about the breakpoints.     

Usefulness of high-resolution comparative genomic hybridization (CGH) for detecting and characterizing constitutional chromosome abnormalities

Comparative genomic hybridization (CGH) is a technique for detection of chromosomal imbalances in a genomic DNA sample. We here report the application of the recently developed method of high-resolution CGH on DNA samples from 66 children having various degrees of delayed psychomotor development with or without clear dysmorphic features and congenital malformations. In 5 of 50 patients with apparently normal karyotypes, a deletion or duplication was revealed by CGH. Only one of these cases had a subtelomeric rearrangement. In one of seven cases with a de novo apparently balanced translocation, deletions were found. In all nine cases where the origin of a marker chromosome or additional chromosomal material was difficult to determine, CGH gave a precise identification. The following findings were from cases having a deletion or duplication as the sole chromosomal imbalance; dup(2)(p16p21), del(4)(q21q21), del(6)(q14q15), del(6)(p12p12), dup(6)(q24qter), and dup(15)(q11q13). One case had dup(9)(p11pter) combined with a very small subtelomeric deletion on 6q. In our hands, CGH is highly useful not only for identifying known chromosomal imbalances, but also for finding elusive deletions or duplications in the large group of children with developmental delay with or without congenital abnormalities. In such cases, the diagnostic yield of CGH appears to be higher than what has been reported from subtelomeric FISH screening.     

Balanced complex rearrangement involving chromosomes 8, 9, and 12 in a normal mother,derivative chromosome 9 with recombinant chromosome 12 in her daughter with minor anomalies

We report on a 19-month-old girl with a derivative chromosome 9 and a recombinant chromosome 12 resulting from a maternal balanced complex rearrangement involving chromosomes 8, 9, and 12. The karyotype of the phenotypically normal mother was 46,XX,t(8;12) (9;12) (8qter→8p23::12q12→12q15::9q32→9qter;9pter→9q32::12q15→12qter;12pter→12q12::8p23→8pter). The child's karyotype was 46,XX,?9,?12, +der(9) (9pter→9q32::12q15→12qter),+rec(12) (12pter→12q15::9q32→9qter) mat. The child had severe growth retardation, minor anomalies including trigonocephaly, hypertelorism, broad nasal root, apparently low-set and posteriorly angulated ears, triangular face, pectus carinatum, clinodactyly of fifth fingers, and almost normal psychomotor development. To the best of our knowledge, there have been only 3 previous reports of recombination derived from parental complex chromosome rearrangements. In the recombination products, the chromosomes were apparently balanced and the offspring had no clinical abnormalities. The present case exhibited abnormalities and may have a submicroscopic aberration of 12q arising from crossing over during maternal meiotic pairing, although her chromosomes appeared to be balanced. © 1993 Wiley-Liss, Inc.     

Amplification of ETS2 oncogene in acute nonlymphoblastic leukemia with t(6;21;18).

Cytogenetic and molecular studies in a case of acute nonlymphoblastic leukemia (ANLL) are reported in this paper. Bone marrow blasts carried a hypodiploid karyotype with a complex t(6;18;21)(6qter----6p21::21q22----21qter;18qter ----18p11::6p22----6pter; 21pter----21q22::6p21----6p22::18p11----18pte r) and other numerical and structural changes. We studied the organization and the expression of the ETS2 gene which is located on chromosome 21 in order to investigate its possible involvement in the disease. DNA analysis showed a 20-fold amplification of ETS2 sequences; an increase of 3- to 4-fold in the mRNAs level compared to normal was shown by Northern hybridization.     

Nonrandom chromosomal imbalances in human ovarian surface epithelial cells immortalized by HPV16-E6E7 viral oncogenes

We had previously immortalized human ovarian surface epithelial (HOSE) cells using HPV16E6E7 ORFs. In order to identify crucial genetic events involved during cell immortalization, the genomic profile of immortalization of five HOSE cell lines was analyzed by comparative genomic hybridization. Our results showed that chromosomal imbalance was common in HOSE cells after immortalization. The common chromosomal imbalances identified in immortal HOSE cells are: +19q13.1 (5/5 lines), −13q12qter (4/5 lines), +5q15q33 (3/5 lines), +20q11.2q13.2 (3/5 lines) and −22q11.2qter (3/5 lines). Other chromosomal imbalances, which were detected in two of the five immortal HOSE cell lines, included gains on chromosome 1 and 11q12q13, and losses on 2p, 4q, 8p, 10p and 11q14qter. The chromosomal imbalances observed in HOSE cells before immortalization include −8pterp11.2, −11q23qter, −13q12qter and +19 which may represent early genetic events during cell immortalization. The genomic profile was examined in one HOSE cell line (HOSE 6-3) at various stages of immortalization. The genomic profiles of HOSE 6-3 cells after crisis were largely stable. A few additional chromosomal imbalances were detected in the immortalized HOSE cells after an extensive culture period including +11pterq23, −15q23qter, and +17q12qter. Identification of nonrandom chromosomal imbalance in immortalized HOSE cells may facilitate the identification of specific chromosomes harboring genes involved in the immortalization of human ovarian surface epithelial cells.     

Syndromal frontonasal dysostosis in a child with a complex translocation involving chromosomes 3, 7, and 11

We report on a 4-year-old boy with typical frontonasal dysostosis and an apparently balanced de novo translocation involving chromosomes 3, 7, and 11, and four breakpoints. The karyotype was 46,XY,t(7;3)(3;11) (7pter→7q21.3::3q27→3qter;3pter→3q23::11q21→11qter;11pter→11q21::3q23→3q27::7q21.3→7qter). In situ hybridization with a chromosome 3 painting probe confirmed the interpretation from GTG banding. The child had a widow's peak, marked hypertelorism, absence of the nasal tip, and widely separated nares. He also had an atrial septal defect, micropenis, small testes, clubfeet, scoliosis, block C2–4, and structural brain abnormalities on MRI. In review we found two other cases of frontonasal dysostosis with chromosome abnormalities, neither of which was similar to our case. The presence of a denovo (apparently) balanced translocation in our patient may help to locate the gene(s) for frontonasal dysplasia and perhaps other midline craniofacial malformations. © 1995 Wiley-Liss, Inc.     

Novel 6p rearrangements and recurrent translocation breakpoints in retinoblastoma cell lines identified by spectral karyotyping and mBAND analyses

Gain of the short arm of chromosome 6, usually through isochromosome 6p formation, is present in approximately 50% of retinoblastoma tumors. The minimal region of gain maps to chromosome band 6p22. Two genes, DEK and E2F3, are implicated as candidate oncogenes. However, chromosomal translocations have been overlooked as a potential mechanism of activation of oncogenes at 6p22 in retinoblastoma. Here, we report combined spectral karyotyping), 4',6-diamidino-2-phenylindole banding, mBAND, and locus-specific fluorescence in situ hybridization analyses of four retinoblastoma cell lines, RB1021, RB247c, RB383, and Y79. In RB1021 and RB247c, 6p undergoes structural rearrangements involving a common translocation breakpoint at 6p22. These data imply that 6p translocations may represent another mechanism of activation of 6p oncogene(s) in a subset of retinoblastomas, besides the copy number increase. In addition to 6p22, other recurrent translocation breakpoints identified in this study are 4p16, 11p15, 17q21.3, and 20q13. Common regions of gain map to chromosomal arms 1q, 2p, 6p, 17q, and 21q.