Cytogenetic abnormalities in 106 oral squamous cell carcinomas

We report karyotypic features of 106 short-term cultured oral squamous cell carcinomas (SCC), 51 new and 55 previously reported cases, with clonal chromosome aberrations. The major cytogenetic findings were as follows: simple karyotypic changes were present in 38 cases (36%) and 68 tumors (64%) displayed complex karyotypes. The most common numerical changes were +7, +8, +9, +16, +18, +20, and -4, -10, -13, -14, -18, -19, -21, -22, and -Y. Structural rearrangements frequently (43% of the breaks) affected the centromeric regions, resulting in the formation of isochromosomes and whole-arm translocations. Among the recurrent structural aberrations identified, the most common were i(1q), i(3q), i(5p), i(8q), del(16)(q22), and hsr. With the exception of chromosomal band 11q13, which was involved in 25 tumors, only centromeric or near-centromeric bands were commonly involved: 3p11 approximately q11 (59 cases), 8p11 approximately q11 (57), 1p11 approximately q11 (48), 13p11 approximately q11 (46), 5p11 approximately q11 (41), 14p11 approximately q11 (41), and 15p11 approximately q11 (37). Losses of genetic material dominated over gains. The most frequent imbalances included loss of 2q33 approximately qter, 3p, 4p, 6q, 8p, 10p, 11q, 13p, 14p, and 15p, and chromosomes 18, 21, 22, and Y, and gain of chromosomes 7 and 20, 8q, and 11q13. No major karyotypic differences could be discerned between the present series of oral SCC and a previously reported series of laryngeal SCC, indicating that common genetic pathways are involved in the initiation and progression of SCC irrespective of site of origin.     

Cytogenetic analysis of pancreatic carcinomas: Intratumor heterogeneity and nonrandom pattern of chromosome aberrations

Twenty-nine nonendocrine pancreatic carcinomas (20 primary tumors and nine metastases) were studied by chromosome banding after short-term culture. Acquired clonal aberrations were found in 25 tumors and a detailed analysis of these revealed extensive cytogenetic intratumor heterogeneity. Apart from six carcinomas with one clone only, 19 tumors displayed from two to 58 clones, bringing the total number of clones to 230. Karyotypically related clones, signifying evolutionary variation, were found in 16 tumors, whereas unrelated clones were present in nine, the latter finding probably reflecting a distinct pathogenetic mechanism. The cytogenetic profile of pancreatic carcinoma was characterized by multiple numerical and structural changes. In total, more than 500 abnormal chromosomes, including rings, markers, homogeneously stained regions, and double minutes, altogether displaying 608 breakpoints, were detected. This complexity and heterogeneity notwithstanding, a nonrandom karyotypic pattern can be discerned in pancreatic cancer. Chromosomes 1, 3, 6, 7, 8, 11, 12, 17, and 19 and bands 1q12, 1q21, 3q11, 6p21, 6q21, 7q11, 7q22, 7q32, 11q13, 13cen, 14cen, 17q11, 17q21, and 19q13 were most frequently involved in structural rearrangements. A total of 19 recurrent unbalanced structural changes were identified, 11 of which were not reported previously: del(1)(q11), del(3)(p11), i(3)(q10), del(4)(q25), del(11)(p13), dup(11)(q13q23), i(12)(p10), der(13;15)(q10;q10), del(18)(q12), del(18)(q21), and i(19)(q10). The main karyotypic imbalances were entire-copy losses of chromosomes 18, Y, and 21, gains of chromosomes 7, 2, and 20, partial or whole-arm losses of 1p, 3p, 6q, 8p, 9p, 15q, 17p, 18q, 19p, and 20p, and partial or whole-arm gains of 1q, 3q, 5p, 6p, 7q, 8q, 11q, 12p, 17q, 19q, and 20q. In general, the karyotypic pattern of pancreatic carcinoma fits the multistep carcinogenesis concept. The observed cytogenetic heterogeneity appears to reflect a multitude of interchangeable but oncogenetically equivalent events, and the nonrandomness of the chromosomal alterations underscores the preferential pathways involved in tumor initiation and progression. Genes Chromosomes Cancer 23:81–99, 1998. © 1998 Wiley-Liss, Inc.     

Karyotypic evolution and tumor progression in head and neck squamous cell carcinomas

Cytogenetic analysis was performed on primary tumors, and paired recurrent or metastatic lesions, in 14 patients with head and neck squamous cell carcinomas (HNSCC), in order to identify chromosomal aberrations associated with tumor initiation and progression. Abnormal karyotypes were found in 12 of the 14 patients, with distinctive karyotypic similarities shown in all informative pairs. For individual patients, the degree of karyotypic complexity was similar for the primaries and paired recurrent or metastatic lesions. All 22 samples with clonal chromosomal aberrations displayed complex karyotypes with multiple numerical and unbalanced structural rearrangements, resulting in extensive genomic imbalances. The pathway of clonal evolution could be traced in a few patients, supporting the notion that some aberrations or imbalances, particularly partial or entire loss of 3p, i(8q), and homogeneously staining regions commonly mapping to 11q13, were early genetic events in the initiation of HNSCC.     

Clonal chromosome abnormalities in premalignant lesions of the skin

Two lesions, actinic keratosis (AK) and squamous cell carcinoma in situ (CIS), are believed to be precursors of squamous cell carcinoma (SCC) of the skin. These lesions can serve as an excellent model system for studying genetic changes associated with the inception of skin SCC. In the present study, five such lesions of the skin, three AKs and two AK+CIS, from three patients were short-term cultured and analyzed cytogenetically. One of the patients (case 3) had also an SCC in addition to three premalignant lesions. All lesions, but one, showed clonal karyotypic abnormalities. The recurrent changes identified were numerical, that is, +7 and +20. The structural rearrangements found in three AK were different, but it could be noted that the distal part of the long arm of chromosome 4 was involved in two AK and the SCC of case 3A. It was also interesting that chromosome 1 participated in structural rearrangements in three AK with band 1p31 being involved in two tumors. The karyotypic profile of these lesions is compared with that of skin SCC; it turns out that the general patterns are different in the sense that the SCC more often have complex karyotypes and display unbalanced aberrations involving the centromeric regions. Some karyotypic similarities between the SCC and their precursors are revealed. The fact that the structural rearrangements involving chromosomal band 3p13 and the centromeric region of chromosome 3 in AK are common features for many types of malignant tumors, including skin SCC, indicates that these changes are early genetic events associated with malignant transformation.     

Karyotypic characterization of urinary bladder transitional cell carcinomas

Samples from 34 primary transitional cell carcinomas (TCCs) of the bladder were short-term-cultured and processed for cytogenetic analysis after G-banding of the chromosomes. Clonal chromosome abnormalities were detected in 27 tumors and normal karyotypes in 3, and the cultures from 4 tumors failed to grow. Losses of genetic material were more common than gains, indicating that loss of tumor suppressor genes may be of major importance in TCC pathogenesis. There was no clonal heterogeneity within individual tumors, consonant with the view that TCCs are monoclonal in origin. The most striking finding was the involvement of chromosome 9 in 92% of the informative cases, as numerical loss of one chromosome copy in 15 cases, but as structural rearrangement in 8. The changes in chromosome 9 always led to loss of material; from 9p, from 9q, or of the entire chromosome. A total of 16 recurrent, unbalanced structural rearrangements were seen, of which del(1)(p11), add(3)(q21), add(5)(q11), del(6)(q13), add(7)(q11), add(11)(p11), i(13)(q10), del(14)(q24), and i(17)(q10) are described here for the first time. The karyotypic imbalances were dominated by losses of the entire or parts of chromosome arms 1p, 9p, 9q, 11p, 13p, and 17p, loss of an entire copy of chromosomes 9, 14, 16, 18, and the Y chromosome, and gains of chromosome arms 1q and 13q and of chromosomes 7 and 20. The chromosome bands and centomeric breakpoints preferentially involved in structural rearrangements were 1q12, 2q11, 5q11, 8q24, 9p13, 9q13, 9q22, 11p11, and 13p10. Rearrangements of 17p and the formation of an i(5)(p10) were associated with more aggressive tumor phenotypes. There was also a general correlation between the tumors' grade/stage and karyotypic complexity, indicating that progressive accumulation of acquired genetic alterations is the driving force behind multistep bladder TCC carcinogenesis.     

Nonrandom karyotypic features in basal cell carcinomas of the skin.

Cytogenetic analysis of short-term cultured 44 basal cell carcinomas (BCC) revealed clonal karyotypic abnormalities in 38 tumors. Relatively complex karyotypes (at least four structural and/or numerical changes per clone) with unbalanced structural as well as numerical aberrations were found in eight (approximately 21%) of the BCC, while the remaining BCC (79%) had simple karyotypes (1 to 3 aberrations per clone). Numerical changes only were found in 16 tumors, 15 BCC displayed both numerical and structural aberrations, and the remaining 7 BCC showed only structural aberrations. Extensive intratumoral heterogeneity, in the form of cytogenetically unrelated clones, was found in 21 tumors, whereas related subclones were present in 10 tumors. In order to obtain an overall karyotypic picture in BCC, the findings of our previously published 25 BCC have been reviewed. Our combined data indicate that BCC are characterized by nonrandom karyotypic patterns. A large subset of BCC is characterized by nonrandom numerical changes, notably, +18, +X, +7, and +9. Structural rearrangements often affect chromosomes 1, 4, 2, 3, 9, 7, 16, and 17. A number of chromosomal bands are frequently involved, including 9q22, 1p32, 1p22, 1q11, 1q21, 2q11, 4q21, 4q31, 1p36, 2q37, 3q13, 7q11, 11p15, 16p13, 16q24, 17q21, and 20q13. When the genomic imbalance is assessed, it has been shown that several chromosome segments are repeatedly involved in losses, namely loss of the distal part of 6q, 13q, 4q, 1q, 8q, and 9p. A correlation analysis between the karyotypic patterns and the clinico-histopathologic parameters has been undertaken in the 44 BCC of the present series. The cytogenetic patterns show a significant correlation with tumor status (P=.025), that is, that cytogenetically more complex tumors are also those clinically the most aggressive. Also, the frequency of cytogenetically unrelated clones is significantly higher in recurrent BCC than that in primary lesions (P=.05). No clear-cut association has been found between the karyotypic patterns and histologic subtypes or tumor sites.     

Centromeric breakage as a major cause of cytogenetic abnormalities in oral squamous cell carcinoma

Cytogenetic analysis of short-term explant tumor cultures derived from 11 human oral squamous cell carcinomas (nine from primary tumors and two from nude mice xenograft cultures) revealed clonal chromosomal aberrations with multiple numerical and structural changes in all tumors. Recurrent breakpoints were located at chromosomal bands 1p13 (five tumors), 11q13 (four tumors), 3q27-29 (three tumors), and 12q13 (three tumors). Four tumors had a homogeneously staining region at band 11q13. Consistent chromosomal losses included 3p, 9p13-pter, and 18q22-qter, each occurring in eight tumors. Gain of material was observed for chromosome arms 3q, 5p, 7p, and 8q. As many as 134 of a total of 218 chromosomal breakpoints (61%) occurred in centromeric regions, often resulting in isochromosomes and unbalanced whole-arm translocations. Using fluorescence in situ hybridization with chromosome-specific centromeric alphoid repeat probes, two whole-arm translocations, der(Xq;11q) and a der(3q;11q), each from a different tumor, were shown to contain juxtaposed centromeric sequences of both participating chromosomes, strongly suggesting that the breakpoints were within the centromeres. We propose that centromeric breakage is an important mechanism for the generation of genetic imbalance in the development of oral squamous cell carcinoma. Genes Chrom Cancer 14:000-000 (1995). © 1996 Wiley-Liss, Inc.     

Multicolor spectral karyotyping of serous ovarian adenocarcinoma.

We applied multicolor spectral karyotyping (SKY) to decipher the chromosomal complexity of a panel of seven cell lines and four primary tumors derived from patients with high‐grade serous adenocarcinoma of the ovary. By this method we identified a total of 188 unbalanced translocations, nine reciprocal translocations [t(2;15)(q13;q23), t(7;17) (q32;q21), t(8;22)(p11;q11), t(8;22) (q24;q13), t(10;19) (q24;q13.2), t(11;19) (q13;p11), t(12;21)(q13;q22),t(18;20) (q?11;q?11), t(18;22)(q?11;q?13)], 6 isochromosomes [i(1q), i(7q), i(8q), i(9p), i(17q), i(21q)], and 23 deletions. By detailed mapping of rearrangement breakpoints, it was possible to identify several recurring breakpoint clusters at chromosomal bands 1p36, 2p11, 2p23, 3p21, 3q21, 4p11, 6q11, 8p11, 9q34, 10p11, 11p11, 11q13, 12p13, 12q13, 17q21, 18p11, 18q11, 20q11, and 21q22. Recurrent interstitial deletion of chromosomal bands 8p11, 11p11, and 12q13 and a recurrent unbalanced translocation—der(6)t(6;8)(q11;q11)—were also identified. In addition, a homogeneously staining region localized in one cell line to 11q13 was found using SKY to be derived from genetic material originating from chromosome 12. Subsequent comparative genomic hybridization (CGH) studies on this tumor revealed the amplification of DNA sequences derived from the short arm of chromosome 12 at the 12p11.2 region. These studies demonstrate the power of SKY, CGH, and G‐banding to resolve the full spectrum of chromosomal rearrangements in serous ovarian adenocarcinoma. © 2002 Wiley‐Liss, Inc.     

Chromosome analysis of 97 primary breast carcinomas: Identification of eight karyotypic subgroups

Chromosome banding analysis of 97 short-term cultured primary breast carcinomas revealed clonal aberrations in 79 tumors, whereas 18 were karyotypically normal. In 34 of the 79 tumors with abnormalities, two to eight clones per case were detected; unrelated clones were present in 27 (34%) cases, whereas only related clones were found in seven. These findings indicate that a substantial proportion of breast carcinomas are of polyclonal origin. Altogether eight abnormalities were repeatedly identified both as sole chromosomal anomalies and as part of more complex karyotypes: the structural rearrangements i(1)(q10), der(1;16)(q10;p10), del(1)(q11–12), del(3)(p12–13p14–21), and del(6)(q21–22) and the numerical aberrations +7, +18, and +20. At least one of these changes was found in 41 (52%) of the karyotypically abnormal tumors. They identify a minimum number of cytogenetic subgroups in breast cancer and are likely to represent primary chromosome anomalies in this type of neoplasia. Other candidates for such a role are translocations of 3p12–13 and 4q21 with various partner chromosomes and inversions of chromosome 7, which also were seen repeatedly. Additional chromosomal aberrations that give the impression of occurring nonrandomly in breast carcinomas include structural rearrangements leading to partial monosomies for 1p, 8p, 11p, 11q, 15p, 17p, 19p, and 19q and losses of one copy of chromosomes X, 8, 9, 13, 14, 17, and 22. The latter changes were seen consistently only in complex karyotypes, however, and we therefore interpret them as being secondary anomalies acquired during clonal evolution.     

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.     

Existence of two distinct processes of chromosomal evolution in near-diploid colorectal tumors

The comparison of all the karyotypes established in each of 18 near-diploid colorectal tumors made it possible to reconstruct a clonal evolution and to distinguish between early and late chromosomal aberrations. Because no abnormalities were observed in all tumors, and as even the most frequent changes, i.e., monosomy 17p and monosomy 18, may be present in mosaic, no chromosomal change can be regarded as a common primary event in the carcinogenetic process. However, the repeated occurrence of several changes favors the hypothesis of two karyotypic evolutionary processes. In most tumors, monosomy 17p and 18 were found, and the karyotypic evolution involved mainly several additional monosomies due to unbalanced rearrangements or losses that affect, by order of decreasing frequency, chromosomes 1p, 4, 14, 5q, 6q, 2p, and 11q, as well as gains of chromosomes 20, 8q, 13, 17q, and X. In this group of tumors, the mean number of chromosomes remains close to 46. In the other tumors, either only a monosomy 17p or a monosomy 18 was found and the karyotypic evolution involved essentially trisomies, resulting from gains with, by order of decreasing frequency, a preferential involvement of chromosomes 7, 8q, 13, 17q, 20, X, 2p, 5, and 16, the only additional recurrent deletion affecting chromosome 1p. In these tumors, the mean chromosome number is close to 51. Ten out of 11 polyploid sidelines emerged from monosomic-type tumors.     

Nonrandom chromosomal aberrations and cytogenetic heterogeneity in gallbladder carcinomas.

Chromosome banding analysis of 11 short-term cultured gallbladder carcinomas revealed acquired clonal aberrations in seven tumors (five primary and two metastases). Three of these had one clone, whereas the remaining four were cytogenetically heterogeneous, displaying two to seven aberrant clones. Of a total of 21 abnormal clones, 18 had highly complex karyotypes and three exhibited simple numerical deviations. Double minutes and homogeneously staining regions were observed in one and two carcinomas, respectively. To characterize the karyotypic profile of gallbladder cancer more precisely, we have combined the present findings with our three previously reported cases, thereby providing the largest cytogenetic database on this tumor type to date. A total of 287 chromosomal breakpoints were identified, 251 of which were found in the present study. Chromosome 7 was rearranged most frequently, followed by chromosomes 1, 3, 11, 6, 5, and 8. The bands preferentially involved were 1p32, 1p36, 1q32, 3p21, 6p21, 7p13, 7q11, 7q32, 19p13, 19q13, and 22q13. Nine recurrent abnormalities could, for the first time, be identified in gallbladder carcinoma: del(3)(p13), i(5)(p10), del(6)(q13), del(9)(p13), del(16)(q22), del(17)(p11), i(17)(q10), del(19)(p13), and i(21)(q10). The most common partial or whole-arm gains involved 3q, 5p, 7p, 7q, 8q, 11q, 13q, and 17q, and the most frequent partial or whole-arm losses affected 3p, 4q, 5q, 9p, 10p, 10q, 11p, 14p, 14q, 15p, 17p, 19p, 21p, 21q, and Xp. These chromosomal aberrations and imbalances provide some starting points for molecular analyses of genomic regions that may harbor genes of pathogenetic importance in gallbladder carcinogenesis. Genes Chromosomes Cancer 26:312-321, 1999.     

Karyotypic characterization of colorectal adenocarcinomas

Cytogenetic analysis of short-term cultures from 52 primary colorectal adenocarcinomas revealed clonal chromosome aberrations in 45 tumors, whereas the remaining 7 had a normal karyotype. More than 1 abnormal clone was detected in 26 tumors; in 18 of them, the clones were cytogenetically unrelated. The modal chromosome number was near-diploid in 32 tumors and near-triploid to near-tetraploid in 13. Only numerical aberrations were identified in 13 carcinomas, only structural aberrations in 3, and 29 had both numerical and structural changes. The most common numerical abnormalities were, in order of decreasing frequency, gains of chromosomes 7, 13, 20, and Y and losses of chromosomes 18, Y, 14, and 15. The structural changes most often affected chromosomes 1, 17, 8, 7, and 13. The most frequently rearranged chromosome bands were, in order of decreasing frequency, 13q10, 17p10, 1p22, 8q10, 17p11, 7q11, 1p33, 7p22, 7q32, 12q24, 16p13, and 19p13. Frequently recurring aberrations affecting these bands were del(1)(p22), i(8)(q10), i(13)(q10), and add(17)(p11–13). The most common partial gains were from chromosome arms 8q, 13q, and 17q and the most common partial losses from chromosome arms 1p, 8p, 13p, and 17p. A correlation analysis between the karyotype and the clinicopathologic features in our total material, which consists of altogether 153 colorectal carcinomas, including 116 with an abnormal karyotype, showed a statistically significant association (P < 0.05) between the karyotype and tumor grade and site. Carcinomas with structural chromosome rearrangements were often poorly differentiated; well and moderately differentiated tumors often had only numerical aberrations or normal karyotypes. Abnormal karyotypes were more common in rectal carcinomas than in carcinomas situated higher up. Near-triploid to near-tetraploid karyotypes were more than twice as frequent in tumors of the distal colon as in those of the proximal colon and rectum. The cytogenetic data indicate that carcinomas located in the proximal colon and rectum, which often are near-diploid with simple numerical changes and cytogenetically unrelated clones, probably arise through different mechanisms than do tumors located in the distal colon, which more often have complex near-triploid to near-tetraploid karyotypes.     

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.     

Uterine leiomyoma cytogenetics

Uterine leiomyoma--a benign smooth muscle tumor--has recently been found to contain tumor-specific chromosome aberrations. Although only normal karyotypes were detected in 50 to 80% of cytogenetically investigated tumors, 104 leiomyomas with karyotypic aberrations have already been reported. At least four cytogenetically abnormal subgroups have been identified thus far, characterized by rearrangements of 6p, del(7)(q21.2q31.2), +12, and t(12;14)(q14-15;q23-24). The remaining abnormal tumors have had various nonrecurrent anomalies. Secondary karyotypic rearrangements, sometimes including ring chromosomes, have been found in one-third and reflect clonal evolution. Occasional leiomyomas have contained multiple numerical and structural rearrangements. Though benign, these cytogenetically grossly aberrant tumors often displayed more atypical histological features than are usually seen in leiomyoma. Multiple leiomyomas have been investigated from 69 patients, with detection of chromosome anomalies in at least two separate tumors from the same uterus in ten cases. In half of these patients unrelated aberrations were found in different leiomyomas from the same uterus. On other occasions the aberrations were identical, indicating that although some uterine leiomyomas originate independently, others may develop by intra-myometrial spreading from a common neoplastic clone. Some common features are discernible between the karyotypic pictures of uterine leiomyoma and angioleiomyoma; rearrangements of 6p, 13q, and 21q have been described in both tumor types. The cytogenetic similarities so far detected between leiomyoma and the malignant muscle tumors--leiomyosarcoma and rhabdomyosarcoma--are few and may be fortuitous. The cytogenetic profiles of leiomyoma and lipoma are strikingly similar; both tumor types have nonrandom rearrangements of 12q13-15, t(12;14) in leiomyoma and t(3;12) in lipoma, as well as variant rearrangements of the same 12q segment. Both also have cytogenetic subgroups characterized by changes in 6p and ring chromosomes. Finally, karyotypic similarities exists also between leiomyoma and pleomorphic adenoma of the salivary gland, which includes a subset of tumors with anomalies of 12q13-15, and with myxoid liposarcoma, which has t(12;16)(q13;p11) as a tumor-specific rearrangement.     

Chromosome aberrations in 35 primary ovarian carcinomas.

Cytogenetic analysis was performed on short-term cultures of primary ovarian carcinomas from 62 patients. Cytogenetic analysis was successful in 59 cases. Clonal chromosome aberrations were detected in 35 tumors. Only numerical changes or a single structural change were found in five carcinomas: trisomy 12 was the sole anomaly in two tumors, one tumor had the karyotype 50,XX, + 5, + 7, + 12, + 14, a fourth tumor had a balanced t(1;5), and the fifth tumor had an unbalanced t(8;15). The fact that four of these five carcinomas were well differentiated suggests that simple karyotypic changes are generally characteristic of these less aggressive ovarian tumors. The majority of the cytogenetically abnormal tumors (n = 30) had complex karyotypes, with both numerical and structural aberrations and often hypodiploid or near-triploid stemlines. The numerical imbalances (comparison with the nearest euploid number) were mostly losses, in order of decreasing frequency -17, -22, -13, -8, -X, and -14. The structural aberrations were mostly deletions and unbalanced translocations. Recurrent loss of genetic material affected chromosome arms 1p, 3p, 6q, and 11p. The breakpoints of the clonal structural abnormalities clustered to several chromosome bands and segments: 19p13, 11p13-15, 1q21-23, 1p36, 19q13, 3p12-13, and 6q21-23. The most consistent change (16 tumors) was a 19p + marker, and in 12 of the tumors the 19p + markers looked alike.     

Comprehensive molecular cytogenetic characterization of cervical cancer cell lines

We applied a combination of molecular cytogenetic methods, including comparative genomic hybridization (CGH), spectral karyotyping (SKY), and fluorescence in situ hybridization (FISH), to characterize the genetic aberrations in eight widely used cervical cancer (CC) cell lines. CGH identified the most frequent chromosomal losses including 2q, 3p, 4q, 6q, 8p, 9p, 10p, 13q, and 18q; gains including 3q, 5p, 5q, 8q, 9q, 11q, 14q, 16q, 17q, and 20q; and high-level chromosomal amplification at 3q21, 7p11, 8q23-q24, 10q21, 11q13, 16q23-q24, 20q11.2, and 20q13. Several recurrent structural chromosomal rearrangements, including der(5)t(5;8)(p13;q23) and i(5)(p10); deletions affecting chromosome bands 5p11, 5q11, and 11q23; and breakpoint clusters at 2q31, 3p10, 3q25, 5p13, 5q11, 7q11.2, 7q22, 8p11.2, 8q11.2, 10p11.2, 11p11.2, 14q10, 15q10, 18q21, and 22q11.2 were identified by SKY. We detected integration of HPV16 sequences by FISH on the derivative chromosomes involving bands 18p10 and 18p11 in cell line C-4I, 2p16, 5q21, 5q23, 6q, 8q24, 10, 11p11, 15q, and 18p11 in Ca Ski, and normal chromosome 17 at 17p13 in ME-180. FISH analysis was also used further to determine the copy number changes of PIKA3CA and MYC. This comprehensive cytogenetic characterization of eight CC cell lines enhances their utility in experimental studies aimed at gene discovery and functional analysis.     

Clonal chromosome abnormalities in two liposarcomas

Two liposarcomas were analyzed with chromosome banding technique. The sole chromosomal abnormality in one of the tumors, a mixed type (myxoid and round cell) liposarcoma, was t(12;16)(q13;p11), a rearrangement previously reported to be associated with myxoid liposarcoma. The other tumor, a pleomorphic liposarcoma, displayed massive numerical rearrangements (modal chromosome number 94-112), and numerous, mostly unidentifiable, marker chromosomes. The following clonal structural aberrations were recognized: del(1)(p22), del(1)(q23), t(7;?)(p22;?), i(17q), and t(19;?)(q13;?).     

Multiple cytogenetic abnormalities in a case of osteosarcoma

Cytogenetic analysis of a highly malignant osteosarcoma in a 17-year-old girl revealed extremely complex karyotypic changes with several different clonal numerical and structural chromosome aberrations. The composite karyotype was interpreted as 39–41,X,t(X;9)(q11;p24), −1,der(1),−4,−4,−5,i(7q),−8,del(8)(q21),t(10;19)(p13;q13),del(11)(p11p13),t(12;18)(q24;q12), −13,13q+,−14,14p+,−15,15q+,17p+,19q+,−21,+22,+3–6 mar.     

Identification of cytogenetic subclasses and recurring chromosomal aberrations in AML and MDS with complex karyotypes using M-FISH.

Complex chromosomal aberrations (CCAs) can be detected in a substantial proportion of AML and MDS patients, de novo as well as secondary or therapy-related, and are associated with an adverse prognosis. Comprehensive analysis of the chromosomal rearrangements in these complex karyotypes has been hampered by the limitations of conventional cytogenetics. As a result, our knowledge concerning the cytogenetics of these malignancies is sparse. Here we describe a multiplex-FISH (M-FISH) study of CCAs in 36 patients with AML and MDS. M-FISH generated a genome-wide analysis of chromosomal aberrations in CCAs, establishing several cytogenetic subgroups. -5/5q- was demonstrated in the majority of patients (86%). Other rearrangements (present with or without -5/5q-) included: deletion of 7q (47%), 3q rearrangements (19%), and MLL copy gain or amplification (17%). These genetic subgroups seem to display biological heterogeneity: MLL copy gain or amplification in association with 5q- was detected only in AML patients and was significantly associated with extremely short survival (median overall survival: 30 days, P = 0.0102). A partially cryptic t(4;5)(q31;q31), a balanced t(1;8)(p31;q22), and an unbalanced der(7)t(7;14)(q21;q13) were detected as possible new recurrent rearrangements in association with CCAs. Novel reciprocal translocations included t(5;11)(q33;p15)del(5)(q13q31) and t(3;6)(q26;q25). We conclude that AML and MDS with CCAs can be subdivided into molecular cytogenetic subclasses, which could reflect different clinical behavior and prognosis, and that three recurrent chromosomal aberrations are associated with karyotype complexity.