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.     

Cytogenetic findings in uterine epithelioid leiomyomas

Epithelioid leiomyomas of the uterus, unlike ordinary leiomyomas, show substantial epithelial differentiation. No chromosome abnormalities have been reported in uterine epithelioid leiomyomas before. We analyzed short-term cultures from five such tumors and detected abnormal karyotypes in four. A del(7) (q21.2q31.2) was found in two tumors, in one as the only change and in the other as a secondary aberration acquired during clonal evolution. Rearrangement of chromosomal band 12815, another of the cytogenetic hallmarks of ordinary uterine leiomyomas, was seen in the form of a t(10;12) in one tumor. Band 17q21 was involved in structural aberrations in two cases. The data we present indicate that epithelioid leiomyomas are fundamentally similar cytogenetically, and hence presumably also pathogenetically, to the much more common smooth muscle-differentiated uterine myomas. The only differences hinted at are that epithelioid tumors may be karyotypically more complex and more often have rearrangements of 17q21.     

Chromosome rearrangements in two uterine sarcomas

Cytogenetic analysis of short-term cultures from two uterine sarcomas revealed clonal chromosome abnormalities in both cases. A locally recurrent mixed mesodermal tumor had the karyotype 61,XX,+2,+3,+del(5)(q11),+6,+7,+del(7)(q32),+8,+8,+8,+10, -11,-11,+der(11)t(1;11)(q12;p15),+der(11)t(1;11)(q12;p15),+der(11)t(1;11)(q12;p15),+del(12)(q14q21),+13,+15,del(17)(q23),+20. The other tumor, a lung metastasis from a uterine leiomyosarcoma, had several karyotypically abnormal clones. Two of them consisted of highly aberrant cells with modal chromosome numbers of 82 and 153, respectively, but because of insufficient quality the complex anomalies could not be identified. Various chromosomal changes that included translocations, deletions, insertions, and numerical rearrangements (always with extra chromosome 7 material) were identified in pseudo- or near-diploid cells, resulting in nine additional cytogenetically abnormal clones.     

Chromosome analysis of 96 uterine leiomyomas

From September 1989 to May 1990, we attempted cytogenetic analysis on 96 uterine leiomyomas removed from 64 women. Of the 90 tumors in which analysis was successful, 59 had a normal karyotype while 31 had clonal abnormalities. The most common aberration (13 tumors) was 7q-, mostly del(7)(q21.2q31.2); in two tumors with +12 and t(12;14) as the primary abnormalities, the 7q- was obviously a secondary change since it was found only in a subclone. A t(12;14)(q14-15;q23-24) was detected in two tumors, complex aberrations involving both 12q14-15 and 14q23-24 were also present in two, and rearrangements of 12q without concomitant 14q changes were seen in another two myomas. Rearrangements of 6p were present in five tumors, and trisomy 12 was found in two. More than one abnormality could be detected in 17 leiomyomas. Evidence of clonal evolution in the form of subclones was found in eight tumors, all of which were cellular and had histologically detectable mitotic activity. In addition to their clonal complexity, these myomas also frequently exhibited clonal telomeric associations (four tumors) and ring chromosome formation (three tumors; twice affecting chromosome 1). Monosomy 22 occurred as a secondary abnormality in three tumors; it, too, may reflect a preferred pathway in the karyotypic evolution of uterine leiomyomas.     

Chromosome aberrations in tenosynovial giant cell tumors and nontumorous synovial tissue

Five tenosynovial giant cell tumors—4 pigmented villonodular synovitis (PVNS) and 1 nodular tenosynovitis (NTS)—were investigated cytogenetically. Clonal chromosome aberrations were detected in 3 of them. One PVNS had t(7;16)(q22;q24) as the sole anomaly, whereas 1 PVNS and the NTS displayed aberrations suggesting clonal evolution: t(1;19)(p11;p12)/t(1;19), + 12 and ins(5;1)(q31;p13p34)/ins(5;1),t(2;4)(p23;q21), respectively. Including our 3 cases, a total of 6 tenosynovial giant cell tumors with karyotypic changes have been reported. Apart from 2 PVNS with trisomies 5 and 7, and 2 NTS with rearrangement of chromosome band 1p13, no recurrent chromosome change has been detected. Although the detection of clonal, acquired chromosome abnormalities has formerly generally been accepted as sufficient to conclude that a lesion is neoplastic, the interpretation of the pathogenetic significance of the karyotypic aberrations in synovial tumors is obscured by the fact that we have also detected comparable aberrations in obviously nonneoplastic synovial tissue. One of 2 lesions from patients with hemorrhagic synovitis carried a clonal del(13)(q12q21), and 2 of 4 synovectomy samples from patients with rheumatoid arthritis displayed –Y and –Y together with +7. The available cytogenetic data therefore cannot be used to resolve the controversy as to whether tenosynovial giant cell tumors are truly neoplastic or only reactive, inflammatory proliferations. © 1993 Wiley-Liss, Inc.     

Different karyotypic abnormalities, t(1;6) and del(7), in two uterine leiomyomas from the same patient

Cytogenetic studies of two uterine leiomyomas from the same patient revealed different karyotypic changes. Both tumors showed only a single chromosome abnormality; one had t(1;6)(q23;p21) and the other del(7)(q21.2q31.2). These findings support the view that multiple leiomyomas of the uterus arise independently.     

Uterine leiomyoma cytogenetics. II. Report of forty cases

Chromosome analysis of 40 cultured uterine leiomyomas revealed the presence of clonal changes in 32.5% of them, confirming the cytogenetic heterogeneity within this type of tumor, mostly referable to a few cytogenetic subgroups. Preferential involvement of 12q14-15 and 14q23-24 bands in reciprocal and complex translocations was most commonly observed. Deletions of chromosome 7 and changes of chromosomes 1, 2, and to a lesser extent, chromosomes 19 and 22 were also found. Constitutional karyotype of patients bearing tumors with karyotypic abnormalities was examined. In one patient, two cells were found with t(12;14)(q14-15;q23-24) translocation and two with del(14)(q13q23-24). The latter rearrangement was also present as a clonal change in the tumor.     

Cytogenetic findings in phyllodes tumors of the breast: Karyotypic complexity differentiates between malignant and benign tumors

Clonal karyotypic abnormalities were detected in short-term cell cultures from six phyllodes tumors of the breast. Whereas all five benign tumors had simple chromosomal changes, the highly malignant one had a near-triploid stemline, indicating that karyotypic complexity is a marker of malignancy in phyllodes tumors. Interstitial deletions of the short arm of chromosome 3, del(3)(p12p14) and del(3) (p21p23), were the only aberrations in two benign tumors. Cytogenetic polyclonality was detected in three benign tumors: two had cytogenetically unrelated clones, whereas the third had three different, karyotypically related cell populations as evidence of clonal evolution. The finding of clonal chromosome abnormalities in both the epithelial and connective tissue components of the phyllodes tumors indicates that they are genuinely biphasic, that is, that both components are part of the neoplastic parenchyma.     

Molecular and cytogenetic analysis of chromosome 7 in uterine leiomyomas

Uterine leiomyomas are benign tumors that arise clonally from smooth muscle cells of the myometrium. Cytogenetic studies of uterine leiomyomas have shown that about 40% have chromosome abnormalities and that deletion of 7q is a common finding. The observations suggest the possible location of a growth-suppressor gene within the 7q21-q22 region. Molecular genetic analysis of cytogenetically normal tumors has frequently shown somatic loss of specific tumor suppressor genes detected by loss of heterozygosity in the critical region. To test the hypothesis that chromosome region 7q21-q22 contains a growth-suppressor gene involved in the development of leiomyomas, we examined 92 leiomyomas for allelic loss of 7q markers spanning the cytogenetically defined critical region. Forty tumors with cytogenetically defined 7q deletion, 45 tumors without cytogenetically visible 7q deletion, and seven tumors with no cytogenetic information were examined for allelic loss of loci D7S489, D7S440, D7S492, D7S518, D7S471, D7S466, and D7S530. Loss of heterozygosity for one or more of these loci was observed in 23 of 40 (57.5%) of the tumors with deletion of 7q and in 2 of 45 cases without a cytogenetically visible deletion. The tumors with cytogenetic deletion of 7q, but no loss of 7q21-q22 markers, were mosaics, with only a minority of cells containing the cytogenetic deletion. The critical region of loss is defined by the markers D7S518 and D7S471, each showing loss in approximately 50% of informative cases. These markers define a 10 cM region of 7q21-q22 that is consistent with the cytogenetically defined smallest region of overlap and exclude loss of the MET oncogene locus and WNT1, the murine mammary tumor-virus integration site, from the critical region. Our results further define a region that is consistently lost in leiomyomas with cytogenetic deletion of chromosome arm 7q. This region may contain a tumor suppressor gene involved in the development of a subset of leiomyomas.     

High resolution mapping of consistent leiomyoma breakpoints in chromosomes 12 and 14 to 12q15 and 14q24.1

A substantial percentage of uterine leiomyomas are cytogenetically characterized by consistent, clonal chromosome abnormalities, including t(12;14)(q14-15;q23-24) and other rearrangements of 12q14-15 that occur without any visible 14q changes. The partly similar banding characteristics of these two regions have hitherto precluded exact mapping of the 12q and 14q breakpoints to any particular band, let alone their assignment to subbands. In the series of four myomas presented here, in which one tumor had inv(12q), two t(12;14), and one a three-way t(7;12;14), we were able to achieve high resolution banding (550 band stage) of the rearranged chromosomes in several metaphases. This enabled us to assign a 12q breakpoint to 12q15 in all tumors and, in the three cases informative in this regard, the 14q breakpoint to 14q24.1. The more precise breakpoint mapping considerably narrows down the area that must be examined with molecular genetic methods in order to identify the gene loci that are rearranged in leiomyomas with 12q and 14q aberrations. It will also help determine to what extent leiomyoma rearrangements of 12q involve the same loci that are affected in 12q changes in other tumor types, e.g., in pleomorphic adenomas of the salivary gland, in lipomas, and in myxoid liposarcomas. At present it seems that the breakpoint in 12q may be cytogenetically identical in the three benign tumors, whereas it in myxoid liposarcomas appears to be more proximal.     

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.     

Nonrandom pattern of cytogenetic abnormalities in squamous cell carcinoma of the larynx

Cytogenetic analysis of short-term cultures from 105 squamous cell carcinomas of the larynx (LSCC) revealed clonal chromosome aberrations in 56 tumors. Simple karyotypic changes (less than four aberrations per clone) were found in 24 cases, and the remaining 32 tumors had complex karyotypes with multiple numerical as well as unbalanced structural rearrangements. Extensive intratumor heterogeneity, in the form of multiple related subclones or unrelated clones, was observed in a large fraction of the tumors. The structural changes most often affected chromosomes 3, 1, 11, 7, 2, 15, 5, 4, 8, and 12, with rearrangements in the centromeric regions, i.e., the centromeric bands p10 and q10 and the juxtacentromeric bands p11 and q11, accounting for 43% of the total breakpoints. The most common imbalances brought about by numerical and unbalanced structural rearrangements were loss of chromosomal region 3p21-pter, chromosome arms 4p, 6q, 8p, 10p, 13p, 14p, 15p, and 17p, and gain of chromosomal regions 3q21-qter, 7q31-pter, and 8q. Among 17 recurrent aberrations identified, the most common were i(8q), hsr(11)(q13), i(3q), i(5p), and del(3)(p11). No statistically significant association was found between major karyotypic features and histological differentiation or TNM stage. The karyotypic features of the LSCC were also compared with previously published oral SCC, a subgroup of SCC that has been more extensively characterized cytogenetically. No clear-cut karyotypic differences were found between LSCC and oral SCC, with the exception that i(8q) was significantly more frequent among the latter.     

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.     

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.     

Inversion (X)(p22q13) in a uterine leiomyoma.

We report a case of uterine leiomyoma which showed a karyotype 46,X,inv(X)(p22q13) as the only clonal change in most of the cells. A few cells had an additional del(7), though del(7) has been found to be a primary change in leiomyomas. These findings indicate that the abnormality involving the X chromosome and particularly Xp22 can be considered as a primary chromosomal abnormality. We discuss the findings together with few reports of cases involving chromosome X in leiomyomas.     

Cytogenetic and histologic findings in 17 pulmonary chondroid hamartomas: Evidence for a pathogenetic relationship with lipomas and leiomyomas

Pulmonary chondroid hamartomas (PCH) are benign tumors that contain mesenchymal and epithelial components. In this series, we identified clonal chromosome aberrations in mesenchymal cells from 10 of 17 PCH. Chromosome band 12q15 was rearranged most frequently (N = 4), and one case had a t(12;14)(q15;q24) that was identical cytogenetically to the characteristic translocation in uterine leiomyomas. Histologic review revealed diverse mesenchymal populations, including undifferentiated cells, cartilage, adipose tissue, and smooth muscle, in most of the PCH. These findings suggest that PCH result from neoplastic transformation of a primitive mesenchymal cell that differentiates along chondroid, adipose, and smooth muscle pathways.     

Uterine leiomyoma cytogenetics. III. Interphase cytogenetic analysis of karyotypically normal uterine leiomyoma excludes possibility of undetected trisomy 12.

Uterine leiomyoma, a benign tumor that histopathologically is rather homogeneous, was recently characterized cytogenetically. About 40% of the investigated tumors are associated with clonal chromosome abnormalities and five different subgroups have been identified, characterized by trisomy 12, t(12;14)(q14-15;q23-24), del(7q), t(1;2)(p36;p24), and 6p rearrangements. In our survey of 76 cases, trisomy 12 was observed in 10% of the abnormal cases. To exclude a possible underscoring of this abnormality, we reexamined 15 of the cases with normal karyotype by interphase cytogenetics using a chromosome 12 alphoid DNA probe.     

Nonrandom cytogenetic changes in leiomyomas of the female genitourinary tract. A report of 35 cases

Cytogenetic analysis of short-term cultures from 35 leiomyomas of the female genitourinary tract showed abnormal karyotypes in 14 cases. In 11 of 14 aberrant tumors, normal cells were also observed. Structural changes were most frequent, resulting in modal chromosome numbers in the diploid range. Our data confirm preferential breakpoint clusters at 7q, 12q14-15, and 14q23-24, mainly resulting from consistent, specific chromosome rearrangements such as t(12;14)(q14-15;q23-24) and del(7)(q21) or del(7)(q22q32). Together with previously published cases, we describe trisomy 12, ring chromosomes, and monosomy 22 as new additional recurrent findings in myomas. Statistical analyses of possible coherencies between tumor karyotype (abnormal versus normal) and clinicopathologic data, as well as age of the patients, menopausal status, and tumor size showed no correlations.     

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.