Primary vs. secondary neoplasia-associated chromosomal abnormalities—balanced rearrangements vs. genomic imbalances?

Johansson, Bertil; Mertens, Fredrik; Mitelman, Felix

doi:10.1002/(sici)1098-2264(199607)16:3<155::aid-gcc1>3.0.co;2-y

Cited by 155 publications

(87 citation statements)

References 58 publications

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“…In fact, all recurrent secondary aberrations were unbalanced, ie resulted in genomic imbalances (Table 2), further strengthening the previously recognized general theme of such changes in acute leukemias, as well as in some solid tumor types, ie they are, for presently unknown reasons, almost always cytogenetically unbalanced. 62 The finding that only +der(4) occurred as an additional aberration, never +der(11), was somewhat unexpected, considering that it is the latter, ie the MLL/AF4 fusion, which, based on cytogenetic as well as molecular genetic studies, is suggested and believed to be the pathogenetically important outcome of the translocation. [18][19][20][21]23,63,64 The same pattern also emerged when reviewing all previously published t(4;11)-positive leukemias: +der(4), or +del(4)(q21), has been described in six cases, whereas +der(11) has never been reported.…”

Section: Discussionmentioning

confidence: 99%

Hematologic malignancies with t(4;11)(q21;q23) – a cytogenetic, morphologic, immunophenotypic and clinical study of 183 cases

et al. 1998

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A total of 183 hematologic malignancies with t(4;11)(q21;q23), including five variant translocations, were collected by the Workshop. Clinical, morphologic and immunophenotypic features were compiled, and karyotypes with variant t(4;11) or secondary chromosomal aberrations were reviewed. All cases were acute leukemias (AL): 173 acute lymphoblastic leukemias (ALL), six acute myeloid leukemias (AML), three unclassifiable AL, and one biphenotypic AL. Ten patients had treatment-associated AL. Females were overrepresented (104 vs 79) and the age distribution was clearly nonrandom; 34% of the cases occurred in infants below the age of 12 months. The remaining AL were evenly distributed among the other age groups, with the oldest patient being 79 years old. An increased white blood cell count (WBC) was reported in more than 90% of the cases, with hyperleukocytosis (у100 × 10 9 /l) in 64%. Additional chromosomal changes were detected in 55 (30%) cases, most often gain of the X chromosome, i(7)(q10), and trisomy 8, with frequent breakpoints in 1p36, 1q21, 7q10, 11p15, 12p13, 17p11, and 17p10. All recurrent secondary changes resulted in genomic imbalances, in particular gains of 1q, 7q, 8, and X and losses of 7p and 17p. Event-free and overall survival (EFS and OS) could be ascertained in 170 and 171 patients, respectively. Kaplan-Meier estimates of EFS and OS showed no differences with regard to gender, WBC, or presence of secondary chromosomal abnormalities, and there was no increase of EFS or OS among the 55 cases that had undergone bone marrow transplantation. However, age had an important prognostic impact, with significantly (P Ͻ 0.0001) longer EFS and OS in children 2-9 years old than among infants and younger children, patients aged between 10 and 39 years and older adults.

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Section: Discussionmentioning

confidence: 99%

Hematologic malignancies with t(4;11)(q21;q23) – a cytogenetic, morphologic, immunophenotypic and clinical study of 183 cases

et al. 1998

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“…;p12) [28],Ϫ12 [28],del(12)(q13) [28], Ϫ14 [28],Ϫ15 [28],Ϫ16 [28],del(18)(q12) [28],der (18)add (18) 65ϳ69͗3n͘,XXX,ϩdel(X)(p11.2) [15],der(3)t(X;3)(q26;q28) [15],der(3)ins(3p;12) [15],ϩdel(4)(q21) [7], ϩdel(5)(q11.2) [15],Ϫ6 [15],t(6;14)(q23;q13) [15],del(7)(p15) [15],der(8)i(8q)hsr(8)(8q24) [15], der(9)ins(9;?) [15],Ϫ13 [15],i(13)(q10) [15],Ϫ14 [13],ϩ15 [15],der (17) [9]/idem,der(4)t(4;8)(q11;q11),der(9)t(9;11)(p11;q11),del(11)(q11), der (15) 75ϳ81͗3n͘,XX,ϪX [15],ϪY [15],del(3)(q25) [3],der(3)t(2;3)(q11;p11) [15],der(5)t(5;18;Y)(p13;p11.2; q11.2) [15],ϩder(5)t(5;18;Y)(p13;p11.2;q11.2) [13],der(6)t(6;12)(p21;q13) [15],ϩder(6)t(6;12)(p21; q13) [12],ϩ7 [10],ϩ8 [14],ϩ9 [14]ϩ10 [9],der(12)t(12;14)(p13;q31) [15],ϩ13 [8],ϩ14 [10],ϩ15 [13], ϩ16 [4],ϩ17 [8],Ϫ18 [15],ϩder (19) 81ϳ86͗4n...…”

Section: Cell Lines Of the Mis Pathwayunclassified

“…Unbalanced chromosomal abnormalities would be secondary events and most likely associated with selective pressures during tumor progression. 13 Therefore, a role for structural chromosome instability in early tumor stages may be hypothesized, whereas observed numerical chromosomal alterations may represent a multistep convergent drift driven by selection. 14 We analyzed the cytogenetic characteristics of chromosome instability in the CRC cell line KM12C and its metastatic counterparts, KM12SM and KM12L4A, using an array of molecular cytogenetic techniques.…”

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confidence: 99%

Genetic evolution in colon cancer KM12 cells and metastatic derivates

Camps

Morales

Prat

et al. 2004

Intl Journal of Cancer

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So far, CRC cell lines have contributed to descriptions of 2 patterns of genetic instability, affecting either microsatellite sequences or chromosome number and structure. Often, these patterns are mutually exclusive; while near-diploid karyotypes usually appear with MSI and chromosomal stability, near-triploid or tetraploid cells display a high degree of CIN and are stable at the microsatellite level. In the present study, we describe the genomic instability pattern of KM12 CRC cells. KM12C and derived cell lines with different metastatic properties were analyzed by conventional cytogenetics, CGH and M-FISH. Results were compared to 5 cell lines usually used as model of MSI and CIN. Concordance between our results and previously published SKY data are also reviewed. Interestingly, the poorly metastatic KM12C cell line displayed a near-diploid karyotype with high levels of structural chromosome instability and microsatellite instability. Most carcinomas show highly complex karyotypes, suggesting that one of the tumor-development events may be related to genomic instability. 1,2 Up to now, MSI has been the only type of genomic instability well characterized in a minority of tumors (about 15% of sporadic CRCs). These tumors show a deficiency in mismatch repair genes with a replication error phenotype and a stable near-diploid karyotype. 3-7 chromosome instability has been described in some CRC cell lines, resulting in numerical changes 8 (CIN) or structural rearrangements. 9 Often, these patterns are mutually exclusive; while near-diploid karyotypes usually appear with MSI and chromosome instability, near-triploid or tetraploid cells display a high degree of CIN and are stable at the microsatellite level.It has been postulated that primary alterations in solid tumors consist of submicroscopic mutations, whereas unbalanced chromosomal rearrangements, whether numerical or structural, are secondary events and most likely associated with selective pressures during tumor progression. 10 A previous report demonstrated clonal chromosomal aberrations in 87% of CRC tumors analyzed. 11 The most frequent numerical changes were, in order of decreasing frequency, ϩ7, -18, -14, ϩ13. Gain of chromosome 8q and loss of 8p, loss of 17p and gain of 17q as well as loss of the entire chromosome 22 are also unbalanced rearrangements that have been reported. 11 Based on cytogenetic alterations, Dutrillaux 12 proposed 3 different evolutionary pathways: monosomic-type tumors undergo structural rearrangements resulting in gains and losses of different chromosome arms and show a relatively high rate of endoreduplication, leading to the formation of hypotetraploid clones that evolve to near-triploid cells; trisomic cells are characterized by tumors with a progressive increase in chromosome number but accompanied by a scarce number of rearrangements; tumors that display a near-normal karyotype and MSI were grouped into the normal type. Unbalanced chromosomal abnormalities would be secondary events and most likely associated with selective pre...

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“…Two distinct neoplasia-associated karyotypic patterns have been defined recently [14]. Primary abnormalities are believed to be essential in establishing the tumors, while secondary abnormalities occur in addition to the primary, and are important in tumor progression and maintenance.…”

Section: Discussionmentioning

confidence: 99%

“…It is important to point out that in this study, a significant in-crease of unbalanced abnormalities, mostly chromosome losses, has been detected in samples at the end of treatment and at relapse, accounting for 75% of all CAs detected. Some authors [14,15] suggest that chemotherapy is an important factor in determining which subclones with secondary aberrations will appear at remission. In contrast to the balanced abnormalities, the molecular consequences of the recurrent unbalanced abnormalities are unknown to date.…”

Section: Discussionmentioning

confidence: 99%

Nonclonal Chromosomal Aberrations Induced by Anti-Tumoral Regimens in Childhood Cancer

Mesa

Sierrasesúmaga

Calasanz

et al. 2000

Cancer Genetics and Cytogenetics

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Cytogenetic studies were performed on 80 pediatric cancer patients to observe the chromosomal damage, both quantitative and qualitative, induced by chemotherapy. Peripheral blood lymphocytes (PBL) (n = 127) were obtained at diagnosis, during treatment, at remission, and at relapse, and chromosome analysis performed utilizing Gbanding standard procedures. The results show a significant increase in the number of altered karyotypes (P = 0.03) in the samples during treatment, returning to values that were similar to those at diagnosis at 2-year remission. Most of the chromosomal aberrations (CA) detected during the chemotherapy regimens were nonclonal, unbalanced (75%), and involved chromosomes 1, 3, 5, 6, 11, 12, 16, and 17 most frequently. There was also a marked increase of CA in samples at relapse with very similar features (type and distribution) to those detected during treatment. There was a good correlation between the chromosomal breakpoints in our series and fragile sites (58%), oncogene (75%), and tumor suppressor gene (33%) loci described in the literature. The results obtained suggest that cytostatic drugs induce a transient increase in chromosome fragility occurring at several cancer-associated breakpoints.

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Primary vs. secondary neoplasia-associated chromosomal abnormalities—balanced rearrangements vs. genomic imbalances?

Cited by 155 publications

References 58 publications

Hematologic malignancies with t(4;11)(q21;q23) – a cytogenetic, morphologic, immunophenotypic and clinical study of 183 cases

Hematologic malignancies with t(4;11)(q21;q23) – a cytogenetic, morphologic, immunophenotypic and clinical study of 183 cases

Genetic evolution in colon cancer KM12 cells and metastatic derivates

Nonclonal Chromosomal Aberrations Induced by Anti-Tumoral Regimens in Childhood Cancer

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