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PubMed1976

Long-term cytogenetic studies in acute leukemia of children; the nature of relapse.

Sequential long-term cytogenetic studies in 71 children with acute leukemia were designed to investigate the nature of relapse after prolonged remission. In the overwhelming majority of the cases the findings suggested clonal identity of the leukemic cell population in relapse with that studied at the onset of the disease, notwithstanding considerable karyotypic instability in almost half of the patients. In a small minority an independent origin of the relapse clone could not be excluded on cytogenetic grounds but was considered unlikely, since mechanisms capable of accounting for the changes observed in these patients could be demonstrated in other cases. The persistence of diploid leukemic cells in the presence of an aneuploid subclone was demonstrated in the relapse bone marrow and/or spinal fluid in all active phases of the disease. On this basis the conversion from an aneuploid to a predominantly or exclusively diploid karyotype could be visualized, and a new model of clonal evolution, involving repetitive formation of abnormal karyotypes from a surviving diploid clone could be suggested.

Adolescent↗
PubMed2026

The Homozygous p.(Arg215Ter) Variant in XRCC2 Is Associated With Atypical Fanconi Anemia Without Major Hematological Abnormalities in Childhood.

Fanconi Anemia (FA) is the most frequent inherited bone marrow failure syndrome. A role for the XRCC2 gene in FA was suspected in 2012 and confirmed in 2016, but only two affected individuals have been described thus far, and no long-term follow-up is available. Here we present two young related adults born to consanguineous parents, in whom we identified the homozygous p.(Arg215Ter) variant in XRCC2. Both patients presented with mild intellectual disability, microcephaly, distinctive facial features, short stature, thumb abnormalities, and abnormal skin pigmentation. Unlike in FA, DEB test resulted negative in peripheral blood during childhood and no cytopenia, clonal evolution, or other hematological complications were detected until the age of 19 and 20 years, respectively. Our report suggests that the homozygous p.(Arg215Ter) variant in XRRC2 causes a distinctive FA-like disorder, characterized by the typical physical characteristics seen in FA, but a lack of major hematological manifestations in childhood, and the presence of a more pronounced neurodevelopmental phenotype than that seen in FA.

Humans↗
PubMed2026

Multi-Omics Biomarker Signatures for Precision Diagnosis and Prognosis in Primary Liver Cancer: A Literature Review.

Primary liver cancer (PLC) is a biologically heterogeneous group of malignancies dominated by hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), and a smaller subset of combined hepatocellular-cholangiocarcinoma (cHCC-CCA), and its clinical burden remains high because current diagnostic and prognostic tools do not adequately capture molecular diversity. Conventional imaging, serum markers, and histopathological assessment remain insufficient for precise early diagnosis, subtype-resolved classification, and outcome stratification, while tissue and liquid biopsy approaches have expanded the range of analytes available for clinical assessment. Recent studies have identified candidate biomarker signatures across genomic, epigenomic, transcriptomic, proteomic, metabolomic, and circulating layers, suggesting that integrated multi-omics profiling may better represent tumor lineage, clonal evolution, immune context, and therapeutic vulnerability than isolated molecular readouts. However, these layers are not equally mature for clinical use: genomic testing is closest to routine therapeutic application in iCCA, plasma methylation assays are advancing for HCC surveillance augmentation, and many proteomic or metabolomic panels remain validation-stage tools. Their clinical value remains constrained by sampling bias, biospecimen-dependent signal loss, assay standardization, cost, and the need for prospective validation across clinically diverse populations. This narrative review critically synthesizes current evidence on multi-omics biomarker signatures for precision diagnosis and prognosis in primary liver cancer and argues that clinically useful signatures should be question-specific, stage-aware, and specimen-aware rather than universal multi-analyte panels.

Humans↗
PubMed1990

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↗
PubMed1990

Leukemia characterized by multiple sub-clones with unbalanced translocations involving different telomeric segments: case report and review of the literature.

A 68-year-old man presented with t(4;11)(q21;q23), B-lineage acute lymphoblastic leukemia (ALL) which was negative for C-ALL antigen and TdT. Clonal evolution to five different, but related karyotypes, in which chromosomal material distal either to 1q11 or 1q21 was translocated to the terminal regions of 4q-, 11q, 16q, and 19p resulted in partial or total trisomy of 1q. The patient, having achieved a short remission, died 14 weeks after diagnosis. Five reports of jumping translocations in hematological malignancies, four with B-lineage malignancy, are reviewed. One (four cases) or both (one case) of the same 1q breakpoints were consistently found and 11q and 16q were repeatedly involved. Such cases, having multiple subclones with trisomy 1q, may form a distinct subgroup of ALL.

Aged↗
PubMed1991

t(18;22)(q21;q11) with rearrangement of BCL2 as a possible secondary change in a lymphocytic lymphoma.

We report a lymphocytic lymphoma showing a combination of two characteristic neoplasia-associated chromosomal changes: trisomy 12, commonly observed in chronic lymphocytic leukemia and lymphocytic lymphoma, and t(18;22)(q21;q11), a variant form of the t(14;18)(q32;q21) found in most follicular lymphomas. Southern blot analysis was performed using probes for the 5' end of the BCL2 gene (18q21) and for the J lambda as well as C lambda immunoglobulin genes (22q11). With these two probes, a unique rearranged fragment was detected. Thus the t(18;22)(q21;q11) can be considered as a variant translocation of t(14;18)(q32;q21). The karyotypic analysis supports the assumption that in our case trisomy 12 occurred first, and t(18;22) appeared during tumor progression as part of the clonal evolution. This is at variance with the typical t(14;18), which has never been found to occur as a secondary change.

Blotting, Southern↗
PubMed1991

Cytogenetics of synovial sarcoma: presentation of ten new cases and review of the literature.

Cytogenetic study of five biphasic and five monophasic synovial sarcomas revealed the specific abnormality t(X;18) (p11;q11) in eight cases and t(X;15;18) (p11;q15;q11) and t(X;7) (q11-12;q32) in one case each. Additional, secondary aberrations were present in eight of these tumors. By combining our data with information on previously published cytogenetically abnormal synovial sarcomas, we were able to evaluate 32 tumor samples from 29 patients. The modal chromosome number was pseudodiploid or near diploid in 26 of the 32 tumors. A t(X;18) was present in 21 of 29 cases (72%). Complex translocations involving chromosomes X and 18 and another autosome were present in five cases, and one displayed a t(5;18). There was no visible rearrangement of chromosome bands Xp11 or 18q11 in only 2 of the 32 synovial sarcomas. Half of the primary tumors (6 of 12) had the X;18-translocation as the sole abnormality. Of the remaining 20 specimens from recurrent or metastatic tumors (in three cases two tumors could be analyzed), only one had t(X;18) as the sole change. The secondary aberrations in cases exhibiting clonal evolution were also generally more extensive in the metastatic and recurrent than in the primary sarcomas (five additional aberrations per case, compared with two). Chromosomes 1 and 12 were the chromosomes most frequently (one fourth of the cases) involved in additional structural changes, but with several different breakpoints. No differences were identified between the karyotypic profiles of monophasic and biphasic synovial sarcomas.

Adolescent↗
PubMed1991

Multiple DNA rearrangements in the BCL2 region in a patient with follicular lymphoma.

A 39-year-old male with follicular non-Hodgkin's lymphoma was repeatedly studied with respect to DNA rearrangements with the two probes pFL-1 and pFL-2, representing two segments of chromosome 18. The oncogene BCL2, detected by pFL-1, was as expected translocated to the J region of the immunoglobulin locus. The standard BCL2 translocation was found in three samples, one obtained at diagnosis, one ten months later, and one after 5 years. Another translocation was found with the probe pFL-2 hybridizing with a region located about 20 kb 3' from BCL2. This latter rearrangement was found only in the first biopsy, which was obtained at the time of diagnosis, but not in the two later samples, when the morphology of the lymphoma was unchanged. No cytotoxic therapy had been given in the interval from diagnosis to disappearance of the latter rearrangement. Thus, one of the observed translocations (pFL-2) was detected only in the first biopsy, while the other (pFL-1) was a clonal marker in all three biopsies. The finding suggests that clonal evolution does not necessarily mean clinical progression.

Adult↗
PubMed1992

Rearrangements of chromosome arm 3q in poorly differentiated nasopharyngeal carcinoma.

Cell lines were established from fresh tumor biopsies from two Saudi patients with poorly differentiated nasopharyngeal carcinoma (NPC). Cytogenetic analysis on Giemsa-banded metaphase cells revealed complex, abnormal karyotypes in both patients with modal chromosome numbers of 77 and 52. A der(3)dup(3)(q25-q2?7) or t(3;?)(q27;?) was observed in both cell lines. The rearrangements involving chromosomes X, 1, 4, 6, 7, 8, 12, 13, 15, 17, and 22 in the first patient and 1, 6, and 22 in the second patient could represent clonal evolution.

Adult↗
PubMed1992

Is cancer cytogenetics reducible to the molecular genetics of cancer cells?

Whether cancer cytogenetics can be reduced to the molecular genetics of cancer cells is a question that must be addressed in three domains, focusing on its ontological, methodological, and epistemological dimensions. The possibility of ontological reduction hinges on whether chromosomes have other important constituents than molecules. Although this must obviously be answered in the negative, it should be emphasized that both cytogenetic and recombinant DNA investigations provide us with very selective pictures of genomic organization. This is of concern because the higher order packing of DNA and its joining with other molecules to form chromosomal structures give rise to emergent properties, functional features that become manifest only at higher levels of complexity and that may not be deducible from the base pair composition of the DNA. A position of extreme methodological reductionism would in our context be that the best research strategy is always to investigate the genetic changes of tumor cells at the highest possible resolution level, as alterations of genes and, ultimately, as changes in DNA primary structure. There are two fundamental differences between cytogenetic and molecular genetic techniques that make this stance untenable. First, whereas cytogenetic investigations are open-framed (all chromosome aberrations are revealed), molecular genetic analyses are highly specific (only those aberrations are revealed that one tests for). Second, whereas the molecular approach determines the genotypic constitution of an idealized, average tumor cell, cytogenetic analysis is of real, individual cells. These may not necessarily be representative of the main population of the tumor, but at least whatever karyotypic differences exist between them are detected. Heterogeneity and clonal evolution within the tumor can thereby be assessed.(ABSTRACT TRUNCATED AT 250 WORDS)

Chromosome Aberrations↗
PubMed1991

Bilateral ovarian carcinoma: cytogenetic evidence of unicentric origin.

Cytogenetic analyses were performed on the tumors from both ovaries in 15 patients with bilateral ovarian carcinoma. In 4 of them, omental implants were also examined. Abnormal karyotypes were detected in 11 cases. The baseline karyotypes in the 2 tumorous ovaries were identical in each patient, indicating that bilateral ovarian cancer develops by metastatic spreading. There was no clear-cut evidence of differences in the clonal evolution between the tumors of the 2 ovaries, and hence the side harboring the primary tumor could never be determined. The metastatic nature of the omental implants was proved by the fact that their karyotypes were indistinguishable from those of the ovarian tumor tissue.

Adenocarcinoma↗
PubMed1992

The natural history of intraepithelial neoplasia: relevance to the search for intermediate endpoint biomarkers.

The development of carcinomas, defined as invasive epithelial neoplasms, is preceded by a preinvasive stage termed intraepithelial neoplasia that typically lasts for years. Intraepithelial neoplasia is the target tissue for the action of chemopreventive agents and the site where biomarkers frequently develop. The term "dysplasia" refers to the morphological alterations that characterize intraepithelial neoplasia and, according to many authors, consists of seven basic changes that are the same for the majority of epithelia. These are increased nuclear size, abnormal nuclear shape, increased nuclear stain uptake, nuclear pleomorphism (increased variation in size, shape, and stain uptake), increased mitoses, abnormal mitoses, and disordered or absent differentiation. Clonal evolution appears to begin early in the neoplastic process during intraepithelial neoplasia. The use of intraepithelial neoplasia as an intermediate endpoint biomarker requires that effective chemopreventive agents cause it to regress. Two examples are the regression of dysplastic oral leukoplakia produced by beta-carotene and the regression of colonic polyps in familial polyposis patients following treatment with the nonsteroidal antiinflammatory drug sulindac. There is a critical need to identify and develop biomarkers that correlate with the appearance and regression of intraepithelial neoplasia.

Biomarkers↗
PubMed1991

Reduction of TGF-beta activity abrogates growth promoting tumor cell-cell interactions in vivo.

We have shown in previous studies that metastatically-competent variant subpopulations (B5, C1) derived from a non-metastatic murine mammary adenocarcinoma (SP1) have a pronounced growth advantage over their non-metastatic tumor cell counterparts in primary tumors. As a result, primary tumors can be progressively overgrown by cells having the competence to spread elsewhere in the body. This occurs despite any evidence to indicate an intrinsic in vivo growth rate advantage of the metastatic cells when grown as isolated populations. This suggested that cell-cell interactions between metastatic and non-metastatic tumor populations may be involved in the metastatic cell growth dominance process. Evidence was therefore sought for growth factors released by SP1 cells which could preferentially stimulate the B5 or C1 variants and thereby mediate this cell-cell interaction process. We found that cocultures of SP1 and C1 or B5 cells with irradiated C1, B5, or SP1 "feeder" cells showed significant stimulation of C1 and B5 by SP1 "feeder" cells. Cell growth stimulation in response to EGF, TGF-alpha, TGF-beta 1, bFGF, PDGF, NGF, IGF-1, or IGF-2 demonstrated that only TGF-beta 1 could duplicate this effect. A repeat of the coculture experiment in the presence of specific neutralizing anti-TGF-beta antibodies was therefore undertaken and this was found to markedly reduce the stimulation of C1 or B5 cells by irradiated SP1 cells. Conditioned media from the SP1 and C1 cell lines was quantitated for TGF-beta activity and contained 4.5 ng/ml and 2.0 ng/ml, respectively. However, the majority of the TGF-beta released by SP1 cells was found to be spontaneously active, whereas 70% of the TGF-beta released by C1 cells was in its latent form. Scatchard analysis revealed approximately four times the number of TGF-beta receptors, of similar type and affinity, present on C1 as compared with SP1 cells. The in vitro results support the hypothesis that active TGF-beta released by SP1 cells may stimulate the proliferation of metastatic variant cells in a paracrine like fashion. In vivo evidence for this was obtained by showing that coinjection of irradiated SP1 cells could selectively stimulate tumor growth of viable C1 cells and this effect was markedly diminished by neutralizing polyclonal anti-TGF-beta antibodies. Taken together, the results suggest a novel role for TGF-beta in clonal evolution of malignant tumor growth and as a molecular mediator of tumor cell-tumor cell interactions involved in facilitating tumor progression.

Adenocarcinoma↗
PubMed1992

Absence of point mutation of N-ras oncogene in bone marrow cells with aplastic anemia.

Point mutation of N-ras oncogene at codons 12, 13 and 61 was studied in the bone marrow cells of patients with typical aplastic anemia using the polymerase chain reaction method for DNA amplification and dot blot hybridization to synthetic oligonucleotide probes. Point mutation was observed in none of the 15 patients studied. These findings indicate either that the pathogenesis of typical aplastic anemia is different from that of preleukemic states of myelodysplastic syndrome or acute leukemia in clonal evolution, or that the overlapping area sharing a common pathogenesis is much smaller than was presumed.

Anemia, Aplastic↗
PubMed1992

DNA ploidy of primary hepatocellular carcinoma and pulmonary metastases.

To better comprehend the differences in deoxyribonucleic acid (DNA) content between a primary hepatocellular carcinoma (HCC) and pulmonary metastatic nodules, tissue specimens taken at autopsy of 25 patients who had not received any drugs to treat the malignancy were examined using microspectrophotometry. The DNA distribution patterns were classified into Types I-III, and low (Types I and II) or high (Type III) ploidies, according to DNA distribution. Changes in the DNA content from high to low ploidies, namely DNA ploidy reduction from the primary lesion to pulmonary metastatic lesions, was evident in 9 of the 25 patients (36%), and changes from low to high were noted in 2 of the 25 patients (8%). The remaining 14 (56%) showed no evidence of changes in the DNA ploidy pattern. Reduction of DNA ploidy seen in HCC and its metastatic lesions in the lung may be one of the aspects of clonal evolution or selection mechanisms during the progression of tumor growth and metastasis.

Autopsy↗
PubMed1977

Comparative cytogenetic and histologic studies on early malignant transformation in mesothelial tumors of the ovary.

Comparative cytogenetic and histologic studies on 18 mesothelial ovarian tumors revealed a normal chromosome complement in benign lesions, and the well-known cytogenetic pattern in cystadenocarcinomas. But all borderline tumors of the series evidenced an abnormal stem line and a more or less marked tendency to polyploidization. Serous papillary cystadenomas of this group showed in five out of six cases a stem line with the karyotype 47,XX+C10 (identified by Q-banding), present in both sides of bilateral lesions. It is evidenced that malignant change on the chromosomal level precedes histologically detectable features of malignancy. Histologic equivalents appeared, when the abnormal cell line was established. The initiation of malignant transformation therefore may be signalized by karyotype abnormalities before structural changes can be detected in the corresponding histologic specimens. The results discussed include the concepts of multicentric origin and clonal evolution of malignancy.

Cell Transformation, Neoplastic↗
PubMed1976

Editorial: Chromosomes and human neoplasms. Achievements using new staining techniques.

Numerical and structural chromosome aberrations are frequently found in neoplastic cells. As demonstrated by the new chromosome banding techniques these aberrations are not random, but tend to show a specific occurrence. A model example is the leukemias where many cytogenetical investigations have been done to date. In leukemia chromosome analysis serves the following purposes: to identify a neoplastic process, to confirm and strengthen the hematological diagnosis, for the early diagnosis of transformation from a chronic leukemia into its blastic phase and for following up the clonal evolution of a leukemic cell line. In the discussion of chromosomes and neoplasms it must be mentioned that individuals demonstrating chromosomal instability and some trisomic patients show a greater tendency toward the development of a malignancy. Malignancy is primarily a cellular phenomenon caused by a disturbance in cellular regulation, whose fine events are not known. Therefore the exact role of the chromosomes in neoplastic processes cannot be stated. From experimental investigations it appears that the affected chromosomes carry cell growth regulating factors and also that a specific aberration is the result of the action of a specific agent.

Acute Disease↗
PubMed1991

Typing of methicillin resistant and susceptible Staphylococcus aureus strains by ribosomal RNA gene restriction patterns using a biotinylated probe.

Nine methicillin-sensitive (MSSA) and 37 methicillin-resistant (MRSA) Staphylococcus aureus isolates of various phage types and resistotypes from seven countries were investigated. Chromosomal DNA was restricted with HindIII or EcoRI, Southern blotted and hybridised with a cDNA probe to 16S+23S rRNA derived from MRSA NCTC 10442. Resulting rDNA profiles could be differentiated on the basis of 22 patterns which were unaffected by changes in plasmid, transposon, enterotoxin A or phage content. Percentage similarity values were calculated using the Dice coefficient and UPGA clustering. Australian and epidemic (EMRSA-1) isolates from the UK showed a high degree of similarity, but the pattern was not unique and was also found in MSSA and other MRSA, e.g. NCTC 10442. An MSSA of phage group II was the most distinct isolate. The method shows potential as an additional tool in a complex typing system, types non-phage typable strains and may provide clues to the clonal evolution of MRSA and MSSA.

Bacterial Typing Techniques↗