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Results for “Clonal Evolution”

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PubMed2026

Late acquisition of BCR::ABL1 during clonal evolution of SAMD9-associated MDS with phenotypic shift from AML to B-ALL.

We describe a unique case of SAMD9-associated myelodysplastic syndrome (MDS) with monosomy 7 that evolved over 16 years into BCR::ABL1-positive acute myeloid leukemia (AML) and subsequently manifested as B-cell acute lymphoblastic leukemia (B-ALL). Genomic analysis at AML diagnosis revealed a germline SAMD9 mutation together with somatic RUNX1 and PPM1D mutations, supporting stepwise clonal evolution, with BCR::ABL1 emerging as a late leukemogenic event. The dominant leukemic population at AML onset showed myeloid morphology and immunophenotype, whereas a minor CD19+CD10+ population was already detectable. Following venetoclax and azacitidine therapy, the dominant leukemic phenotype shifted to B-ALL while retaining BCR::ABL1 positivity. Detection of the Philadelphia chromosome in mature neutrophils at both AML onset and ALL relapse supported multilineage involvement of a multipotent BCR::ABL1-positive clone. Ponatinib achieved disease control. This case highlights late acquisition of BCR::ABL1 during SAMD9-associated clonal evolution and therapy-driven phenotypic shift within a shared Ph-positive leukemic stem-cell hierarchy.

Humans↗

PubMed2000

Downregulation of 14-3-3sigma prevents clonal evolution and leads to immortalization of primary human keratinocytes.

In human epidermal keratinocytes, replicative senescence, is determined by a progressive decline of clonogenic and dividing cells. Its timing is controlled by clonal evolution, that is, by the continuous transition from stem cells to transient amplifying cells. We now report that downregulation of 14-3-3sigma, which is specifically expressed in human stratified epithelia, prevents keratinocyte clonal evolution, thereby forcing keratinocytes into the stem cell compartment. This allows primary human keratinocytes to readily escape replicative senescence. 14-3-3sigma-dependent bypass of senescence is accompanied by maintenance of telomerase activity and by downregulation of the p16(INK4a) tumor suppressor gene, hallmarks of keratinocyte immortalization. Taken together, these data therefore suggest that inhibition of a single endogenous gene product fosters immortalization of primary human epithelial cells without the need of exogenous oncogenes and/or oncoviruses.

14-3-3 Proteins↗

PubMed2004

Identification of cytogenetic subgroups and karyotypic pathways of clonal evolution in follicular lymphomas.

Follicular lymphoma (FL) is characterized by the activation of BCL2 through t(14;18)(q32;q21). Additional acquired mutations are necessary to generate a fully malignant clonal proliferation. Many of these secondary genetic alterations are visible in the clonal karyotype; however, the sequence by which they arise and their influence on clinical behavior have not been determined. The ability to address these issues has been hampered by the lack of computational methods to manipulate complex chromosomal data in a sufficiently large cohort of cases. In the present investigation, we analyzed secondary karyotypic alterations in 336 cases of FL with t(14;18) to identify the most common regions of recurrent chromosomal gain or loss. This revealed 29 recurrent changes present in more than 5% of the tumors. Each tumor karyotype was then assessed for the presence or absence of each of these 29 specific changes. By statistical means, we show that the chromosomal changes arise in an apparent temporal order, with distinct early and late changes. We identify, by principal-components analysis, four possible cytogenetic pathways that characterize the early stages of clonal evolution, which converge to a common route at later stages. We show that FLs with t(14;18) may be classified into cytogenetic subgroups determined by the presence or absence of 6q-, +7, or der(18)t(14;18). Correlation with clinical outcomes in a subset of cases with clinical data revealed del(17p) and +12 to be correlated with an adverse clinical outcome. The clinical implications of these pathways of clonal evolution need to be examined on a prospective basis in a large cohort of FLs.

Chromosome Aberrations↗

PubMed1997

The evidence of clonal evolution with monosomy 7 in aplastic anemia following granulocyte colony-stimulating factor using the polymerase chain reaction.

We present here the case of a Japanese female patient with aplastic anemia who developed monosomy 7 and clonal evolution following a treatment with recombinant human granulocyte colony-stimulating factor (rhG-CSF). At the onset of aplastic anemia, cytogenetic analysis was 46, XX and X-inactivation/methylation analysis revealed a polyclonal pattern. After 4 months of administration of rhG-CSF, she had 45, XX, -7 and a clonal pattern, although there were no morphological evidence of a myelodysplastic syndrome or leukemia. The ratio of monosomy 7 to normal analyzed by fluorescence in situ hybridization decreased after discontinuation of rhG-CSF and there were still no dysplastic changes and/or increased numbers of blasts. These results indicate that the acquisition of monosomy 7 following rhG-CSF treatment dose not always cause clonal evolution to induce hematological malignancies.

Anemia, Aplastic↗

PubMed2003

p53 loss of function enhances genomic instability and accelerates clonal evolution of murine myeloid progenitors expressing the p(210)BCR-ABL tyrosine kinase.

BACKGROUND AND OBJECTIVES: The p210 bcr-abl fusion protein has a key role in the pathogenesis of chronic myeloid leukemia (CML). However, its influence on disease progression to blast crisis is marginal and mostly due to its effect of impairing the genomic stability of clonal myeloid progenitors through pathways still largely unknown. DESIGN AND METHODS: To elucidate the role of p53 in CML progression we generated, from the 32D murine myeloid cell line, several clones co-expressing the E6 product gene of human papilloma virus (HPV) 16, which abrogates p53 function, and a temperature-sensitive bcr-abl construct encoding a fully active p210 protein only at the permissive temperature of 33 degrees C. RESULTS: Co-expression of the two proteins resulted in a significant enlargement of the G(2)/M phase of cell cycle and in the appearance of a poly-aneuploid cell population. Furthermore, with continuous in vitro passages the p210 tyrosine kinase became dispensable for growth. Increased levels of cyclin B(1) and enhanced activity of its associated cyclin-dependent kinase (cdc2) became apparent during the clonal evolution of p210 bcr-abl-transduced 32D cell clones lacking p53. INTERPRETATION AND CONCLUSIONS: The acceleration of clonal evolution of p210 bcr-abl-transduced 32D myeloid progenitors associated with p53 functional abrogation is consistent with oncosuppressor loss having a key role in CML progression. This would allow emergence of additional genomic aberrations which would lead to the fully transformed phenotype of blast crisis. Deregulated activity of the cyclin B1-cdc2 complex may be involved in the loss of temporal co-ordination of mitotic events and further free the barrier to genomic instability of CML clonal myeloid progenitors lacking p53.

Aneuploidy↗

PubMed1996

Little evidence for clonal evolution of malignant haematopoietic cells following relapse after autologous bone marrow transplantation.

By screening for immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements in bone marrow samples aspirated at different time points during the course of disease from 43 patients with acute leukaemia we have analysed the extent of clonal evolution after autologous bone marrow transplantation (ABMT) and addressed the issue of whether the Southern Blot method has the power to reveal clonal proliferations representing minimal residual disease (MRD) in the autologous bone marrow grafts. Our results show that no clonal proliferations were detectable in any of the 43 bone marrow grafts analysed, even after we analysed DNA preparations in 5 cases from cells highly enriched for cells of the original malignant immunophenotype. Moreover, as judged by the Ig- and TCR gene configurations in 11 patients, relapse arose from the original clone even though minor clonal variations did occur in about half of the relapsing patients. We conclude that while the Southern Blot method can detect gene receptor rearrangements in the majority of patients with acute leukaemias and high-grade non-Hodgkins lymphomas, it is not useful for predicting relapse after ABMT. On the other hand, it is possible-by employing it-to evaluate whether or not relapse after ABMT arises from the original malignant clone and to what extent clonal evolution has taken place.

Acute Disease↗

PubMed2005

Genotype stability and clonal evolution of hepatocellular carcinoma assessed by autopsy-based genome-wide microsatellite analysis.

It is widely accepted that chromosomal instability is an essential feature of cancer cells including hepatocellular carcinoma (HCC) cells. For an accurate characterization of clonal evolution of HCC cells, we studied chromosomal alterations in various metastatic lesions in an autopsy case of HCC. Tissues from the main tumor, which consisted of 2 macroscopically distinct portions, and from intrahepatic metastasis, portal vein thrombus, epiploic lymph node metastasis, and pulmonary metastasis as well as from the non-tumorous liver were analyzed with comprehensive microsatellite analysis. Alleles showing imbalance of the main tumor were further subjected to comparative duplex PCR, with use of a retained allele as an internal control, to determine whether the imbalance was the result of chromosomal gain or loss. A striking finding was that allelic imbalances detected in the main tumor and metastatic lesions were almost identical, showing -1p, +1q, -4q, -7, -8p, +8q, +9q, +10, -13q, -17p, +19p, -19q, and -X. Additional alterations of +2q and -16q were detected in one portion of the main tumor and the portal vein thrombus. In conclusion, clonal evolution of the HCC cells during metastatic progression seems rare, in contrast to many recurrent chromosomal aberrations that may have accumulated before the clinical manifestation.

Allelic Imbalance↗

PubMed2005

Clonal evolution with inv(11)(p15q22) and NUP98/DDX10 fusion gene in imatinib-resistant chronic myelogenous leukemia.

The BCR/ABL tyrosine kinase inhibitor imatinib has shown remarkable efficacy in treating patients with chronic myelogenous leukemia (CML). In a small portion of patients treated with imatinib, however, the disease may progress to advanced stages, frequently accompanied by cytogenetic clonal evolution with the appearance of additional chromosomal aberrations besides the Philadelphia chromosome. Here we report the appearance of an inv(11)(p15q22) as a clonal evolution in a CML patient undergoing treatment with imatinib. Leukemic cells from the patient were found to express the fusion transcript of NUP98 and DDX10, which is in accordance with previously reported cases of de novo or therapy-related acute myelogenous leukemia and myelodysplastic syndrome with inv(11)(p15q22). Although the patient showed resistance to imatinib with the disease rapidly progressing to blast crisis, sequence analysis failed to reveal any mutation in the kinase domain of BCR/ABL that would explain the imatinib resistance. Furthermore, ex vivo treatment of leukemic cells with imatinib significantly reduced tyrosine phosphorylation of CrkL, a target of the BCR/ABL kinase. These observations raise a possibility that the NUP98/DDX10 fusion might be involved in imatinib resistance as well as in acute transformation of CML.

Antineoplastic Agents↗

PubMed1999

Clonal evolution of B cells in transformation from low- to high-grade lymphoma.

An outcome of low-grade B cell non-Hodgkins's lymphomas is the transformation to high-grade diffuse large B cell lymphomas (DLBL). To investigate the mechanisms of clonal evolution in the transformation to DLBL, we performed longitudinal molecular analyses of immunoglobulin (Ig), V(H)DJ(H) gene sequences expressed in cases of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and follicular lymphoma (FL) that transformed to DLBL. Among the neoplastic CLL and SLL cells and their respective high-grade transformants, there was no evidence for a clonotypic shift or acquired mutations in the expressed Ig V(H)DJ(H) gene segments, as further confirmed by a specific and sensitive PCR-single strand polymorphism analysis. In contrast, among the FL cells there was a high degree of intraclonal diversification with highly divergent V(H)DJ(H) gene sequences. Despite this intraclonal heterogeneity, the related DLBL expressed a collinear but unique V(H)DJ(H) gene sequence. The intraclonal genealogical tree for the FL case demonstrated that the DLBL emerged in association with unique V(H)DJ(H) gene mutational events. Among the intraclonal FL and related DLBL transformants, the nature and distribution of the Ig V(H)DJ(H) gene mutations were consistent with antigenic selection. Thus, clonal evolution in the transformation from low- to high-grade B cell lymphoma may involve distinct pathways which vary according to the cellular origin and the type of the progenitor B cell tumor.

Amino Acid Sequence↗

PubMed1991

Clonality and clonal evolution of hepatocellular carcinoma with multiple nodules.

To determine the clonal evolution of hepatocellular carcinoma, the integrated hepatitis B virus DNA patterns of the main tumor, satellites and/or metastatic lesions were analyzed by Southern-blot hybridization in 28 hepatocellular carcinomas, including three HBsAg-seronegative cases. Unicentric or multicentric hepatocellular carcinoma was confirmed by histopathological criteria in 89% of the cases. Among 17 unicentric hepatocellular carcinomas, minor changes of the integration pattern--including partial loss or addition of the integration sites or both--were detected in the metastatic lesions in 29% of the cases. Furthermore, none of five cases with free-form hepatitis B virus DNA in the primary tumor had detectable free hepatitis B virus DNA in the metastatic lesions. These results suggest that the alteration of integrated hepatitis B virus DNA pattern during the course of tumor growth and metastasis may occur more often than previously perceived and that the switch-off of virus replication may be related to tumor metastatic potential. In eight cases with unilateral, multicentric hepatocellular carcinoma, two clones were detected in six cases, three were seen in another and four were seen in one. One case of note was a 9-yr-old boy with two histological types and two different integration patterns, one associated with vascular invasion and lung metastasis. Three patients with bilateral hepatocellular carcinoma were confirmed to have bicentric or tricentric hepatocellular carcinoma rather than intrahepatic dissemination and had survival rates similar to those in unicentric hepatocellular carcinoma. Three invasive HBsAg-seronegative hepatocellular carcinomas were found to have hepatitis B virus DNA integration and were of unicentric origin.(ABSTRACT TRUNCATED AT 250 WORDS)

Blotting, Southern↗

PubMed1993

Clonal evolutions during long-term cultures of bone marrow from de novo acute myeloid leukaemia with trilineage myelodysplasia and with myelodysplastic remission marrow.

We previously established a long-term bone marrow culture (LTBMC) system in which novel abnormal karyotypes could emerge in vitro prior to the appearance of the same karyotypes in vivo in patients with myelodysplastic syndrome (MDS). We extended our study to examine whether acute myeloid leukaemia (AML) transformed from MDS (MDS/AML) and de novo AML with trilineage myelodysplasia (AML/TMDS) show clonal evolution in LTBMC similar to that of typical AML or MDS. We also analysed the cytogenetic changes in cultures with bone marrows from AML with myelodysplastic remission marrow (AML/MRM) as well as chronic myeloid leukaemia (CML) to compare them with typical AML with respect to the liability of clonal evolution. Among the 34 AML cases, abnormal karyotypes were newly detected in four of seven MDS/AML, three of six AML/TMDS and three of three AML/MRM. Novel abnormal karyotypes were also observed in nine out of 13 CML cases after culture. In contrast, no other abnormal karyotypes were found after culture in 18 typical AML without myelodysplasia. These findings suggest that AML/TMDS and AML/MRM are different from typical AML and are similar to MDS/AML and CML in view of their potential for disease progression from latent multiple clones. Typical AML may develop from a single abnormal clone without any subclones.

Anemia, Aplastic↗

PubMed2002

Microsatellite analysis of primary and recurrent glial tumors suggests different modalities of clonal evolution of tumor cells.

Gliomas are characterized by highly variable biological behavior. After surgical resection and postoperative therapy they frequently recur with the same or higher-grade histology. Although a number of genetic aberrations have been described in gliomas of different histological types, the molecular mechanisms of the histological and clinical progression are poorly understood. In this study, we performed longitudinal microsatellite and mismatch repair gene analysis in paired samples of primary and recurrent gliomas in order to reveal whether genetic instability is associated with tumor progression. The 7 microsatellite loci of the 7 patients displayed a total of 18 (54.5%) alterations in the primary and 15 (45.5%) alterations in the recurrent gliomas as compared with the corresponding non-neoplastic cells, but no alterations were found in the hMLH1 and hMSH2 genes. These results suggest that microsatellite instability is associated with the development of the primary gliomas rather than with the recurrence or progression, and it is not associated with structural alterations in the hMLH1 or hMSH2 genes. Comparison of the microsatellite patterns in primary and secondary gliomas revealed 4 different modalities of clonal evolution, involving clonal identity, clonal deletion, clonal progression, and different clonality, suggesting that intensive clonal selection may play a central part in the recurrence of gliomas.

Adult↗

PubMed1982

Clonal evolution demonstrated by flow cytometric DNA analysis of a human colonic carcinoma grown in nude mice.

A spontaneous change in DNA content of a human colonic carcinoma grown in nude mice was observed fortuitously. The tumor initially had a G1 cell DNA content of 1.3 times that of normal cells. Flow cytometric DNA analysis showed in transplant generation 56 the appearance of a new subpopulation which in three passages completely overgrew the original population. The DNA content of the new subpopulation was twice that of the original population. The observation supports the hypothesis of clonal evolution of tumor cell populations. The growth rates of the tumor before and after the change showed no significant difference (p greater than 0.05). Cell kinetic factors, therefore, offer no obvious explanation of how the overgrowth took place. It is not known whether the original population disappeared completely or survived as a small population below the detection limit. The heterogeneity created by clonal evolution of a tumor would be less pronounced if old subpopulations often become extinct as new ones emerge. Heterogeneity of human tumors is of clinical importance because the individual subpopulations may have different sensitivity patterns to antineoplastic drugs.

Animals↗

PubMed2002

Retroviral-mediated expression of recombinant Fancc enhances the repopulating ability of Fancc-/- hematopoietic stem cells and decreases the risk of clonal evolution.

Fanconi anemia (FA) is a chromosomal instability disorder characterized by a progressive bone marrow (BM) failure and an increased incidence of myeloid leukemias. Children with FA are currently being enrolled in clinical trials to evaluate the safety of retroviral-mediated gene transfer. Previously, we used Fancc(-/-) mice to show that Fancc(-/-) hematopoietic stem cells (HSCs) have a profound defect in repopulating ability. Here, we examined whether retroviral-mediated gene transfer of recombinant Fancc (rFancc) would restore the repopulating ability of Fancc(-/-) HSC to wild-type levels. Fancc(-/-) HSCs transduced with a retrovirus encoding rFancc exhibited a repopulating ability that approached wild-type levels. Interestingly, approximately 30% of primary recipients (7 of 22) transplanted with uncorrected Fancc(-/-) cells developed a range of hematopoietic abnormalities including pancytopenia and BM hypoplasia similar to individuals with FA. Hematopoietic abnormalities were detected in only 1 of 22 mice transplanted with Fancc(-/-) cells transduced with a retrovirus encoding rFancc. Moreover, several mice with hematopoietic defects had progenitors that displayed a marked resistance to IFN-gamma, TNF-alpha, and MIP-1alpha compared to both Fancc(-/-) progenitors, which are uniquely hypersensitive to these cytokines, and wild-type progenitors. These data are analogous to studies using progenitors from patients with myelodysplasia and provide functional support for clonal evolution in these mice. Collectively, these data show that gene transfer can enhance HSC repopulating ability and suppresses the tendency for clonal evolution. These studies also reveal potential detrimental effects of ex vivo manipulation for untransduced Fancc(-/-) HSCs.

Animals↗

PubMedDate not supplied

Identical cytogenetic clones and clonal evolution in pediatric monozygotic twins with acute myeloid leukemia: presymptomatic disease detection by interphase fluorescence in situ hybridization and review of the literature.

PURPOSE: Observation of identical acquired genetic changes in infant monozygotic (MZG) twins with acute leukemia has provided strong evidence for in utero twin-twin transfusion as the cause of concordance. Documentation of similar phenomenon in older MZG twins offers insight into the latency period for leukemia and may provide the opportunity for presymptomatic disease detection in one twin. DESIGN: The literature describing leukemia in MZG twins is reviewed and the results of classical and molecular cytogenetic studies of one pair of MZG twins at 3 and 4 years with acute nonlymphocytic leukemia-FAB type M1 are reported. RESULTS: The twins studied had cytogenetically identical neoplastic clones with identical clonal evolution. Retrospective fluorescence in situ hybridization studies demonstrated the presence of the abnormal clone in the asymptomatic twin at the time of bone marrow transplant of the first twin. CONCLUSIONS: These observations support in utero twin-twin transfer as the origin of leukemic clones in pediatric and infant leukemia, demonstrate that clonal evolution of a leukemic clone may occur years before onset of overt disease, and indicate that knowledge of acquired genetic change(s) in one twin may provide markers to assess disease in the asymptomatic twin.

Child, Preschool↗

PubMed2003

Prognostic significance of cytogenetic clonal evolution in patients with chronic myelogenous leukemia on imatinib mesylate therapy.

Cytogenetic clonal evolution (CE) is a known poor prognostic factor in Philadelphia chromosome-positive chronic myelogenous leukemia (Ph-positive CML). However, its prognostic relevance in the era of imatinib therapy is unknown. We investigated the independent prognostic relevance of CE in 498 patients with Ph-positive CML treated with imatinib for chronic or accelerated phases. One hundred twenty-one patients had CE alone (n = 70) or with other accelerated phase criteria (n = 51). Patients were compared in 4 categories: chronic phase (n = 295), CE only (n = 70), accelerated phase without CE (n = 82), and accelerated phase with CE (n = 51). Statistical methods used established methodologies for univariate and multivariate analyses. In chronic and accelerated phases of CML, CE was not associated with significant differences in major or complete cytogenetic response rates, but it was an independent poor prognostic factor for survival by multivariate analyses in both chronic (P =.005) and accelerated phase (P =.03). Multivariate analyses conducted at the 3-month landmark (including the 3-month cytogenetic response) identified the lack of cytogenetic response at 3 months to be a stronger independent poor prognostic factor for survival than CE for both chronic (major cytogenetic response versus other) and accelerated phase (any cytogenetic response versus other). We conclude that cytogenetic CE is not an important factor for achieving major or complete cytogenetic response with imatinib mesylate therapy, but it is an independent poor prognostic factor for survival in both chronic and accelerated phases of CML. The 3-month cytogenetic response to imatinib mesylate refined the prognostic relevance of such studies in patients on imatinib mesylate therapy.

Age Factors↗

PubMed1999

Allelic imbalance in the clonal evolution of prostate carcinoma.

BACKGROUND: To understand better the genetic basis of the clonal evolution of prostate carcinoma, the authors analyzed the pattern of allelic loss in 25 matched primary and metastatic prostate tumors. METHODS: Twenty-five cases were selected from the surgical pathology files of the Mayo Clinic from patients who had undergone radical retropubic prostatectomy and bilateral lymphadenectomy between 1987-1991. All patients had regional lymph node metastases at the time of surgery. DNA samples for the analysis of allelic loss pattern were prepared from primary tumors and matched synchronous lymph node metastases by tissue microdissection. The oligonucleotide primer pairs for the microsatellite DNA markers were D8S133, D8S136, D8S137, ANK1 on chromosome 8p12-21, LPLTET on chromosome 8p22, and D17S855 (intragenic to the BRCA1 gene) on chromosome 17q21. One case was not informative at any of the loci tested and was excluded from further analysis. RESULTS: The overall frequency of allelic imbalance was 79% in primary tumors and 88% in paired metastases. Of 24 informative cases, 14 patients (58%) showed the same pattern of allelic loss or retention in matched primary and metastatic tumors at all marker locus; discordant allelic loss was observed in the remaining 10 patients (42%). Four patients showed loss of the same allele at one or more marker loci in both primary and metastatic tumors, but discordant allelic loss was observed at other marker loci. Five patients showed allelic loss in at least one genetic marker in the metastatic tumor but not in its matched primary tumor. Five patients displayed loss of one allele at one or more marker loci in a primary tumor but not in the matched metastases. There was no significant difference in the frequency of allelic imbalance between primary and metastatic tumors at any marker analyzed (P>0.05). CONCLUSIONS: These data suggest that different patterns of allelic deletion may be acquired during cancer progression to metastases. The differences in genetic composition between primary prostate carcinoma and its metastases may be related to intrinsic cancer heterogeneity, overall genetic instability, and clonal divergence.

Aged↗

PubMed2000

The clonal origin and clonal evolution of epithelial tumours.

While the origin of tumours, whether from one cell or many, has been a source of fascination for experimental oncologists for some time, in recent years there has been a veritable explosion of information about the clonal architecture of tumours and their antecedents, stimulated, in the main, by the ready accessibility of new molecular techniques. While most of these new results have apparently confirmed the monoclonal origin of human epithelial (and other) tumours, there are a significant number of studies in which this conclusion just cannot be made. Moreover, analysis of many articles show that the potential impact of such considerations as patch size and clonal evolution on determinations of clonality have largely been ignored, with the result that a number of these studies are confounded. However, the clonal architecture of preneoplastic lesions provide some interesting insights --many lesions which might have been hitherto regarded as hyperplasias are apparently clonal in derivation. If this is indeed true, it calls into some question our hopeful corollary that a monoclonal origin presages a neoplastic habitus. Finally, it is clear, for many reasons, that methods of analysis which involve the disaggregation of tissues, albeit microdissected, are far from ideal and we should be putting more effort into techniques where the clonal architecture of normal tissues, preneoplastic and preinvasive lesions and their derivative tumours can be directly visualized in situ.

Cell Transformation, Neoplastic↗