Aneuploid Tumor Genomes Undergo Punctuated and Gradual Diversification

2021 ◽  
Keyword(s):  
Aneuploid Tumor

scholarly journals Reconstructing single-cell karyotype alterations in colorectal cancer identifies punctuated and gradual diversification patterns

2021 ◽  
Author(s):  
Yannik Bollen ◽  
Ellen Stelloo ◽  
Petra van Leenen ◽  
Myrna van den Bos ◽  
Bas Ponsioen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Single Cell ◽  
Temporal Dynamics ◽  
De Novo ◽  
Tumor Evolution ◽  
Genome Wide ◽  
Aneuploid Tumor ◽  
Evolutionary Paths ◽  
Tumor Biopsies ◽  
Punctuated Evolution

AbstractCentral to tumor evolution is the generation of genetic diversity. However, the extent and patterns by which de novo karyotype alterations emerge and propagate within human tumors are not well understood, especially at single-cell resolution. Here, we present 3D Live-Seq—a protocol that integrates live-cell imaging of tumor organoid outgrowth and whole-genome sequencing of each imaged cell to reconstruct evolving tumor cell karyotypes across consecutive cell generations. Using patient-derived colorectal cancer organoids and fresh tumor biopsies, we demonstrate that karyotype alterations of varying complexity are prevalent and can arise within a few cell generations. Sub-chromosomal acentric fragments were prone to replication and collective missegregation across consecutive cell divisions. In contrast, gross genome-wide karyotype alterations were generated in a single erroneous cell division, providing support that aneuploid tumor genomes can evolve via punctuated evolution. Mapping the temporal dynamics and patterns of karyotype diversification in cancer enables reconstructions of evolutionary paths to malignant fitness.

DNA content in human colon cancer and non-neoplastic adjacent mucosa

1995 ◽  
Vol 10 (1) ◽  
pp. 11-16 ◽  
Author(s):  
G. Saccani Jotti ◽  
M. Fontanesi ◽  
N. Orsi ◽  
L. Sarli ◽  
N. Pietra ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Dna Content ◽  
Human Colon ◽  
Human Colon Cancer ◽  
Fresh Tissue ◽  
Tissue Samples ◽  
Adjacent Mucosa ◽  
Aneuploid Tumor ◽  
The Relationship

DNA content was determined by flow cytometry in a series of 51 paired fresh tissue samples of primary colorectal carcinomas and the respective non-neoplastic adjacent mucosa in order to assess the relationship between DNA ploidy and the most commonly used prognostic factors. Aneuploidy was observed in 70.6% of the tumors and more than one aneuploid peak was present in 3.9%. Aneuploid tumor frequency was higher in left (93.3%) and right colon (64.7%) cancers than in rectal carcinomas (60.0%), and multiple aneuploid clones were detected more frequently in men than in women and in patients with advanced disease (Dukes stage D). Non-neoplastic mucosa adjacent to aneuploid tumors showed aneuploidy in 4 out of 51 samples (7.8%). The mucosa adjacent to diploid cancers had only diploid characteristics. Polidy did not correlate with histological abnormalities. These findings suggest that DNA content as determined by flow cytometry needs further study with adequate follow-up to evaluate possible correlations with relapse-free and overall survival. Furthermore the aneuploidy of non-neoplastic mucosa provides evidence for a field defect in mucosa adjacent to colorectal cancer and supports the concept that this alteration may be of influence on carcinogenesis.

scholarly journals Phenotypic heterogeneity in aneuploid multiple myeloma indicates pre-B cell involvement

Blood ◽  
1988 ◽  
Vol 71 (4) ◽  
pp. 861-865
Author(s):  
J Epstein ◽  
B Barlogie ◽  
J Katzmann ◽  
R Alexanian
Keyword(s):  
Multiple Myeloma ◽  
B Cell ◽  
Tumor Cells ◽  
Plasma Cell ◽  
Lymphoblastic Leukemia ◽  
Cell Markers ◽  
Aneuploid Tumor ◽  
Beta 2 Microglobulin ◽  
Normal Differentiation ◽  
Mature Plasma Cell

The expression of early and mature B cell markers, surface beta 2- microglobulin (B2M) and cytoplasmic immunoglobulin (clg) by aneuploid tumor cells in bone marrow aspirates from 44 patients with multiple myeloma was evaluated by correlated DNA immunofluorescence flow cytometry. Myeloma tumor cells of almost 90% of the patients contained monoclonal clg and expressed the mature plasma cell antigen R1–3 as well as surface B2M; common acute lymphoblastic leukemia antigen (CALLA) was present in 55%, B2 in 17%, and B4 in 23% of samples studied. Coexpression of CALLA and clg in 46% of all patients identified a novel myeloma phenotype without known counterpart in the normal differentiation of B cells. CALLA and clg were independently expressed and gave rise to CALLA+/clg-, CALLA+/clg+, and CALLA-/clg+ cells. The association of CALLA and mature plasma cell markers may define discrete stages of neoplastic plasma cell differentiation.

Correlated flow cytometric analysis of H-ras p21 and nuclear DNA in multiple myeloma

Blood ◽  
1988 ◽  
Vol 72 (2) ◽  
pp. 796-800 ◽  
Author(s):  
H Tsuchiya ◽  
J Epstein ◽  
P Selvanayagam ◽  
JR Dedman ◽  
G Gallick ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Nuclear Dna ◽  
Plasma Cells ◽  
Bone Marrow Cells ◽  
Flow Cytometric Analysis ◽  
Nuclear Dna Content ◽  
Normal Donor ◽  
Aneuploid Tumor ◽  
Ras P21 ◽  
Diploid Cells

Abstract Correlated analysis of the H-ras oncogenes product (p21) and of nuclear DNA content was performed by flow cytometry (FCM) in patients with DNA- aneuploid multiple myeloma (MM). Bone marrow cells from normal donors and MM patients in remission served as controls. Seventy-four percent of 23 patients with active MM had higher p21 fluorescence in aneuploid tumor cells than were observed in normal donor or myeloma remission bone marrows; 39% of the 23 patients also showed high H-ras p21 expression in diploid cells. There was an inverse relationship between p21 levels and the presence of trisomy 11; especially high p21 levels were noted in patient without trisomy 11. The frequent elevation of p21 protein in aneuploid plasma cells suggests the involvement of the H-ras oncogene in the pathophysiology of MM, which is further supported by a shorter survival among patients with high p21 levels.

scholarly journals P-glycoprotein expression in plasma-cell myeloma is associated with resistance to VAD

Blood ◽  
1989 ◽  
Vol 74 (3) ◽  
pp. 913-917 ◽  
Author(s):  
J Epstein ◽  
HQ Xiao ◽  
BK Oba
Keyword(s):  
Nuclear Dna ◽  
De Novo ◽  
Disease Process ◽  
Nuclear Dna Content ◽  
Clinical Implications ◽  
Systematic Analysis ◽  
Resistant Disease ◽  
P Glycoprotein ◽  
Aneuploid Tumor ◽  
Diploid Cells

Abstract Tumor cell-associated expression of multidrug resistance (MDR) was quantitated in 22 patients with DNA-aneuploid myeloma using 2-parameter flow cytometry with monoclonal antibody (MoAb) C-219 for the detection of cytoplasmic p-170 and propidium iodide for nuclear DNA content. The proportion of cells expressing p-170 and the intensity of p-170-related fluorescence were determined for each patient. Among the 14 patients treated with vincristine-adriamycin-dexamethasone (VAD), the proportion of p-170-positive cells distinguished sensitive from resistant disease (P less than .01). Among a subgroup of seven patients with MDR analysis available prior to VAD therapy, two subsequent nonresponders had high proportions of C-219-reactive cells. The presence de novo of high proportions of p-170-expressing cells in another still untreated patient and in a further individual with resistance to dexamethasone and interferon (not associated with MDR) warrants systematic analysis of p-170 expression prior to therapy to determine its clinical implications for response to MDR-associated drugs as combined in the VAD regimen. Concurrent MDR expression by aneuploid tumor cells and cells in the diploid subcompartment may represent involvement of diploid cells in the myeloma disease process.

scholarly journals Flow cytometric analysis of DNA content of bone marrow cells in patients with plasma cell myeloma: clinical implications

Blood ◽  
1982 ◽  
Vol 59 (3) ◽  
pp. 528-535 ◽  
Author(s):  
PA Jr Bunn ◽  
S Krasnow ◽  
RW Makuch ◽  
ML Schlam ◽  
GP Schechter
Keyword(s):  
Tumor Cells ◽  
Plasma Cell ◽  
Dna Content ◽  
Plasma Cells ◽  
Plasma Cell Myeloma ◽  
Waldenström’S Macroglobulinemia ◽  
Aneuploid Tumor ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenström's Macroglobulinemia ◽  
Tumor Dna

Abstract DNA content analysis by flow cytometry was performed in 32 patients with plasma cell myeloma and 3 patients with Waldenstrom's macroglobulinemia to determine the biologic and potential clinical usefulness of this technique. Hyperdiploid tumor DNA content was found in 23 myeloma patients (72%) during the course of illness, including 16/28 at presentation, but in none of 3 patients with Waldenstrom's macroglobulinemia. There was no significant association of aneuploidy in myeloma patients with age, sex, race, or M-protein class. Myeloma patients with aneuploid tumor cells were more likely to have advanced stage (p = 0.032) than patients with diploid plasma cells, and all patients with renal failure had aneuploid tumors. Pretreatment factors significantly associated with survival included stage (p = 0.01), serum creatinine (p = 0.003), and tumor DNA content (p = 0.005). Multivariate analysis using the Cox life table regression procedure indicated that the significant relation of tumor DNA content with survival remained after adjusting for stage (p less than 0.005). Myeloma patients with diploid tumors at diagnosis frequently had aneuploid plasma cells at the time of relapse, indicating a possible relationship of chromosomal alterations in the tumor to clinical drug resistance. We conclude that aneuploid tumor cells at the time of diagnosis of myeloma are of independent prognostic significance, and the development of aneuploidy is a frequent occurrence at clinical relapse, suggesting the change in DNA content are of biologic and clinical significance.

scholarly journals Evaluation of Tumor Heterogeneity of Prostate Carcinoma by Flow- and Image DNA Cytometry and Histopathological Grading

2000 ◽  
Vol 20 (1) ◽  
pp. 49-62 ◽  
Author(s):  
Naining Wang ◽  
Claudia Wilkin ◽  
Alfred Böcking ◽  
Bernhard Tribukait
Keyword(s):  
Cell Cycle ◽  
Tumor Cells ◽  
Prostate Carcinoma ◽  
Tumor Heterogeneity ◽  
Dna Ploidy ◽  
Biological Significance ◽  
Image Cytometry ◽  
Tumor Grade ◽  
Aneuploid Tumor ◽  
Simultaneous Study

Background. Heterogeneity of prostate carcinoma is one of the reasons for pretreatment underestimation of tumor aggressiveness. We studied tumor heterogeneity and the probability of finding the highest tumor grade and DNA aneuploidy with relation to the number of biopsies. Material and methods. Specimens simulating core biopsies from five randomly selected tumor areas from each of 16 Böcking’s grade II and 23 grade III prostate carcinomas were analyzed for tumor grade and DNA ploidy by flow‐ and fluorescence image cytometry (FCM, FICM). Cell cycle composition was measured by FCM. Results. By determination of ploidy and cell cycle composition, morphologically defined tumors can further be subdivided. Heterogeneity of tumor grade and DNA ploidy (FCM) was 54% and 50%. Coexistence of diploid tumor cells in aneuploid specimens represents another form of tumor heterogeneity. The proportion of diploid tumor cells decreased significantly with tumor grade and with increase in the fraction of proliferating cell of the aneuploid tumor part. The probability of estimating the highest tumor grade or aneuploidy increased from 40% for one biopsy to 95% for 5 biopsies studied. By combining the tumor grade with DNA ploidy, the probability of detecting a highly aggressive tumor increased from 40% to 70% and 90% for one and two biopsies, respectively. Conclusion. Specimens of the size of core biopsies can be used for evaluation of DNA ploidy and cell cycle composition. Underestimation of aggressiveness of prostate carcinoma due to tumor heterogeneity is minimized by simultaneous study of the tumor grade and DNA ploidy more than by increasing the number of biopsies. The biological significance of coexistent diploid tumor cell in aneuploid lesions remains to be evaluated.

scholarly journals Correlated flow cytometric analysis of H-ras p21 and nuclear DNA in multiple myeloma

Blood ◽  
1988 ◽  
Vol 72 (2) ◽  
pp. 796-800 ◽  
Author(s):  
H Tsuchiya ◽  
J Epstein ◽  
P Selvanayagam ◽  
JR Dedman ◽  
G Gallick ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Nuclear Dna ◽  
Plasma Cells ◽  
Bone Marrow Cells ◽  
Flow Cytometric Analysis ◽  
Nuclear Dna Content ◽  
Normal Donor ◽  
Aneuploid Tumor ◽  
Ras P21 ◽  
Diploid Cells

Correlated analysis of the H-ras oncogenes product (p21) and of nuclear DNA content was performed by flow cytometry (FCM) in patients with DNA- aneuploid multiple myeloma (MM). Bone marrow cells from normal donors and MM patients in remission served as controls. Seventy-four percent of 23 patients with active MM had higher p21 fluorescence in aneuploid tumor cells than were observed in normal donor or myeloma remission bone marrows; 39% of the 23 patients also showed high H-ras p21 expression in diploid cells. There was an inverse relationship between p21 levels and the presence of trisomy 11; especially high p21 levels were noted in patient without trisomy 11. The frequent elevation of p21 protein in aneuploid plasma cells suggests the involvement of the H-ras oncogene in the pathophysiology of MM, which is further supported by a shorter survival among patients with high p21 levels.

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