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PubMed1996

Trypanosoma brucei s.l: evolution, linkage and the clonality debate.

The Index of Association (IA) has been proposed by Maynard Smith et al. (1993) as a general method for characterizing the population structures of microorganisms as either: clonal, epidemic, cryptic species or panmictic. With reference to the current debate surrounding the mode of reproduction in parasitic protozoa, this study explores (i) the suitability and limitations of the IA for characterizing populations of Trypanosoma brucei s.l., and (ii) the idea that the significance of genetic differences between populations may be better understood if the evolution, spread and temporal stability of certain parasite genotypes are also considered. Four populations of T. brucei from Côte d'Ivoire, Uganda and Zambia are analysed using the IA and a complementary test for linkage disequilibrium, test f of Tibayrenc, Kjellberg & Ayala (1990). The two populations from Uganda are characterized as epidemic, while the others appear more or less clonal; the merits of the two methods are compared. The implications of the various population classifications are discussed with reference to genotype longevity in each region; the evolution and biomedical consequences of the genetic non-homogeneity of T. brucei are reviewed.

Africa↗
PubMed2005

Negative clonal selection in tumor evolution.

Development of cancer requires the acquisition of multiple oncogenic mutations and selection of the malignant clone. Cancer evolves within a finite host lifetime and mechanisms of carcinogenesis that accelerate this process may be more likely to contribute to the development of clinical cancers. Mutator mutations are mutations that affect genome stability and accelerate the acquisition of oncogenic mutations. However, mutator mutations will also accelerate the accumulation of mutations that decrease cell proliferation, increase apoptosis, or affect other key fitness parameters. These "reduced-fitness" mutations may mediate "negative clonal selection," i.e., selective elimination of premalignant mutator clones. Target reduced-fitness loci may be "recessive" (both copies must be mutated to reduce fitness) or "dominant" (single-copy mutation reduces fitness). A direct mathematical analysis is applied to negative clonal selection, leading to the conclusion that negative clonal selection against mutator clones is unlikely to be a significant effect under realistic conditions. In addition, the relative importance of dominant and recessive reduced-fitness mutations is quantitatively defined. The relative predominance of mutator mutations in clinical cancers will depend on several variables, including the tolerance of the genome for reduced-fitness mutations, particularly the number and potency of dominant reduced-fitness loci.

Cell Lineage↗
PubMed2006

Evolution of resistance during clonal expansion.

Acquired drug resistance is a major limitation for cancer therapy. Often, one genetic alteration suffices to confer resistance to an otherwise successful therapy. However, little is known about the dynamics of the emergence of resistant tumor cells. In this article, we consider an exponentially growing population starting from one cancer cell that is sensitive to therapy. Sensitive cancer cells can mutate into resistant ones, which have relative fitness alpha prior to therapy. In the special case of no cell death, our model converges to the one investigated by Luria and Delbrück. We calculate the probability of resistance and the mean number of resistant cells once the cancer has reached detection size M. The probability of resistance is an increasing function of the detection size M times the mutation rate u. If Mu << 1, then the expected number of resistant cells in cancers with resistance is independent of the mutation rate u and increases with M in proportion to M(1-1/alpha) for advantageous mutants with relative fitness alpha>1, to l nM for neutral mutants (alpha = 1), but converges to an upper limit for deleterious mutants (alpha<1). Further, the probability of resistance and the average number of resistant cells increase with the number of cell divisions in the history of the tumor. Hence a tumor subject to high rates of apoptosis will show a higher incidence of resistance than expected on its detection size only.

Antineoplastic Agents↗
PubMed2000

Two cases showing clonal progression with full evolution from aplastic anemia-paroxysmal nocturnal hemoglobinuria syndrome to myelodysplastic syndromes and leukemia.

We report 2 paroxysmal nocturnal hemoglobinuria (PNH) patients who were initially diagnosed with aplastic anemia and sequentially developed PNH, myelodysplastic syndromes (MDS), and leukemia. Flow cytometry and cytogenetic analysis showed the initial appearance and expansion of PNH clones, gradual replacement of PNH clones by MDS clones with monosomy 7, and then expansion of MDS clones or their subclones with additional chromosomal abnormalities. In relation to these developments, expression increased of the Wilms' tumor gene WT1, a marker for leukemic progression. These patients not only shared bone marrow failure but also might have harbored a hematopoietic environment favorable for the emergence of abnormal clones leading to leukemogenesis.

Adult↗
PubMed1992

Clonal development and karyotype evolution during leukemogenesis of BCR/ABL transgenic mice.

The Philadelphia (Ph) translocation is responsible for the generation of the chimeric BCR/ABL oncogene. The Ph chromosome constitutes the earliest detectable chromosome abnormality in chronic myelogenous leukemia and is also found in acute lymphoblastic leukemia. Mice transgenic for a P190 BCR/ABL-producing DNA construct develop lymphoblastic leukemia/lymphoma and provide an opportunity to study early stages of the disease as well as progression. In this study, we have karyotyped the bone marrow of 10 19-day-old BCR/ABL P190 transgenic mice from a line that reproducibly develops leukemia/lymphoma. Leukemic cells from 17 terminally ill transgenic founders and progeny were also karyotyped as well as bone marrow transplant recipients of leukemic donor marrow. Karyotypically visible aberrations were absent from the early stages of BCR/ABL P190-generated leukemia and normal metaphases could be found even in the terminal stages of the disease. A high frequency of aneuploidy was found in advanced leukemia, with a marked preference for the gain of mouse chromosomes 12, 14, or 17. These results point to a primary role for BCR/ABL in leukemogenesis and suggest a destabilizing effect of the BCR/ABL gene on the regulation of cell division.

Aneuploidy↗
PubMed2026

Paired Whole-Genome Sequencing of Scalp Angiosarcoma and Matched Lung Metastasis Reveals Common Clonal Origin and Lung-Specific Evolution.

Background and Clinical Significance: Cutaneous angiosarcoma frequently metastasizes to the lungs, where it may rarely present as diffuse cystic lung disease with recurrent pneumothorax, resulting in substantial diagnostic difficulty. We report a case of pulmonary metastatic cutaneous angiosarcoma in which paired whole-genome sequencing (WGS) of the primary and metastatic lesions was performed to clarify clonal origin and characterize metastatic evolution. Case Presentation: A 65-year-old man with recurrent right-sided pneumothorax and progressive bilateral cystic lung lesions underwent skin and lung biopsies. Histopathological examination and immunohistochemistry established the diagnosis of cutaneous angiosarcoma with pulmonary metastases. Paired WGS was performed on matched scalp and lung tumor specimens to evaluate shared and lesion-specific genomic alterations, pathway enrichment, and copy-number changes. Histopathology confirmed metastatic angiosarcoma involving the lungs. WGS identified 128 shared somatic alterations, supporting a common clonal origin, together with lung-specific and skin-specific mutations indicative of continued genomic divergence. Recurrent alterations involving POT1 and FLT4 were preserved in both lesions, whereas additional POT1 and TP53 alterations were detected only in the pulmonary metastasis. Pathway analysis demonstrated preferential enrichment of IGF1-mTOR, RAS, and WNT/LRP6 signaling in the metastatic lesion, while Gene Ontology analysis suggested functional divergence associated with metastatic progression. Conclusions: Pulmonary metastatic angiosarcoma should be considered in patients presenting with unexplained diffuse cystic lung disease and recurrent pneumothorax, particularly when pathological findings are inconclusive. Paired WGS complemented conventional histopathology by confirming the metastatic origin and providing insights into clonal evolution and lesion-specific molecular alterations, highlighting its potential value in the investigation of rare metastatic malignancies.

angiosarcoma↗
PubMed2026

Genomic characterization of aggressiveness in pituitary neuroendocrine tumors.

BACKGROUND: Aggressive evolution of PitNETs is rare; metastatic spread is even more. Defining aggressiveness and malignancy is challenging, subsequently hard to predict, and to understand. The aim was to provide a molecular definition of aggressiveness using genomic approaches. METHODS: PitNETs from 206 patients were included. Associations between 9 clinicopathological features of aggressiveness and PitNETs' omics were explored. Omics included transcriptome, DNA methylation, chromosomal alterations, and mutations. Clonal tumor evolution was monitored in 7 patients. RESULTS: Among the 9 clinicopathological features of aggressiveness, only rapid progression, progression after radiotherapy, Ki67/MIB1 proliferation index &#x2265;10%, temozolomide treatment, metastases, and specific death were associated with specific omics signatures, while tumour maximal diameter &#x2265;40 mm, cavernous, and sphenoid invasion were not. The omic signatures associated with these features of aggressiveness overlapped but remained distinct between corticotroph and mammo-somato-thyrotroph lineages. For each lineage, a common signature of aggressiveness was identified, associating a proliferative transcriptome signature and DNA hypermethylation. Alterations in specific genes were associated with aggressive features, including a novel PitNET gene, LRP1B, and known cancer genes (TP53, CDKN2A), while USP8 and GNAS alterations were not. Integration of gene alterations with methylome and transcriptome signatures isolated a subset of molecularly aggressive PitNETs. Molecular signatures were stable during the course of the disease, despite evolution toward aggressiveness and potential clonal divergence. CONCLUSION: This systematic analysis of clinicopathological features of aggressiveness using an integrated multiomic approach establishes a histomolecular definition of aggressiveness in PitNETs. Prospective cohort studies are needed to validate these molecular signatures and establish their prognostic value.

Humans↗
PubMed2004

Experimental life-history evolution: selection on growth form and its plasticity in a clonal plant.

The growth form along the continuum from compact phalanx plants to more loosely packed guerilla plants is an important life-history trait in clonal plants. Prerequisite for its evolution is heritable genetic variation. Starting with 102 genotypes of the stoloniferous herb Ranunculus reptans, we performed one selection experiment on spatial spread per rosette as measure of guerillaness (broad-sense heritability 0.198) and another on plasticity in this trait in response to competition (broad-sense heritability 0.067). After two generations, spatial spread was 36.9% higher in the high line than in the low line (realized heritability +/- SE 0.149 +/- 0.039). Moreover, compared with the low line genotypes of the high line had fewer rosettes, a lower proportion of flowering rosettes, a higher proportion of rooted rosettes, more branches per rosette, longer internodes and longer leaves. In the second experiment, we found no significant direct response to selection for high and low plasticity in spatial spread (realized heritability +/- SE -0.029 +/- 0.063), despite a significant correlated response in plasticity in the length of the first three stolon internodes. Our study indicates a high potential for further evolution of the clonal growth form in R. reptans, but not for its plasticity, and it demonstrates that the clonal growth form does not evolve independently of other clonal life-history characteristics.

Analysis of Variance↗
PubMed1994

Childhood acute lymphoblastic leukaemia and aplastic anaemia.

Aplastic anaemia (AA) can be associated with disorders that are known to exhibit clonal haematopoiesis, like paroxysmal nocturnal haemoglobinuria (PNH), myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). It appears that the long term survivors of severe AA treated with immunosuppressive agents such as ATG have a continuing, late mortality caused by the evolution of clonal disorders which are not usually seen when bone marrow transplant is used. In children, typical AA may precede the onset of acute lymphoblastic leukemia (ALL). The aplastic phase is often transient and remission may be spontaneous or rapidly induced by steroid, and followed a few months later by acute leukaemia. This modality of presentation may be observed in up to 2-3% of all cases of paediatric ALL. A 13-year old girl who presented with two spontaneously reversible episodes of marrow aplasia has been reported recently. She developed ALL 8 months later. Southern analysis showed identical clonal immunoglobulin heavy chain gene rearrangement bands in her leukaemic cells as well as the marrow cells obtained at the two aplastic episodes. Hypoxanthine phosphoribosyltransferase polymorphism studies showed that all the ALL blast cells, bone marrow and peripheral cells during the two aplastic episodes all exhibited clonal haematopoiesis with the same X-chromosome inactivated. This case provides strong evidence that AA and ALL can represent evolution of the same abnormal clone.

Adolescent↗
PubMed2007

Correlated evolution of self-incompatibility and clonal reproduction in Solanum (Solanaceae).

It has been suggested that clonality provides reproductive assurance in cross-fertilizing species subject to pollen limitation, relieving one of the main selective pressures favoring the evolution of self-fertilization. According to this hypothesis, cross-fertilizing species subject to pollen limitation should often be clonal. Here, we investigated the association between clonality and a genetic mechanism enforcing outcrossing, self-incompatibility, in Solanum (Solanaceae). We collected self-incompatibility and clonality information on 87 species, and looked for an association between these two traits. To account for the contribution of shared evolutionary history to this association, we incorporated phylogenetic information from chloroplast (NADH dehydrogenase subunit F) sequence data. We found that self-incompatibility is strongly associated with clonal reproduction: all self-incompatible species reproduce clonally, while the absence of clonality is widespread among self-compatible taxa. The observed correlation persists after taking into account shared phylogenetic history, assumptions about the evolutionary history of self-incompatibility, uncertainty associated with phylogeny estimation, and associations with life history (annual/perennial). Our results are consistent with the hypothesis that clonality provides reproductive assurance, and suggest that the consequences of clonal growth in the evolution of plant reproductive strategies may be more significant than previously thought.

Biological Evolution↗
PubMed2002

Reconstruction of microsatellite mutation history reveals a strong and consistent deletion bias in invasive clonal snails, Potamopyrgus antipodarum.

Direct observations of mutations and comparative analyses suggest that nuclear microsatellites show a tendency to expand, with reports of deletion biases limited to very long alleles or a few loci in multilocus studies. Here we investigate microsatellite evolution in clonal snails, Potamopyrgus antipodarum, since their introduction to Britain in the 19th century, using an analysis based on minimum spanning networks of multilocus microsatellite genotypes. British populations consist of a small number of highly distinct genotype groups with very few outlying genotypes, suggesting clonal lineages containing minor variation generated by mutation. Network patterns suggest that a single introduced genotype was the ancestor of all extant variation and also provide support for wholly apomictic reproduction within the most common clonal lineage (group A). Microsatellites within group A showed a strong tendency to delete repeats, with an overall bias exceeding 88%, irrespective of the exact method used to infer mutations. This highly unusual pattern of deletion bias is consistent across populations and loci and is unrelated to allele size. We suggest that for persistence of microsatellites in this clone, some change in the mutation mechanism must have occurred in relatively recent evolutionary time. Possible causes of such a change in mechanism are discussed.

Animals↗
PubMed1990

Clonal karyotype abnormalities and clinical progress in the myelodysplastic syndrome.

Clonal karyotype abnormalities in 124 patients with myelodysplastic syndrome are reviewed. 36% of patients had abnormalities at referral, the most common being 5q-, +8 and lesions of chromosomes 7 and 20. Reduced survival was associated with the presence of either single or multiple clonal abnormalities at referral, abnormalities of chromosome 7 or 8 (either alone or with other lesions) and exclusively abnormal metaphases. The presence of 5q- alone did not appear to affect survival. Sequential studies were carried out in 77 patients of whom 12 showed karyotypic evolution. Reduced survival was observed in patients with an evolving karyotype but appeared to be due almost entirely to evolution in those patients whose initial karyotype was normal. Leukaemic transformation occurred more commonly in patients with an abnormal karyotype, particularly those with multiple abnormalities, and in patients with an evolving karyotype. Although the first appearance of an abnormal karyotype or an apparent evolution are important phenomena, it is probable that in some cases they merely represent expansion of a previously existing clone that has escaped detection. The distinction between true karyotypic evolution or clonal expansion and statistical variations due to small sample size and variability of samples may be difficult but needs to be taken into account in considering clinical significance.

Adult↗
PubMed1988

DNA content and genetic evolution of human colorectal adenocarcinoma. A study by flow cytometry and cytogenetic analysis.

We have conducted in parallel DNA flow cytometry (FCM) and cytogenetic (CG) analysis of a series of surgical specimens from 35 human colorectal adenocarcinomas. An excellent quantitative correlation was observed (r = 0.99) between modal peak values of FCM histograms and chromosome counts. This observation confirms that aneuploidy, as defined by FCM, accurately reflects the deviation from diploidy of the genomic DNA. FCM-derived DNA patterns have been analyzed in the context of the clonal chromosomal evolution determined by CG analysis. In the metaphases of a given tumor, even if karyotypes of different ploidy exist, the presence of identical marker chromosomes suggests a common origin for the multiple populations observed by FCM. Thus, heterogeneity in DNA content within a tumor, including the polyploidization step, would be indicative of genetic evolution.

Adenocarcinoma↗
PubMed2006

Horizontal transfer of a virulence operon to the ancestor of Mycobacterium tuberculosis.

The contribution of interspecies horizontal gene transfer (HGT) to the evolution and virulence of Mycobacterium tuberculosis, the agent of tuberculosis in humans, has been barely investigated. Here we have studied the evolutionary history of the M. tuberculosis Rv0986-8 virulence operon recently identified, through functional genomics approaches, as playing an important role in parasitism of host phagocytic cells. We showed that among actinobacteria, this operon is specific to the M. tuberculosis complex and to ancestral Mycobacterium prototuberculosis species. These data, together with phylogenetic reconstruction and other in silico analyses, provided strong evidence that this operon has been acquired horizontally by the ancestor of M. tuberculosis, before the recent evolutionary bottleneck that preceded the clonal-like evolution of the M. tuberculosis complex. Genomic signature profiling further suggested that the transfer was plasmid mediated and that the operon originated from a gamma-proteobacterium donor species. Our study points out for the first time the contribution of HGT to the emergence of M. tuberculosis and close relatives as major pathogens. In addition, our data underline the importance of deciphering gene transfer networks in M. tuberculosis in order to better understand the evolutionary mechanisms involved in mycobacterial virulence.

Agrobacterium tumefaciens↗
PubMed2026

Translational case series comparing next-generation sequencing profiles of primary breast cancer and brain metastases.

BACKGROUND: Breast cancer (BC) is a heterogeneous disease, and its molecular and immunohistochemical (IHC) profiles may change over time, particularly under therapeutic pressure. IHC discordance between primary tumors and BC brain metastases (BCBM) has been reported, yet its biological and clinical significance remains incompletely defined. Genomic profiling using next-generation sequencing (NGS) may provide additional insight into tumor evolution and clonal selection, although data from paired BC and BCBM are limited. METHODS: This translational case series included six patients randomly selected from an institutional cohort of BC patients who underwent neurosurgical resection of BCBM. IHC reassessment (ER, PR, and HER2) and NGS profiling using targeted panels were performed. RESULTS: Three of the six cases presented with IHC discordance, mainly loss of HR expression and gain of HER2 in BCBM. Genomic profiling identified 23 mutations in primary tumors compared with four in BCBM. BRCA1/2 variants predominated in primary tumors (21/23, 91%), most predicted to result in loss-of-function alterations. One mutation (PIK3CA/N345K) was shared between primary and metastatic tissues within the same patient. Overall survival ranged from 28 to 146 months. CONCLUSION: This paired analysis demonstrates immunophenotypic and genomic divergence between BC and BCBM, supporting the concept of dynamic tumor evolution. Receptor conversion and emergence or loss of actionable genomic alterations highlight the potential value of repeat molecular assessment in advanced stages. Although limited by a small sample size, retrospective design, and absence of matched germline testing, these findings reinforce the importance of integrating biomarker reevaluation into the management of selected patients.

Humans↗
PubMed2005

Evolution of B-cell clonal expansions with age.

B-cell clonal expansions (BCE) in young mice are transient, detectable for less than 4 weeks. In contrast, BCE in old mice persist more than 2 months. The greater persistence of BCE in old mice does not appear to be due to the age of the host as the survival of phenyloxazolone chicken serum albumin-induced BCE in most old mice was shorter than in young mice. This raises the possibility that persistent BCE seen in old mice develop over time from transient BCE present earlier in life. To test this hypothesis, young C57BL/6 mice were immunized with hen egg lysozyme (HEL) during the first year of life. By 28 months of age, the majority of these mice had developed a benign, persistent BCE associated with a HEL-specific serum mIg. We also investigated whether benign, persistent BCE, present in 18-month-old mice, can evolve into B-cell lymphomas. We observed that four of eight C57BL/6 mice that survived to 29 months of age had developed diffuse large cell lymphomas. In three of these mice, this diagnosis was made by microscopic analysis of the lymphoid organs. In one mouse, a macroscopic lymphoma was present that permitted us to demonstrate that the IgH mRNA CDR3 length and sequence in the malignant lymphoma was derived from a persistent BCE present 11 months earlier. Together these observations are consistent with the hypothesis that stepwise accumulation of genetic alterations combined with Darwinian selection underlies the evolution of B cells from transient BCE in young mice into persistent BCE, serum mIg, and B-cell lymphomas observed in older mice.

Aging↗
PubMed1998

Independent origin of multiple foci of prostatic intraepithelial neoplasia: comparison with matched foci of prostate carcinoma.

BACKGROUND: Prostate carcinoma usually is heterogeneous and multifocal, with diverse clinical and morphologic manifestations. Understanding of the molecular basis for this heterogeneity is limited, particularly for the putative precursor, high grade prostatic intraepithelial neoplasia (PIN). In this study, the authors attempted to determine the genetic relation between multiple foci of PIN and matched foci of carcinoma, and whether they are independent in origin. METHODS: The distribution and prevalence of allelic imbalance at 6 microsatellite polymorphic markers on chromosomes 7q, 8p, 8q, and 18q were examined in 84 microscopically excised PIN foci (mean, 1.6 foci/case) and 95 foci of prostate carcinoma (mean, 1.8 foci/case) from 52 completely embedded, mapped whole mount prostates. RESULTS: PIN contained a lower overall proportion of allelic imbalance than matched prostate carcinoma foci for the 6 polymorphic microsatellite markers (65% vs. 82%), but this difference was not significant. The rate of allelic imbalance in PIN was similar to that in prostate carcinoma at 5 of 6 loci studied; the exception, D18S34 (18q12.2-12.3), had a significantly lower rate of allelic imbalance in PIN than in prostate carcinoma (19% vs. 52%), suggesting that genetic alterations in this chromosomal region may be important in carcinogenesis. Of 22 cases with allelic imbalance in at least 1 focus of PIN and 1 focus of prostate carcinoma, 21 informative cases (95%) showed a similar pattern of allelic imbalance at > or = 1 markers in the matched PIN and prostate carcinoma foci. Significant genetic heterogeneity was observed in both PIN and prostate carcinoma. Allelic imbalance was observed in at least 1 focus in 11 of 25 cases with multiple foci of PIN (44%) and 20 of 25 cases with multiple foci of prostate carcinoma (80%). There was no significant correlation between allelic imbalance and pathologic stage or tumor grade. CONCLUSIONS: Our findings indicate that multiple foci of PIN arise independently within the same prostate. This observation suggests that a field effect underlies prostatic neoplasia. Multiple foci of prostate carcinoma also often arise independently, lending additional support for this hypothesis. The strong genetic similarities between PIN and prostate carcinoma strongly suggest that evolution and clonal expansion of PIN may account for the multifocal etiology of carcinomas.

Aged↗