Estimation of the number of mutations necessary to cause chronic myeloid leukaemia from epidemiological data

Vickers, Mark A.

doi:10.1046/j.1365-2141.1996.d01-1751.x

Cited by 41 publications

(6 citation statements)

References 24 publications

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“…Perhaps most surprisingly, histologically advanced microscopic tumors are detected in many tissues of adult humans (22, 26), but which appear to be mostly held in check by unknown mechanisms. In addition, even though it is thought that the incidence of chronic myeloid leukemia (CML), which increases exponentially late in life, is limited by the occurrence of the initiating Bcr-Abl translocation (27), in frame Bcr-Abl fusions are detected in leukocytes of ~1 in 3 healthy individuals (28, 29), the vast majority of which will fortunately never develop this leukemia (despite persistence of the translocation in leukocytes for long enough to suggest an HSC origin (30)). Notably, CML in chronic phase is thought to be a simple leukemia (a myeloproliferative disorder), with Bcr-Abl as the only recurrent mutation (31).…”

Section: Oncogenic Mutations Are Frequently Detected In Non-diseased mentioning

confidence: 99%

Challenging the axiom: does the occurrence of oncogenic mutations truly limit cancer development with age?

DeGregori

2012

Oncogene

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Section: Oncogenic Mutations Are Frequently Detected In Non-diseased mentioning

confidence: 99%

Challenging the axiom: does the occurrence of oncogenic mutations truly limit cancer development with age?

DeGregori

2012

Oncogene

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“…Current models of cancer operate with the assumption that the extent of fitness effects is a defined property of oncogenic mutations [ 11 - 13 ]. From this perspective, oncogenic mutations are capable of driving somatic evolution upon their occurrence, and their occurrence thus determines the timing of a multi-stage process of selection for pre-malignant clones, eventually leading to cancer.…”

Section: Introductionmentioning

confidence: 99%

“…Importantly, currently accepted models of age-dependent carcinogenesis have not taken into account a number of key age-altered factors that should interact in a complex manner to shape somatic evolution, such as the dynamics of mutation accumulation, changing size of stem cell pools with body growth, alterations in stem cell division rates, and the role of tissue microenvironments [ 12 , 13 , 16 , 33 - 35 ]. Indeed, these previous studies model cancer evolution as a purely cell intrinsic process.…”

Section: Introductionmentioning

confidence: 99%

Stochastic modeling indicates that aging and somatic evolution in the hematopoietic system are driven by non-cell-autonomous processes

Rozhok

Salstrom

DeGregori

2014

Aging

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Age-dependent tissue decline and increased cancer incidence are widely accepted to be rate-limited by the accumulation of somatic mutations over time. Current models of carcinogenesis are dominated by the assumption that oncogenic mutations have defined advantageous fitness effects on recipient stem and progenitor cells, promoting and rate-limiting somatic evolution. However, this assumption is markedly discrepant with evolutionary theory, whereby fitness is a dynamic property of a phenotype imposed upon and widely modulated by environment. We computationally modeled dynamic microenvironment-dependent fitness alterations in hematopoietic stem cells (HSC) within the Sprengel-Liebig system known to govern evolution at the population level. Our model for the first time integrates real data on age-dependent dynamics of HSC division rates, pool size, and accumulation of genetic changes and demonstrates that somatic evolution is not rate-limited by the occurrence of mutations, but instead results from aged microenvironment-driven alterations in the selective/fitness value of previously accumulated genetic changes. Our results are also consistent with evolutionary models of aging and thus oppose both somatic mutation-centric paradigms of carcinogenesis and tissue functional decline. In total, we demonstrate that aging directly promotes HSC fitness decline and somatic evolution via non-cell-autonomous mechanisms.

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“…In addition, leukemias induced by the oncogene Bcr-Abl (Ph + ), including chronic myelogenous leukemia (CML) and Philadelphia Chromosome + B-cell acute lymphoblastic leukemia (Ph + B-ALL), show age-dependent increases in incidence [102]. This age-dependence is more striking for CML, with the majority of diagnosis occurring in individuals over 50 years old [103]. For Ph + B-ALLs, the average age of diagnosis is 50 [104, 105], and the increased incidence with advancing age is less dramatic than for CMLs.…”

Section: Introductionmentioning

confidence: 99%

Aging-Associated Changes in Hematopoiesis and Leukemogenesis: What's the Connection?

Henry

Marusyk²,

DeGregori

2011

Aging

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Aging is associated with a marked increase in a number of diseases, including many types of cancer. Due to the complex and multi-factorial nature of both aging and cancer, accurate deciphering of causative links between aging and cancer remains a major challenge. It is generally accepted that initiation and progression of cancers are driven by a process of clonal evolution. In principle, this somatic evolution should follow the same Darwinian logic as evolutionary processes in populations in nature: diverse heritable types arising as a result of mutations are subjected to selection, resulting in expansion of the fittest clones. However, prevalent paradigms focus primarily on mutational aspects in linking aging and cancer. In this review, we will argue that age-related changes in selective pressures are likely to be equally important. We will focus on aging-related changes in the hematopoietic system, where age-associated alterations are relatively well studied, and discuss the impact of these changes on the development of leukemias and other malignancies.

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Estimation of the number of mutations necessary to cause chronic myeloid leukaemia from epidemiological data

Cited by 41 publications

References 24 publications

Challenging the axiom: does the occurrence of oncogenic mutations truly limit cancer development with age?

Challenging the axiom: does the occurrence of oncogenic mutations truly limit cancer development with age?

Stochastic modeling indicates that aging and somatic evolution in the hematopoietic system are driven by non-cell-autonomous processes

Aging-Associated Changes in Hematopoiesis and Leukemogenesis: What's the Connection?

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