Dataset Information

Lack of Correlation between Stem-Cell Proliferation and Radiation- or Smoking-Associated Cancer Risk.

ABSTRACT:

Background

A recent paper by Tomasetti and Vogelstein (Science 2015 347 78-81) suggested that the variation in natural cancer risk was largely explained by the total number of stem-cell divisions, and that most cancers arose by chance. They proposed an extra-risk score as way of distinguishing the effects of the stochastic, replicative component of cancer risk from other causative factors, specifically those due to the external environment and inherited mutations.

Objectives

We tested the hypothesis raised by Tomasetti and Vogelstein by assessing the degree of correlation of stem cell divisions and their extra-risk score with radiation- and tobacco-associated cancer risk.

Methods

We fitted a variety of linear and log-linear models to data on stem cell divisions per year and cumulative stem cell divisions over lifetime and natural cancer risk, some taken from the paper of Tomasetti and Vogelstein, augmented using current US lifetime cancer risk data, and also radiation- and tobacco-associated cancer risk.

Results

The data assembled by Tomasetti and Vogelstein, as augmented here, are inconsistent with the power-of-age relationship commonly observed for cancer incidence and the predictions of a multistage carcinogenesis model, if one makes the strong assumption of homogeneity of numbers of driver mutations across cancer sites. Analysis of the extra-risk score and various other measures (number of stem cell divisions per year, cumulative number of stem cell divisions over life) considered by Tomasetti and Vogelstein suggests that these are poorly predictive of currently available estimates of radiation- or smoking-associated cancer risk-for only one out of 37 measures or logarithmic transformations thereof is there a statistically significant correlation (p<0.05) with radiation- or smoking-associated risk.

Conclusions

The data used by Tomasetti and Vogelstein are in conflict with predictions of a multistage model of carcinogenesis, under the assumption of homogeneity of numbers of driver mutations across most cancer sites. Their hypothesis that if the extra-risk score for a tissue type is high then one would expect that environmental factors would play a relatively more important role in that cancer's risk is in conflict with the lack of correlation between the extra-risk score and other stem-cell proliferation indices and radiation- or smoking-related cancer risk.

SUBMITTER: Little MP

PROVIDER: S-EPMC4816383 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Publications

Lack of Correlation between Stem-Cell Proliferation and Radiation- or Smoking-Associated Cancer Risk.

Little Mark P MP Hendry Jolyon H JH Puskin Jerome S JS

PloS one 20160331 3

<h4>Background</h4>A recent paper by Tomasetti and Vogelstein (Science 2015 347 78-81) suggested that the variation in natural cancer risk was largely explained by the total number of stem-cell divisions, and that most cancers arose by chance. They proposed an extra-risk score as way of distinguishing the effects of the stochastic, replicative component of cancer risk from other causative factors, specifically those due to the external environment and inherited mutations.<h4>Objectives</h4>We te ...[more]

PMID: 27031507

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Project description:There is compelling biological data to suggest that cancer arises from a series of mutations in single target cells, resulting in defects in cell renewal and differentiation processes which lead to malignancy. Because much mutagenic damage is expressed following cell division, more-rapidly renewing tissues could be at higher risk because of the larger number of cell replications. Cairns suggested that renewing tissues may reduce cancer risk by partitioning the dividing cell populations into lineages comprising infrequently-dividing long-lived stem cells and frequently-dividing short-lived daughter transit cells. We develop generalizations of three recent cancer-induction models that account for the joint maintenance and renewal of stem and transit cells, also competing processes of partially transformed cell proliferation and differentiation/apoptosis. We are particularly interested in using these models to separately assess the probabilities of mutation and development of cancer associated with "spontaneous" processes and with those linked to a specific environmental mutagen, specifically ionizing radiation or cigarette smoking. All three models demonstrate substantial variation in cancer risks, by at least 20 orders of magnitude, depending on the assumed number of critical mutations required for cancer, and the stem-cell and transition-cell mutation rates. However, in most cases the conditional probabilities of cancer being mutagen-induced range between 7-96%. The relative risks associated with mutagen exposure compared to background rates are also stable, ranging from 1.0-16.0. Very few cancers, generally <0.5%, arise from mutations occurring solely in stem cells rather than in a combination of stem and transit cells. However, for cancers with 2 or 3 critical mutations, a substantial proportion of cancers, in some cases 100%, have at least one mutation derived from a mutated stem cell. Little difference is made to relative risks if competing processes of proliferation and differentiation in the partially transformed stem and transit cell population are allowed for, nor is any difference made if one assumes that transit cells require an extra mutation to confer malignancy from the number required by stem cells. The probability of a cancer being mutagen-induced correlates across cancer sites with the estimated cumulative number of stem cell divisions in the associated tissue (p<0.05), although in some cases there is sensitivity of findings to removal of high-leverage outliers and in some cases only modest variation in probability, but these issues do not affect the validity of the findings. There are no significant correlations (p>0.3) between lifetime cancer-site specific radiation risk and the probability of that cancer being mutagen-induced. These results do not depend on the assumed critical number of mutations leading to cancer, or on the assumed mutagen-associated mutation rate, within the generally-accepted ranges tested. However, there are borderline significant negative correlations (p = 0.08) between the smoking-associated mortality rate difference (current vs former smokers) and the probability of cancer being mutagen-induced. This is only the case where values of the critical number of mutations leading to cancer, k, is 3 or 4 and not for smaller values (1 or 2), but does not strongly depend on the assumed mutagen-associated mutation rate.

Project description:For correct application and interpretation of cerebral autoregulation (CA) measurements in research and in clinical care, it is essential to understand differences and similarities between dynamic and steady-state CA. The present study found no correlation between dynamic and steady-state CA indices in healthy older adults. There was variability between individuals in all (steady-state and dynamic) autoregulatory indices, ranging from low (almost absent) to highly efficient CA in this healthy population. These findings challenge the assumption that assessment of a single CA parameter or a single set of parameters can be generalized to overall CA functioning. Therefore, depending on specific research purposes, the choice for either steady-state or dynamic measures or both should be weighed carefully.The present study aimed to investigate the relationship between dynamic (dCA) and steady-state cerebral autoregulation (sCA). In 28 healthy older adults, sCA was quantified by a linear regression slope of proportionate (%) changes in cerebrovascular resistance (CVR) in response to proportionate (%) changes in mean blood pressure (BP) induced by stepwise sodium nitroprusside (SNP) and phenylephrine (PhE) infusion. Cerebral blood flow (CBF) was measured at the internal carotid artery (ICA) and vertebral artery (VA) and CBF velocity at the middle cerebral artery (MCA). With CVR = BP/CBF, Slope-CVRICA , Slope-CVRVA and Slope-CVRiMCA were derived. dCA was assessed (i) in supine rest, analysed with transfer function analysis (gain and phase) and autoregulatory index (ARI) fit from spontaneous oscillations (ARIBaseline ), and (ii) with transient changes in BP using a bolus injection of SNP (ARISNP ) and PhE (ARIPhE ). Comparison of sCA and dCA parameters (using Pearson's r for continuous and Spearman's ρ for ordinal parameters) demonstrated a lack of linear correlations between sCA and dCA measures. However, comparisons of parameters within dCA and within sCA were correlated. For sCA slope-CVRVA with Slope-CVRiMCA (r = 0.45, P < 0.03); for dCA ARISNP with ARIPhE (ρ = 0.50, P = 0.03), ARIBaseline (ρ = 0.57, P = 0.03) and PhaseLF (ρ = 0.48, P = 0.03); and for GainVLF with GainLF (r = 0.51, P = 0.01). By contrast to the commonly held assumption based on an earlier study, there were no linear correlations between sCA and dCA. As an additional observation, there was strong inter-individual variability, both in dCA and sCA, in this healthy group of elderly, in a range from low to high CA efficiency.

Dataset Information

Lack of Correlation between Stem-Cell Proliferation and Radiation- or Smoking-Associated Cancer Risk.

Background

Objectives

Methods

Results

Conclusions

Publications

Lack of Correlation between Stem-Cell Proliferation and Radiation- or Smoking-Associated Cancer Risk.

Similar Datasets

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