Negative Clonal Selection in Tumor Evolution

Beckman, Robert A.; Loeb, Lawrence A.

doi:10.1534/genetics.105.040840

Cited by 43 publications

(53 citation statements)

References 31 publications

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“…3D), similar to experimentally measured rates in cancer of 10 −8 (7). Above μ opt , population meltdown is very common, whereas below μ opt , progression is too slow.…”

Section: Significancesupporting

confidence: 81%

“…Cancer progression is an example of a rapidly adapting population: cancers develop as many as 10 new traits (6), exhibit a high mutation rate (6)(7)(8), and rapidly change in population size (9). Progression is driven by a handful of mutations (10) and chromosomal abnormalities (11) in cancer-related genes (oncogenes and tumor suppressors), collectively called "drivers."…”

mentioning

confidence: 99%

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Tug-of-war between driver and passenger mutations in cancer and other adaptive processes

McFarland

Mirny

Korolev

2014

Proc. Natl. Acad. Sci. U.S.A.

151

187

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Cancer progression is an example of a rapid adaptive process where evolving new traits is essential for survival and requires a high mutation rate. Precancerous cells acquire a few key mutations that drive rapid population growth and carcinogenesis. Cancer genomics demonstrates that these few driver mutations occur alongside thousands of random passenger mutations-a natural consequence of cancer's elevated mutation rate. Some passengers are deleterious to cancer cells, yet have been largely ignored in cancer research. In population genetics, however, the accumulation of mildly deleterious mutations has been shown to cause population meltdown. Here we develop a stochastic population model where beneficial drivers engage in a tug-of-war with frequent mildly deleterious passengers. These passengers present a barrier to cancer progression describable by a critical population size, below which most lesions fail to progress, and a critical mutation rate, above which cancers melt down. We find support for this model in cancer age-incidence and cancer genomics data that also allow us to estimate the fitness advantage of drivers and fitness costs of passengers. We identify two regimes of adaptive evolutionary dynamics and use these regimes to understand successes and failures of different treatment strategies. A tumor's load of deleterious passengers can explain previously paradoxical treatment outcomes and suggest that it could potentially serve as a biomarker of response to mutagenic therapies. The collective deleterious effect of passengers is currently an unexploited therapeutic target. We discuss how their effects might be exacerbated by current and future therapies.

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“…3D), similar to experimentally measured rates in cancer of 10 −8 (7). Above μ opt , population meltdown is very common, whereas below μ opt , progression is too slow.…”

Section: Significancesupporting

confidence: 81%

mentioning

confidence: 99%

Tug-of-war between driver and passenger mutations in cancer and other adaptive processes

McFarland

Mirny

Korolev

2014

Proc. Natl. Acad. Sci. U.S.A.

151

187

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“…However, mathematical models do not indicate that negative clonal selection would mitigate against a mutator phenotype (29,30). Moreover, we find clear evidence for ongoing elevation of mutagenesis in at least some clinically detected tumors.…”

Section: Discussionmentioning

confidence: 62%

Human cancers express a mutator phenotype

Bielas

Loeb²,

Rubin

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

338

271

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Cancer cells contain numerous clonal mutations, i.e., mutations that are present in most or all malignant cells of a tumor and have presumably been selected because they confer a proliferative advantage. An important question is whether cancer cells also contain a large number of random mutations, i.e., randomly distributed unselected mutations that occur in only one or a few cells of a tumor. Such random mutations could contribute to the morphologic and functional heterogeneity of cancers and include mutations that confer resistance to therapy. We have postulated that malignant cells exhibit a mutator phenotype resulting in the generation of random mutations throughout the genome. We have recently developed an assay to quantify random mutations in human tissue with unprecedented sensitivity. Here, we report measurements of random single-nucleotide substitutions in normal and neoplastic human tissues. In normal tissues, the frequency of spontaneous random mutations is exceedingly low, less than 1 × 10 −8 per base pair. In contrast, tumors from the same individuals exhibited an average frequency of 210 × 10 −8 per base pair, an elevation of at least two orders of magnitude. Our data document tumor heterogeneity at the single-nucleotide level, indicate that accelerated mutagenesis prevails late into tumor progression, and suggest that elevation of random mutation frequency in tumors might serve as a novel prognostic indicator.

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“…Our study clearly shows that TSCs have a distinctive mitochondrialnuclear signature within a tumor, and gives a rare glimpse of changing mutational patterns accompanying varying stem cell dynamics and turnover within the organ during tumor evolution. It has been realized that the classically defined 'two hits' (first germ line and second somatic) produce only a benign precursor lesion and that additional events are necessary for transformation (Knudson, 1996;Beckman and Loeb, 2005). Based on our findings, the likely cascade of events could be (i) Alterations in the mitochondrial genome: at present, it is not clear whether this altered pattern gives a selective advantage, or only leads to increased reactive oxygen species production.…”

Section: Discussionmentioning

confidence: 80%