Germline Fitness-Based Scoring of Cancer Mutations

Fischer, Andrej; Greenman, Chris; Mustonen, Ville

doi:10.1534/genetics.111.127480

Cited by 16 publications

(17 citation statements)

References 63 publications

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“…4D; Kaminker et al 2007;Forbes et al 2008). This corresponds with the observation that driver mutations are preponderant at protein functional sites (Dixit et al 2009;Izarzugaza et al 2009;Talavera et al 2010), and that they occur in regions that have significant consequences for germline fitness in addition to the somatic fitness of clonally expanding neoplastic cell populations (Fischer et al 2011). This is different from noncancerous complex diseases, where the genetic basis of each disease is attributable to many causal variants with very small fitness effects.…”

Section: Evolutionary Distributions Of Disease-associated Variantssupporting

confidence: 71%

Human genomic disease variants: A neutral evolutionary explanation

Dudley¹,

Kim²,

Liu³

et al. 2012

Genome Res.

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Many perspectives on the role of evolution in human health include nonempirical assumptions concerning the adaptive evolutionary origins of human diseases. Evolutionary analyses of the increasing wealth of clinical and population genomic data have begun to challenge these presumptions. In order to systematically evaluate such claims, the time has come to build a common framework for an empirical and intellectual unification of evolution and modern medicine. We review the emerging evidence and provide a supporting conceptual framework that establishes the classical neutral theory of molecular evolution (NTME) as the basis for evaluating disease- associated genomic variations in health and medicine. For over a decade, the NTME has already explained the origins and distribution of variants implicated in diseases and has illuminated the power of evolutionary thinking in genomic medicine. We suggest that a majority of disease variants in modern populations will have neutral evolutionary origins (previously neutral), with a relatively smaller fraction exhibiting adaptive evolutionary origins (previously adaptive). This pattern is expected to hold true for common as well as rare disease variants. Ultimately, a neutral evolutionary perspective will provide medicine with an informative and actionable framework that enables objective clinical assessment beyond convenient tendencies to invoke past adaptive events in human history as a root cause of human disease.

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Section: Evolutionary Distributions Of Disease-associated Variantssupporting

confidence: 71%

Human genomic disease variants: A neutral evolutionary explanation

Dudley¹,

Kim²,

Liu³

et al. 2012

Genome Res.

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“…The chosen driver strength [s d ∼0.1 (i.e., 10% growth increase per driver); range 0.01-1] was shown to be congruent with cancer onset (19). Passenger deleteriousness (s p ∼10 −3 ; range 10 −1 -10 −4 ) was estimated from to the effects of near-neutral germ-line mutations in humans (33) and randomly introduced mutations in yeast (14). Simulations where drivers or passengers conferred a distribution of s p and s d did not significantly differ from our fixed-effect model (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 99%

“…deleterious mutations (14,33). Such small selection coefficients for individual passengers are typically undetectable in cell cultures, yet critical for long-term cancer dynamics.…”

Section: Moderately Deleterious Passengers Fixate and Alter Cancer Prmentioning

confidence: 99%

Impact of deleterious passenger mutations on cancer progression

McFarland

Korolev

Kryukov

et al. 2013

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

294

341

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Cancer progression is driven by the accumulation of a small number of genetic alterations. However, these few driver alterations reside in a cancer genome alongside tens of thousands of additional mutations termed passengers. Passengers are widely believed to have no role in cancer, yet many passengers fall within protein-coding genes and other functional elements that can have potentially deleterious effects on cancer cells. Here we investigate the potential of moderately deleterious passengers to accumulate and alter the course of neoplastic progression. Our approach combines evolutionary simulations of cancer progression with an analysis of cancer sequencing data. From simulations, we find that passengers accumulate and largely evade natural selection during progression. Although individually weak, the collective burden of passengers alters the course of progression, leading to several oncological phenomena that are hard to explain with a traditional driver-centric view. We then tested the predictions of our model using cancer genomics data and confirmed that many passengers are likely damaging and have largely evaded negative selection. Finally, we use our model to explore cancer treatments that exploit the load of passengers by either (i) increasing the mutation rate or (ii) exacerbating their deleterious effects. Though both approaches lead to cancer regression, the latter is a more effective therapy. Our results suggest a unique framework for understanding cancer progression as a balance of driver and passenger mutations.

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“…32,33 The scoring reveals that, as a set, the mutations are significantly less deleterious than random in silico–generated missense mutations (P<0.001) (Fig. 3A).…”

Section: Resutsmentioning

confidence: 96%

SomaticSF3B1Mutation in Myelodysplasia with Ring Sideroblasts

Papaemmanuil¹,

Cazzola²,

Boultwood³

et al. 2011

N Engl J Med

1,111

905

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Background Myelodysplastic syndromes are a diverse and common group of chronic hematologic cancers. The identification of new genetic lesions could facilitate new diagnostic and therapeutic strategies. Methods We used massively parallel sequencing technology to identify somatically acquired point mutations across all protein-coding exons in the genome in 9 patients with low-grade myelodysplasia. Targeted resequencing of the gene encoding RNA splicing factor 3B, subunit 1 (SF3B1), was also performed in a cohort of 2087 patients with myeloid or other cancers. Results We identified 64 point mutations in the 9 patients. Recurrent somatically acquired mutations were identified in SF3B1. Follow-up revealed SF3B1 mutations in 72 of 354 patients (20%) with myelodysplastic syndromes, with particularly high frequency among patients whose disease was characterized by ring sideroblasts (53 of 82 [65%]). The gene was also mutated in 1 to 5% of patients with a variety of other tumor types. The observed mutations were less deleterious than was expected on the basis of chance, suggesting that the mutated protein retains structural integrity with altered function. SF3B1 mutations were associated with down-regulation of key gene networks, including core mitochondrial pathways. Clinically, patients with SF3B1 mutations had fewer cytopenias and longer event-free survival than patients without SF3B1 mutations. Conclusions Mutations in SF3B1 implicate abnormalities of messenger RNA splicing in the pathogenesis of myelodysplastic syndromes. (Funded by the Wellcome Trust and others.)

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Germline Fitness-Based Scoring of Cancer Mutations

Cited by 16 publications

References 63 publications

Human genomic disease variants: A neutral evolutionary explanation

Human genomic disease variants: A neutral evolutionary explanation

Impact of deleterious passenger mutations on cancer progression

SomaticSF3B1Mutation in Myelodysplasia with Ring Sideroblasts

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