Putative homeostatic role of cancer driver mutations

Venkatachalam, Avanthika; Pikarsky, Eli; Ben‐Neriah, Yinon

doi:10.1016/j.tcb.2021.07.002

Cited by 6 publications

(4 citation statements)

References 59 publications

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“…In this multifactorial context, somatic mutations may favor cell type imbalances in tissue composition due to the prevalence of cell proliferation over differentiation 75 . Intriguingly, a putative beneficial role of somatic variation in sustaining the renewal capacity of exhausted stem cells over time has also been proposed 76 . This multitude of interpretations indicate that the functional role of somatic variation is still mostly unknown and warrants further studies.…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

Somatic variation in normal tissues: friend or foe of cancer early detection?

2022

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Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

Somatic variation in normal tissues: friend or foe of cancer early detection?

2022

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“…This may reveal how and when mutations occur, while considering the relevant epigenetic states and driver genes' expression levels. The explosive research on cancer driver mutations in normal tissue [82] will likely shed more light on tissue-specific cancer mutations. These "normal" mutant tissues are perfect biological systems for applying the technologies that are needed to understand the impact of confounding variables such as chromatin states and mutation rates in comparison to their non-mutant counterparts of the same normal cell type.…”

Section: Discussionmentioning

confidence: 99%

Tissue-Predisposition to Cancer Driver Mutations

Peters,

Venkatachalam,

Ben-Neriah

2024

Cells

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Driver mutations are considered the cornerstone of cancer initiation. They are defined as mutations that convey a competitive fitness advantage, and hence, their mutation frequency in premalignant tissue is expected to exceed the basal mutation rate. In old terms, that translates to “the survival of the fittest” and implies that a selective process underlies the frequency of cancer driver mutations. In that sense, each tissue is its own niche that creates a molecular selective pressure that may favor the propagation of a mutation or not. At the heart of this stands one of the biggest riddles in cancer biology: the tissue-predisposition to cancer driver mutations. The frequency of cancer driver mutations among tissues is non-uniform: for instance, mutations in APC are particularly frequent in colorectal cancer, and 99% of chronic myeloid leukemia patients harbor the driver BCR-ABL1 fusion mutation, which is rarely found in solid tumors. Here, we provide a mechanistic framework that aims to explain how tissue-specific features, ranging from epigenetic underpinnings to the expression of viral transposable elements, establish a molecular basis for selecting cancer driver mutations in a tissue-specific manner.

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“…There are some cancers in which no recurrent mutations could be identified [161,162], and there has not been any proven set of mutations known to transform a normal cell to a cancerous one [163]. More bewilderingly, there are some oncogenic driver mutations appearing in benign diseases at a high frequency, sometimes even much higher than in malignant tumors [164][165][166]. There also are cancer-driver mutations that are found in normal cells or culminate in only clonal proliferation of normal cells, but not cancers [132,133,167,168].…”

Section: Dissenting Evidence 1: Some Biological Phenomena Are Paradox...mentioning

confidence: 99%

“…There also are cancer-driver mutations that are found in normal cells or culminate in only clonal proliferation of normal cells, but not cancers [132,133,167,168]. A conjecture on these observations is that, besides causing neoplastic transformation, these mutations can also improve fitness of relatively old cells and thus extend their life span; therefore, there is no need for the mutations to drive these fitter cells to a neoplastic state [132,165,168]. All of the observations enumerated above do not seem to be consonant with the mutation theory, although there may be other explanations.…”

Section: Dissenting Evidence 1: Some Biological Phenomena Are Paradox...mentioning

confidence: 99%