Decoy fitness peaks, tumor suppression, and aging

Higa, Kelly; DeGregori, James

doi:10.1111/acel.12938

Cited by 19 publications

(19 citation statements)

References 27 publications

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“…Inactivation of NOTCH1 has been postulated to drive the evolutionary dead-end of nascent precancerous population of cells (Higa and DeGregori). This is based on the observation that the frequency of NOTCH1 mutations decreases in esophageal and skin cancers, relative to physiologically normal epithelial tissues (Higa and DeGregori, 2019;Martincorena et al, 2018;Yokoyama et al, 2019). Consistent with this, in our previously reported Onc3 screen, we noted that the frequency of Notch1 inactivation was decreased in cuSCC versus keratoacanthoma tissues, suggesting that Notch1 loss is not essential for cuSCC development (Aiderus et al).…”

Section: Discussionsupporting

confidence: 81%

Promoterless Transposon Mutagenesis Drives Solid Cancers via Tumor Suppressor Inactivation

Aiderus

Contreras-Sandoval

Meshey

et al. 2020

Preprint

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A central challenge in cancer genomics is the systematic identification of single and cooperating tumor suppressor genes driving cellular transformation and tumor progression in the absence of oncogenic driver mutation(s). Multiple in vitro and in vivo gene inactivation screens have enhanced our understanding of the tumor suppressor gene landscape in various cancers. However, these studies are limited to single or combination gene effects, specific organs, or require sensitizing mutations. In this study, we developed and utilized a Sleeping Beauty transposon mutagenesis system that functions only as a gene trap to exclusively inactivate tumor suppressor genes. Using whole body transposon mobilization in wild type mice, we observed that cumulative gene inactivation can drive tumorigenesis of solid cancers. We provide a quantitative landscape of the tumor suppressor genes inactivated in these cancers, and show that despite the absence of oncogenic drivers, these genes converge on key biological pathways and processes associated with cancer hallmarks.

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Section: Discussionsupporting

confidence: 81%

Promoterless Transposon Mutagenesis Drives Solid Cancers via Tumor Suppressor Inactivation

Aiderus

Contreras-Sandoval

Meshey

et al. 2020

Preprint

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“…One interpretation of these data is that competition with other mutant clones restrains Trp53-mutant cell proliferation. It may be possible, therefore, that the accumulation of somatic mutations with age has a role in preventing the clonal expansion of cells with increased fitness through tumoursuppressive competition (Higa and DeGregori, 2019).…”

Section: Anti-tumourigenic Rolesmentioning

confidence: 99%

Cell competition: the winners and losers of fitness selection

2019

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The process of cell competition results in the elimination of cells that are viable but 'less fit' than surrounding cells. Given the highly heterogeneous nature of our tissues, it seems increasingly likely that cells are engaged in a 'survival of the fittest' battle throughout life. The process has a myriad of positive roles in the organism: it selects against mutant cells in developing tissues, prevents the propagation of oncogenic cells and eliminates damaged cells during ageing. However, 'super-fit' cancer cells can exploit cell competition mechanisms to expand and spread. Here, we review the regulation, roles and risks of cell competition in organism development, ageing and disease.

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“…Another important finding was though mutations connected to benign clonal expansion may appear frequently in cancer cell genomes, these particular mutations may not necessarily contribute to carcinogenesis because these tissues already have a naturally high mutation frequency. Furthermore, an analysis by Higa and DeGregori demonstrated that even classic “oncogenic drivers” like NOTCH1 might not often contribute to carcinogenesis [ 18 ].…”

Section: Clonal Development Circulating Tumor Dna and Cancer Detectmentioning

confidence: 99%

Mutations in normal tissues—some diagnostic and clinical implications

Fiala

Diamandis

2020

BMC Med

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Background It has long been known that mutations are at the core of many diseases, most notably cancer. Mutational analysis of tissues and fluids is useful for cancer and other disease diagnosis and management. Main body The prevailing cancer development hypothesis posits that cancer originates from mutations in cancer-driving genes that accumulate in tissues over time. These mutations then confer special characteristics to cancer cells, known as the hallmarks of cancer. Mutations in specific driver genes can lead to the formation of cancerous subclones and mutation risk increases with age. New research has revealed an unexpectedly large number of mutations in normal tissues; these findings could have significant implications to the understanding of the pathobiology of cancer and for disease diagnosis and therapy. Here, we discuss how the prevalence of mutations in normal tissues provides novel and relevant insights about clonal development in cancer and other diseases. Specifically, this review will focus on discussing mutations in normal tissues in the context of developing specific, circulating tumor DNA (ctDNA) tests for cancer, and evaluating clonal hematopoiesis as a predictor of blood cancers and cardiovascular pathology, as well as their implications to the phenomena of neural mosaicism in the context of Alzheimer’s disease. Conclusions In view of these new findings, the fundamental differences between the accumulation of genetic alterations in healthy, aging tissues compared to cancer and cardiovascular or neural diseases will need to be better delineated in the future.

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Decoy fitness peaks, tumor suppression, and aging

Cited by 19 publications

References 27 publications

Promoterless Transposon Mutagenesis Drives Solid Cancers via Tumor Suppressor Inactivation

Promoterless Transposon Mutagenesis Drives Solid Cancers via Tumor Suppressor Inactivation

Cell competition: the winners and losers of fitness selection

Mutations in normal tissues—some diagnostic and clinical implications

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