Are oncogenes sufficient to cause human cancer?

Woodman, Scott E.; Mills, Gordon B.

doi:10.1073/pnas.1015563107

Cited by 7 publications

(5 citation statements)

References 17 publications

(21 reference statements)

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“…It has been speculated that lack of malignant potential in seborrheic keratoses might be due to the absence of alterations in tumor suppressor genes [6, 7]. In this study we did detect deletions within CDKN2A in three lesions.…”

Section: Discussionsupporting

confidence: 40%

“…Unlike many malignant tumors, seborrheic keratoses appear to be genetically stable but harbor multiple somatic alterations [ 6 ]. Despite lack of malignant potential, 89 percent of the lesions carry at least one and 45 percent more than one mutation in a well characterized oncogene [ 6 , 7 ]. Frequent alterations affect FGFR3 and PIK3CA , with mutations frequencies of 40-85% and 40%, respectively [ 3 , 6 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

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Genetic alterations in seborrheic keratoses

et al. 2017

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Seborrheic keratoses are common benign epidermal lesions that are associated with increased age and sun-exposure. Those lesions despite harboring multiple somatic alterations in contrast to malignant tumors appear to be genetically stable. In order to investigate and characterize the presence of recurrent mutations, we performed exome sequencing on DNA from one seborrheic keratosis lesion and corresponding blood cells from the same patients with follow up investigation of alterations identified by exome sequencing in 24 additional lesions from as many patients. In addition we investigated alterations in all lesions at specific genes loci that included FGFR3, PIK3CA, HRAS, BRAF, CDKN2A and TERT and DHPH3 promoters. The exome sequencing data indicated three mutations per Mb of the targeted sequence. The mutational pattern depicted typical UV signature with majority of alterations being C>T and CC>TT base changes at dipyrimidinic sites. The FGFR3 mutations were the most frequent, detected in 12 of 25 (48%) lesions, followed by the PIK3CA (32%), TERT promoter (24%) and DPH3 promoter mutations (24%). TERT promoter mutations associated with increased age and were present mainly in the lesions excised from head and neck. Three lesions also carried alterations in CDKN2A. FGFR3, TERT and DPH3 expression did not correlate with mutations in the respective genes and promoters; however, increased FGFR3 transcript levels were associated with increased FOXN1 levels, a suggested positive feedback loop that stalls malignant progression. Thus, in this study we report overall mutation rate through exome sequencing and show the most frequent mutations seborrheic keratosis.

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Section: Discussionsupporting

confidence: 40%

Section: Introductionmentioning

confidence: 99%

Genetic alterations in seborrheic keratoses

et al. 2017

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“…However, the demonstration of a mechanistic, truly causative link between oncogenes and cancer is still lacking, and the supposed correlation is suggestive of association and not causation. As clearly stated by Woodman and Mills [24] "the spectrum of events that must occur in a single cell, including which oncogene activation and tumor suppressor gene inactivation events can cooperate to induce malignant transformation, has remained elusive".…”

Section: Mutationsmentioning

confidence: 99%

Paradoxical Behavior of Oncogenes Undermines the Somatic Mutation Theory

et al. 2022

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The currently accepted theory on the influence of DNA mutations on carcinogenesis (the Somatic Mutation Theory, SMT) is facing an increasing number of controversial results that undermine the explanatory power of mutated genes considered as “causative” factors. Intriguing results have demonstrated that several critical genes may act differently, as oncogenes or tumor suppressors, while phenotypic reversion of cancerous cells/tissues can be achieved by modifying the microenvironment, the mutations they are carrying notwithstanding. Furthermore, a high burden of mutations has been identified in many non-cancerous tissues without any apparent pathological consequence. All things considered, a relevant body of unexplained inconsistencies calls for an in depth rewiring of our theoretical models. Ignoring these paradoxes is no longer sustainable. By avoiding these conundrums, the scientific community will deprive itself of the opportunity to achieve real progress in this important biomedical field. To remedy this situation, we need to embrace new theoretical perspectives, taking the cell–microenvironment interplay as the privileged pathogenetic level of observation, and by assuming new explanatory models based on truly different premises. New theoretical frameworks dawned in the last two decades principally focus on the complex interaction between cells and their microenvironment, which is thought to be the critical level from which carcinogenesis arises. Indeed, both molecular and biophysical components of the stroma can dramatically drive cell fate commitment and cell outcome in opposite directions, even in the presence of the same stimulus. Therefore, such a novel approach can help in solving apparently inextricable paradoxes that are increasingly observed in cancer biology.

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“…Is a neuron that merely relays commands to downstream circuits causal to the resulting behavior or not? More differentiated statements require additional classifications, like the distinction between necessary and sufficient which has been thoroughly explored in epidemiology, oncology, and genetics [134–136].…”

Section: Introductionmentioning

confidence: 99%

The promise and perils of causal circuit manipulations

Wolff

Ölveczky

2018

Current Opinion in Neurobiology

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The development of increasingly sophisticated methods for recording and manipulating neural activity is revolutionizing neuroscience. By probing how activity patterns in different types of neurons and circuits contribute to behavior, these tools can help inform mechanistic models of brain function and explain the roles of distinct circuit elements. However, in systems where functions are distributed over large networks, interpreting causality experiments can be challenging. Here we review common assumptions underlying circuit manipulations in behaving animals and discuss the strengths and limitations of different approaches.

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Are oncogenes sufficient to cause human cancer?

Cited by 7 publications

References 17 publications

Genetic alterations in seborrheic keratoses

Genetic alterations in seborrheic keratoses

Paradoxical Behavior of Oncogenes Undermines the Somatic Mutation Theory

The promise and perils of causal circuit manipulations

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