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I assume that all carcinogens must be mutagens, but I've read that this is not the case. However, I can't find any good examples or an explanation of why it is not the case.

How can a non-mutagenic agent be carcinogenic?

How can something lead to uncontrolled division of abnormal cells without changing the genetic material of the organism?

The only explanation I've found is that normal replication of genetic material during normal cell division includes occasional errors, so any physical or chemical agent that simply speeds up cell division will increase the number of errors per time and can therefore be considered a potential carcinogen even though it is not directly mutagenic.

But that example doesn't satisfy me because such a compound would not increase the number of errors created per cell division, but is that the only way something non-mutagenic can be "carcinogenic"?

I've also read in This Question that Alcohol is an example of a non-mutagenic carcinogen because Alcohol does not damage DNA, but I think that's not accurate because I've also read that Ethanol is mutagenic via its first metabolite, acetaldehyde, or are they just using wordplay to say that Alcohol is not mutagenic because only its first metabolite is?

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    $\begingroup$ It depends a bit on what you consider carcinogenic. If in the strictest sense possible, it's a long list. For example, the NIEHS list contains estrogen, UV radiation and wood dust. Some of the items on that list will be non-mutagenic. $\endgroup$
    – Mast
    Jan 13 '20 at 12:01
  • $\begingroup$ @Mast But those are all mutagenic $\endgroup$
    – user45969
    Jan 13 '20 at 14:08
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    $\begingroup$ The entire list is long, very long. Did you check them all? $\endgroup$
    – Mast
    Jan 13 '20 at 14:09
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How can a non-mutagenic agent be carcinogenic?

An agent that causes overexpression of oncogenes or inhibition of tumor suppressors, would be carcinogenic but not mutagenic.

HPV, for instance, produces proteins that cause inactivation and degradation of tumor suppressors, p53 and pRb[1].

Regarding alcohol. As you guessed, alcohol is metabolized to form acetaldehyde which is mutagenic as well as carcinogenic. Moreover, alcohol metabolism can lead to production of ROS which can also be mutagenic. Overall, alcohol is considered a potential carcinogen by IARC due to the observed effects. These classifications are not based on molecular mechanisms.

More recently, a study by Riva et al (2020) has found that only three out of the twenty carcinogens they tested had a mutagenic effect.

Thus, to conclude, not all carcinogens are mutagens.

Reference:

[1] IARC Working Group on the Evaluation of Carcinogenic Risk to Humans. Human Papillomaviruses. Lyon (FR): International Agency for Research on Cancer; 2007. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 90.) 4, Molecular Mechanisms of HPV-induced Carcinogenesis.

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  • $\begingroup$ Is there an example of a type of cancer that doesn't have high mutation rates/genome instability or acquired lots of mutations? I expect even viral infections ultimately lead to mutagenesis that make a tumour malignant? $\endgroup$
    – Cell
    Jan 13 '20 at 18:09
  • $\begingroup$ @Cell Any tumorigenic signal has to be sustained for a cancer to become stable. Therefore mutations are necessary. HPV induced tumor is dependent on the virus. Certainly higher growth rate and bypassing of essential cell cycle checkpoints will increase the mutation rate. However, if a cancer cell keeps mutating then it will accumulate deleterious mutations. From the analysis of CTVT (a transmissible tumor), it has been found that five driver mutations are sufficient for increasing the fitness of the cancer cells and cancer cells then undergo selection against deleterious mutations. $\endgroup$
    – WYSIWYG
    Jan 14 '20 at 8:59
  • $\begingroup$ @Cell to summarize, I guess there are no cancers (not lab models) without any driver mutations. $\endgroup$
    – WYSIWYG
    Jan 14 '20 at 9:01
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Alcohol itself is non-mutagenic because it does not directly alter DNA. (Additionally ethanol enhances carcinogenesis and is itself not a carcinogen - updated) There are similar non-mutagenic carcinogens such as estrogen - which is a carcinogen. Another important thing to realize is that a non-mutagenic carcinogen may not alter DNA, but instead alter receptors. This can lead to changes in expression of the DNA without actually changing the DNA. Research, such as in this article (https://www.ncbi.nlm.nih.gov/m/pubmed/2372870/) show that these compounds may alter membranous receptor sites or base their effects on long-term residence in the cells proper. Also, a somewhat older research article may also help your discovery: https://www.ncbi.nlm.nih.gov/m/pubmed/8476535/?i=3&from=/2372870/related. There are plenty of non-genotoxic carcinogens but also some that do alter DNA via intermediates, so it is important to check which one of these is the case.

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    $\begingroup$ Since when has ethanol been classified as a carcinogen? Not in the catalogues of laboratory chemical suppliers who, it least in Europe would have to label it as such with statutory warnings. $\endgroup$
    – David
    Jan 12 '20 at 20:28
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    $\begingroup$ Ethanol enhances carcinogenesis induced by other compounds, and it may influence the initial as well as the promotional phase of carcinogenesis. Reference: ncbi.nlm.nih.gov/pubmed/7050573 $\endgroup$
    – Asad Yamin
    Jan 12 '20 at 21:41
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    $\begingroup$ That is not the same as classifying as a carcinogen. In a question about carcinogens you and the poster need to be absolutely precise in your usage of the term. $\endgroup$
    – David
    Jan 12 '20 at 22:04
  • $\begingroup$ If Ethanol is not a carcinogen, then it's not a non-mutagenic carcinogen. Also, I read that Estrogen is a weak carcinogen and a weak mutagen, so it's also not an example of a non-mutagenic carcinogen. $\endgroup$
    – user45969
    Jan 12 '20 at 23:17
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    $\begingroup$ @David IARC considers alcohol as a potential carcinogen. $\endgroup$
    – WYSIWYG
    Jan 13 '20 at 8:54
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"Some retroviruses contain cancer-causing genes (oncogenes), and cells infected by such retroviruses are oncogenically transformed into tumor cells"

Molecular Cell Biology Lodish et al. 8th ed

DNA is integrated into the genome and cancer is not technically caused by "mutation". That is the case in some of the types of cervical cancers(HPV)

I believe that "not all carcinogens are mutagens" and "not all mutagens are carcinogens".

You may also consider the situation in which a chemical/protein effects the DNA in a way that causes a change in epigenetic code of the genome .Consequently that would also result in cancer by changing the gene expression patterns/amounts of products etc.

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    – tyersome
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