For at least 2000 years, doctors and researchers have been trying to understand what may be causing cancer, with just as little success as Egyptologists before the Rosetta stone. And just like for hieroglyphs, all kinds of theories were proposed to explain the cause of cancer, but none gained general acceptance.
All that changed 111 years ago.
In 1914, Theodor Boveri, wrote a book – Zur Frage der Entstehung maligner Tumoren [1]– in which he postulated that cancer originates from a single cell that has inherited an abnormal set of chromosomes.
This postulate is remarkable in two respects:
1. it was a mere extrapolation of his observations of the link between aneuploidy in embryonic cells and abnormal development of… sea urchins (!);
2. it gave birth to the somatic mutation theory (SMT) of carcinogenesis that is the DNA of every orthodox cancer researcher (pun intended).
People prefer simple explanations of complex phenomena, and the SMT hit the nail of simplicity on the head: cancer is caused by specific mutations, so everything that causes mutations can cause cancer. It is thus no surprise that the medical establishment embraced the somatic mutation theory as the central paradigm of the oncology enterprise, influencing research, diagnostics, therapeutics and prevention.
There’s only one problem: this theory is not aging well.
On the one hand, it is now absolutely clear that mutations in themselves, no matter how nasty, are not sufficient to cause cancers. Healthy tissues in aging individuals are riddled with “cancer-causing” mutations [2]
On the other hand, there is no bona fide proof that any mutation is the initial event, the trigger, the root cause of any kind of cancer. It may well be impossible to obtain such proof since cancer as a clinical entity can only be diagnosed “very late”, when hundreds of thousands of malignant cells are already present. Everything before is fuzzy, a mystery.
Additionally, any meaningful discussion about “what may cause cancer” presupposes that everyone shares the same basic definition of what cancer is. It may seem like an obvious prerequisite, but … try asking different people around you … you may be surprised*.
Now, do not get me wrong! Of course, mutations are important in understanding cancer progression and extremely important for targeted therapies, with drugs that target only mutated or over-expressed proteins, sparing healthy cells. But all we know for certain is that some germline mutations are risk factors and that some somatic mutations are merely correlated with cancers, usually at late stages and only in some types.
Is the SMT dead?
There is nobody to establish its death certificate.
But the evidence of its shortcomings [3] and more importantly what it implies cannot be ignored by the global cancer research community. Not with the cancer epidemic that looms upon us.
So ,where do we go from here?
IMHO, as a theoretical framework, the SMT has given cancer research all it could give and it is time for the old cargo ship to retire.
A new theory on the root causes of cancers is needed, perhaps one that gives center stage not to mutations but to cancer hallmarks, a much more robust framework to define cancers.
What could such a theory postulate, I do not know (and hope to learn from you).
But I do know that we need to figure it out collectively, in a concerted effort, with curiosity, humility and courage.
References:
[1] On the Origin of Malignant Tumors, Williams & Wilkins, 1929.
[2] Evans, Edward J Jr, and James DeGregori. “Cells with Cancer-associated Mutations Overtake Our Tissues as We Age.” Aging and cancer vol. 2,3 (2021): 82-97. https://pubmed.ncbi.nlm.nih.gov/34888527/
[3] Brücher, Björn L D M, and Ijaz S Jamall. “Somatic Mutation Theory – Why it’s Wrong for Most Cancers.” Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology vol. 38,5 (2016) https://pubmed.ncbi.nlm.nih.gov/27160408/
* My own definition of cancer : a class of diseases characterized by proliferating cells with abnormal gene expression profiles that can migrate throughout the body and invade healthy tissues.
Some of the more salient findings that question the validity of the SMT:
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Finding |
Comment |
Reference |
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No specific causative genes have ever been found for the vast majority of cancers. |
Despite decades of research |
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Nearly 90% of all human genes mentioned in all papers in Pubmed (17,371 genes) are also reported in papers mentioning cancer |
This statistic suggests that almost all most human genes are involved in cancer in one way or another … |
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Most powerful carcinogens are not mutagenic |
In direct contradiction with the SMT |
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Cancer cells are extraordinarily resistant to extinction |
If mutations according to the SMT are random, their accumulation should lead to cancer extinction |
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Newly formed tumors in mice can be eliminated by mutant clones in adjacent normal tissues |
The observed effect of mutations is actually anti-oncogenic, opposite of what the SMT would predict |
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Mutational burden in low-cancer risk tissues is similar to that of high cancer risk tissues |
SMT can hardly explain why mutations can cause more cancers in some tissues as opposed to others |
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Cells with Cancer-associated Mutations Overtake Our Tissues as We Age |
But without any cancers developing |
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Some deletions of genes in transgenic mice supposed to cause cancer led to tumors with no deletions |
According to the SMT inducing mutations must be in the tumor. |
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Pan-cancer analysis of whole genomes of many tumors yielded no cancer- causing mutations |
absence of driver mutations in 181 of 2,658 tumors |
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Tobacco induces non-adenocarcinoma lung tumors through non-mutational mechanisms |
Based on the unexpected low frequency of K-ras mutations in comparison with adenocarcinoma |
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Some pediatric neuroblastomas can regress to benign lesions |
The SMT would predict that mutant cancer cells should remain malignant |
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The physical shape of a medical implant can make it carcinogenic or not |
regardless of the material used |
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Pore size in filter implants determines foreign body tumorogenesis |
The SMT offers no explanation for this strange finding |