Hi Maria,

Before even asking about experiments on driver mutations as the cause of cancer, it’s noteworthy that the very concept is still under certain scrutiny. Generally, some of the identified mutations are called passengers as they do not drive progression to metastatic disease, whereas others called genetic drivers are considered crucial for cancer cell survival and growth. According to Vogelstein opinion, a driver gene mutation as a mutation that directly or indirectly confers a selective growth advantage to the cell in which it occurs, whereas a passenger mutation is a mutation that has no direct or indirect effect on the selective growth advantage of the cell in which it occurred. Although it is difficult to determine driver mutations from DNA sequences alone, drivers tend to be the most commonly shared mutations between tumors and cluster around known oncogenes and also tend to be non-silent, whereas passenger mutations are randomly distributed throughout the genome. Clones bearing driver mutations are assumed to be positively selected in the evolution of neoplasia to invasive and advanced cancer. To be more specific, the still-evolving targeted therapy suffers resistance suggesting that DNA mutations considered as drivers MAY NOT HAVE A ROLE in tumor initiation. Particularly, while evaluating the role of DNA mutations as drivers and passengers in cancer initiation and development, Adjiri discerned the role of these DNA mutations as initiating events causing cancer or as contributors crucial for the development of a tumor once it has initiated. So, mutations in the DNA do occur and for a multitude of reasons but without necessarily causing cancer. New directions will draw themselves when more focus is given to the event responsible for the switch of a cell from normalcy to malignancy.

Best wishes,

Ilya

Dear Ilya,

Thank you for your detailed answer and, especially, for mentioning Adjijri - for some reason I've omitted his papers. May I take an opportunity to ask a couple more questions?

As "Vogelstein opinion", "are assumed" etc are about belief not proof, the prevailing multistage model is just a hypothesis the only base of which was and still remains the similarity of age-incidence curve and 6-power function, used by Armitage & Doll. Do you know any alternative theories about the origin of cancer except TOFT by Sonnenschein & Soto  (which seems to be foggy but maybe can be translated to mathematical language as the proclamation that all the processes in organism are correlated with different scales and degrees)?

And the other question is: how justified is the statement that smoking (and some other carcinogens) increases the probability of cancer? Correlation doesn't mean causation - maybe there is some mechanism making smoking lovers the same people who are susceptible to lung cancer?

There is an idea that X-ray (or ultraviolet) influence the mutation rate via energy supply increasing the molecular collisions number (Schroedinger) but do we have the proper idea of the smoking influence?

Sorry:

Best regards,

Maria

Maria, may I reply by the end of this week, as now I'm on my way to Hongkong's 3-day meeting? Thanks

Thank you, Ilya, I'll wait.

Have a good journey!

Dear Ilya,

A year ago you've kindly answered my question about driver mutations as a cause of cancer. Since then I've analyzed the mathematical foundations of the somatic mutation theory and found them questionable. Now I'm preparing a paper about that and I'd like to quote your opinion. Could you please point me any of your articles or reports which I can refer to?

Best regards,

Maria

P.S. I'm aware of the research by Adjiri, Sonnenschein & Soto and other authors who also either doubt SMT or completely deny it. I'm sure that adding your working to the list of references will improve my paper.