Response

I thank Dr. Kaye for the correspondence; it gives me an opportunity to clarify my commentary and address possible misperceptions. My themes were: 1) a causative role of acquired mutations in carcinogenesis is not a fact but a theory, often called the somatic mutation theory (SMT); 2) the alternative tissue organization field theory (TOFT) says that cancer is development gone awry (1); 3) a cancer theory kerfuffle comparing SMT and TOFT should encompass, to the extent possible, all relevant experimental and observational results, especially those that challenge either theory; and 4) this kerfuffle can lead to new lines of research, especially related to cancer prevention.

Dr. Kaye maintains that SMT has been validated, stating, for example, that SMT provides a solid framework for targeted cancer therapy. It seems to me that validation is a high bar, requiring an SMT explanation of the many puzzling results that I presented, including some related to targeted cancer therapy.

Dr. Kaye wrote that concerns about the large number of candidate cancer genes are misplaced because “efforts are underway to define core mutational events and organize cancer genes into a manageable number of parallel and interconnecting signaling pathways.” Although I welcome bioinformatics cancer research (having done some myself), I am not optimistic about a bioinformatics search for driver mutations. Current bioinformatics methods prioritize mutations in terms of their likelihood of being driver mutations, but do not prove the existence of driver mutations (2). Gold standards for evaluating bioinformatics predictions of driver mutations (3) are based on postulated driver mutations and not on unambiguously established driver mutations. Also, there has been little overlap in sets of driver mutations selected under different bioinformatics methods (4).

Dr. Kaye mentioned two controversial commentaries that were later discredited; however, it does not follow that all controversial commentaries will be later discredited. Dr. Kaye thought my commentary pitted the role of tissue microenvironment against the role of somatic mutations; however, the microenvironment plays a role in both SMT and TOFT.

I wrote my commentary to encourage new directions of research based on paradoxes under SMT. For example, I have not seen in the literature an SMT explanation of how subcutaneously implanted Millipore filters with small, but not large, pores lead to tumors in mice (5); I hope that researchers will use modern technology to understand why tumors arise only when the pore size is small. In addition, I hope that researchers will perform more extensive sequencing studies (involving noncoding regions) on tumors with zero reported mutations to determine if, in fact, there are really zero mutations. I agree with Dr. Kaye on the need to move forward together; my emphasis is on paradox-driven cancer, as opposed to technology-driven cancer research. (6)

The opinions presented should not be viewed as official opinions or positions of the National Cancer Institute.