# Single rate-limiting event of carcinogenesis

## TL;DR

The paper proposes that the final genetic change in cancer development is the key limiting step, explaining why cancer is rare despite common pre-cancerous changes.

## Contribution

The authors extend the Peto-Mack postulate to identify the last multistage 'hit' as the rate-limiting event in carcinogenesis.

## Key findings

- A decades-long incidence plateau is observed in contralateral kidneys for renal-cell carcinoma, similar to breast cancer.
- Cell competition and somatic evolution in aging stem-cell compartments may explain prolonged incidence stability.
- The final mutational event is proposed as the critical bottleneck in cancer development.

## Abstract

Single-cell studies have discovered abundant cancer-associated genetic/phenotypic changes in non-cancerous cells, strikingly contrasting with the infrequency of cancer. Epidemiological data have revealed decades-long plateaus of breast cancer incidence in the contralateral breast and twins/relatives following the first/proband’s diagnosis, unlike the well-known continuous increase of population-level incidence with age, the latter ostensibly attributable to the successive accumulation of multiple genetic/epigenetic changes necessary for transformation. Here, we explain these contradicting observations by differentiating cell-level, individual-level, and population-level evidence. First, we show the same decades-long incidence plateau for renal-cell carcinoma in the contralateral kidney following the first diagnosis, expanding the individual-level evidence from breast cancer. We then consider somatic evolution and cell competition in stem-cell compartments and their bounded nature in ageing as a hypothesized mechanism for the abundant cancer-associated cell-level changes and the prolonged constancy of individual-level incidence. Individual-specific propensity with heritable/familial components underlies this process, with which we show congruence between individual-level’s constant incidence vs. population-level’s increasing incidence. The resulting postulate, an extension of one by Peto and Mack 25 years ago, distinguishes the last multistage “hit” as the critically rate-limiting event in carcinogenesis. Its supporting evidence calls for a reappraisal of the precise nature of multistage carcinogenesis in cancer biology.

The multistage carcinogenesis theory is largely established and supported, but it can be contradicted by features such as abundant cancer-like genetic or phenotypic changes in normal tissues and the rates of cancer in contralateral organs and patients’ relatives. Here, the authors extend the Peto-Mack postulate to reconcile such incongruences, distinguishing the last multistage hit as the critically rate-limiting event in carcinogenesis.