As we learn more about gene regulation, it is becoming increasingly apparent that regulatory pathways are extraordinarily complex. The existence of these networks of interconnected pathways means that if one pathway is mutated, this will likely lead to multiple knock-on effects. In the pathway tuning model of cancer, the sum of these many positive and negative effects determines the likelihood of cancer development. This model predicts that relatively small alterations in some parts of the pathways could tip the balance for cancer development.
To investigate this model further, Ludwig Oxford’s Virginia Schmid and colleagues from David Mole’s and Peter Ratcliffe’s labs examined the pathway that responds to low oxygen (hypoxia) in renal clear cell carcinoma (RCC), a cancer in which a key regulator of the hypoxic response, HIF, is often over-activated. In this paper published in Scientific Reports, the scientists discovered a high overlap between DNA regions that regulate the HIF pathway and variations in DNA sequences that affect cancer susceptibility. Interestingly, this overlap was not observed in other cancer such as breast and prostate, where overlap was instead seen with oestrogen and androgen receptor binding sites, important factors that drive these cancers. This analysis therefore supports the pathway tuning model of cancer and future work should focus on identifying the nature and consequences of the selective pressures that alter pathways during cancer development.