• Christiana A Demetriou, Davide Degli Esposti, Kristi Pullen Fedinick, Federica Russo, Oliver Robinson, and Paolo Vineis.
• Neurology Clinic D, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
• Eur. J. Clin. Invest. 2018 Jun 1; 48 (6): e12933e12933.

BackgroundCancer is believed to arise through the perturbation of pathways and the order of pathway perturbation events can enhance understanding and evaluation of carcinogenicity. This order has not been examined so far, and this study aimed to fill this gap by attempting to gather evidence on the potential temporal sequence of events in carcinogenesis.DesignThe methodology followed was to discuss first the temporal sequence of hallmarks of cancer from the point of view of pathological specimens of cancer (essentially branched mutations) and then to consider the hallmarks of cancer that one well-known carcinogen, benzo(a)pyrene, can modify.ResultsEven though the sequential order of driving genetic alterations can vary between and within tumours, the main cancer pathways affected are almost ubiquitous and follow a generally common sequence: resisting cell death, insensitivity to antigrowth signals, sustained proliferation, deregulated energetics, replicative immortality and activation of invasion and metastasis. The first 3 hallmarks can be regarded as almost simultaneous while angiogenesis and avoiding immune destruction are perhaps the only hallmarks with a varying position in the above sequence.ConclusionsOur review of hallmarks of cancer and their temporal sequence, based on mutational spectra in biopsies from different cancer sites, allowed us to propose a hypothetical temporal sequence of the hallmarks. This sequence can add molecular support to the evaluation of an agent as a carcinogen as it can be used as a conceptual framework for organising and evaluating the strength of existing evidence.© 2018 Stichting European Society for Clinical Investigation Journal Foundation.

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