Umberto Veronesi

Biomolecular mechanisms of cancer: the clinical perspective

Cancer arises from the accumulation within a single cell of a defined set of genetic alterations that ultimately lead to the loss or gain of crucial functions that regulate cellular division and cell death. The exponential increase in our knowledge concerning the molecular mechanisms that underlie tumorigenesis combined with the deciphering of the human genome has dramatically changed our vision of cancer, and is bound to have a major impact in prevention, diagnosis and drug development.

Hereditary genetic variants are linked to an increased predisposition for specific tumors. Cancer-predisposing variants, such as those of the BRCA genes that are associated to hereditary breast cancers, can confer up to 40-fold increase in the risk of developing a specific type of tumor in the course of the individual’s lifespan. Their identification and classification is one of the most promising approaches for the development of programs aimed at preventing disease onset.
Acquired genetic abnormalities that arise in the course of an individual’s life span are linked to the pathogenesis of specific tumors, and confer distinctive clinical characteristics. Consequently, their detection plays a major role in diagnostic settings. In the case of hematologic tumors, such as acute leukemias, for example, the identification of specific genetic abnormalities serves for correct diagnosis and has a direct impact in the clinical management of patients and choice of therapeutic regimens.
One of the main objectives in cancer research is the discovery of specific biomarkers that correlate with the natural history of the disease (prognostic markers) and/or with the likelihood of response to a treatment (predictive markers). These can be exploited, alongside other clinical information for the personalized choice of therapeutic regimens, with the aim of avoiding unnecessarily aggressive treatment of tumors with favorable biological characteristics. Finally, the discovery of genetic alterations resulting in specific functional abnormalities in cancer cells has led to the development of a new generation of targeted drugs that bear the promise of higher efficacy and lower toxicity.