Why precursors matter.

Cancer precursors are the tissue antecedents of cancer. They are distinguished from biomarkers in that they reflect a morphologic as opposed to a merely biochemical or genetic association with a specific cancer. Precursors to cancers are increasingly recognized as universal, relevant to carcinogenesis, and providing a unique potential for primary and secondary prevention. As the molecular, imaging, and genomic tools to investigate them evolve, it is becoming increasingly evident that virtually allmalignancies are precededby these clinically silent stateswhere the molecular lesions that characterize the specific cancer emerge. In terms of both time and antecedent molecular events, cancer is the visible iceberg; the 90% submerged is the precursor. We also take it as axiomatic that all morphologic changes must be accompanied by an extensive and proximal scaffolding of molecular alterations. Biologically, molecular and morphologic lesions must correspond, but our understanding of their relationship is still limited. Vogelstein’s classic paradigm (1) for the molecular steps in progression to colon cancer and similar schemas for other tumors remain incomplete. A key theme of this review is that the most direct path to understanding the molecular taxonomy of tumors and what determines their progression (precursor > tumor > metastasis) should emphasize investigating precursor lesions in population studies (Fig. 1). Here, detailed information on exposure and outcome combined with biomarker studies (serial where possible) can characterize molecular steps in progression and refine their relation to morphology. New technologies and the rapidly expanding database of molecular and genomic lesions in tumors are expected to reveal the underpinnings ofmalignancywith attendant benefits: new insight into etiology, reinvigoration of screening and prevention, and potential to enhance the therapeutic armamentarium. Large-scale advanced technology initiatives such as the Tumor Cancer Genome Atlas (TCGA) focuses on tumor tissue characterization and ENCODE on functional elements of the genome (2). These efforts and others that aim to elucidate the somatic underpinnings (as well as expression, methylation, and other manifestations of a dynamic genome) of neoplasia have appropriately focused on those with frank malignancy. Regarding the environmental exposures that account for most cancer, metabolomic, microbiome, and related approaches (3, 4) will offer insight into chemical and infectious exposures, whereas mobile technologies will allow more quantitative, detailed, and accurate assessment of sleep, physical activity, light exposure, diet, and circadian variation in unprecedented detail. A priority is to extend this exciting body of work to the earlier steps on the pathway to malignancy (5), that is, cancer precursors. These approaches will not only to assess clues to their origin but will investigate what determines progression. Precursors provide a substrate for early intervention and prevention. Frank malignancy represents the endpoint of a series of molecular steps and is difficult to treat or reverse. Precursors represent a more malleable and potentially reversible state where less aggressive interventions may avert or slow progression. Screening may offer the greatest advantage when detection of an asymptomatic cancer/precursor is possible and a curative intervention (in the so-called Detectable Preclinical Phase) exists, as it does for cervix (6) and colorectal (7) and selected skin precursors (i.e., actinic keratosis). In other cancers such as breast (8), prostate, lung, and melanoma, screening-based early detection has a more complex riskbenefit and further research is needed to understand how to best avoid adverse outcomes and identify the most critical determinants of progression. Some of the clearest gains in avoiding cancer deaths have been made from cervical and colon cancer screening.Although they arenot explicit precursors as earlier defined, infectious agents associated with specific malignancies offer opportunities for cancer prevention where vaccination is established, that is, hepatitis B virus (liver), human papillomavirus (cervix, anus, oral) and for identification of individuals at elevated risk for follow-up based on infection with hepatitis C virus (liver), Epstein–Barr virus (Burkitt’s), and HTLV1 (ATL). Themolecular dissection of cancer promises to redefine the taxonomy of cancer, eventually superseding the traditional morphologic definition. Among the diverse molecular abnormalities observed in a given tissue sample, it is not always easy to identify the "drivers" that specify the malignant phenotype. A comparison of tissue obtained in precursors, early, and advanced cancer can provide an unparalleled opportunity to dissect out the critical elements. Biomarkers are increasingly proposed as plausible surrogates to follow cancer and provide diagnostic, prognostic, or therapeutic guidance. Complementary markers (that fill "gaps" in screening by other modalities Author's Affiliation: Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health