Precancer Atlas to Drive Precision Prevention Trials

Abstract

Cancer development is a complex process driven by inherited and acquired molecular and cellular alterations. Prevention is the holy grail of cancer elimination, but making this a reality will take a fundamental rethinking and deep understanding of premalignant biology. In this Perspective, we propose a national concerted effort to create a Precancer Atlas (PCA), integrating multi-omics and immunity - basic tenets of the neoplastic process. The biology of neoplasia caused by germline mutations has led to paradigm-changing precision prevention efforts, including: tumor testing for mismatch repair (MMR) deficiency in Lynch syndrome establishing a new paradigm, combinatorial chemoprevention efficacy in familial adenomatous polyposis (FAP), signal of benefit from imaging-based early detection research in high-germline risk for pancreatic neoplasia, elucidating early ontogeny in BRCA1-mutation carriers leading to an international breast cancer prevention trial, and insights into the intricate germline-somatic-immunity interaction landscape. Emerging genetic and pharmacologic (metformin) disruption of mitochondrial (mt) respiration increased autophagy to prevent cancer in a Li-Fraumeni mouse model (biology reproduced in clinical pilot) and revealed profound influences of subtle changes in mt DNA background variation on obesity, aging, and cancer risk. The elaborate communication between the immune system and neoplasia includes an increasingly complex cellular microenvironment and dynamic interactions between host genetics, environmental factors, and microbes in shaping the immune response. Cancer vaccines are in early murine and clinical precancer studies, building on the recent successes of immunotherapy and HPV vaccine immune prevention. Molecular monitoring in Barrett's esophagus to avoid overdiagnosis/treatment highlights an important PCA theme. Next generation sequencing (NGS) discovered age-related clonal hematopoiesis of indeterminate potential (CHIP). Ultra-deep NGS reports over the past year have redefined the premalignant landscape remarkably identifying tiny clones in the blood of up to 95% of women in their 50s, suggesting that potentially premalignant clones are ubiquitous. Similar data from eyelid skin and peritoneal and uterine lavage fluid provide unprecedented opportunities to dissect the earliest phases of stem/progenitor clonal (and microenvironment) evolution/diversity with new single-cell and liquid biopsy technologies. Cancer mutational signatures reflect exogenous or endogenous processes imprinted over time in precursors. Accelerating the prevention of cancer will require a large-scale, longitudinal effort, leveraging diverse disciplines (from genetics, biochemistry, and immunology to mathematics, computational biology, and engineering), initiatives, technologies, and models in developing an integrated multi-omics and immunity PCA - an immense national resource to interrogate, target, and intercept events that drive oncogenesis. Cancer Res; 77(7); 1510-41. ©2017 AACR.

Figure 1.

An integrated multi-omics and immunity precancer atlas (PCA). Inherited and acquired molecular alterations and their interaction with the local microenvironment/immune system influence oncogenic progression to invasive carcinoma. Normal cells (light orange, far left) that have a germline mutation (green nuclei) acquire somatic mutations (dark orange) or molecular alterations due to viral infection (purple). These all can potentially have an altered cell state with dysregulated molecular pathways that result in the loss of cell growth control and other hallmarks of cancer (228), which can then result in the development of advanced precancers (multicolored, subclonal diversity/heterogeneity) that immediately precede invasive cancer (red). Molecular alterations, depicted by symbols in the nucleus, represent mutations, SNPs, or epigenetic modifications. The accumulation of mutations (e.g., UV, ABOBEC) during life creates signatures (shown by the chromosomal insets and colored dots in gradient from cancer to normal). Somatic mutations in nuclear and mitochondrial genes, mutational signatures, other omic events, and germline changes/interactions are key drivers of oncogenesis. The mutational signatures, often identified in cancers, may predict early events, now extending to the precancer state (depicted by the orange/red cells with bold, yellow border). These omic alterations interact (bidirectionally) with the complex tissue microenvironment, including immune cells, stromal cells (adipocytes and fibroblasts), and other events, which promote oncogenesis and invasion/escape; microbiota can prevent or promote oncogenesis (see text). The continuum between the immune state modulated by cytokines and growth factors includes immune surveillance, composed of the antigenic repertoire, adaptive and immune cells (upper left box), and immune suppression/escape (upper right box) along with vascular and endothelial cells (not shown) that can lead to immune escape – another hallmark of cancer. The elucidation of the integrated multi-omics and immunity PCA will continue to evolve in complexity (e.g., recent SCNA finding), requiring continuous updating in this fast moving field.