title: 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 inBRCA1-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.
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.|Department of Pathology and Bioinformatics, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Avrum
authors.initials: A
authors.lastname: Spira
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Yurgelun
authors.affiliation: Theoretical Division, Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico.
authors.forename: Ludmil
authors.initials: L
authors.lastname: Alexandrov
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, California.
authors.forename: Anjana
authors.initials: A
authors.lastname: Rao
authors.affiliation: Department of Medicine, Moores Cancer Center, University of California San Diego, La Jolla, California.
authors.forename: Rafael
authors.initials: R
authors.lastname: Bejar
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Kornelia
authors.initials: K
authors.lastname: Polyak
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Marios
authors.initials: M
authors.lastname: Giannakis
authors.affiliation: Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Ali
authors.initials: A
authors.lastname: Shilatifard
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Olivera J
authors.initials: OJ
authors.lastname: Finn
authors.affiliation: Department of Hematology and Immunology, Yale Cancer Center, New Haven, Connecticut.
authors.forename: Madhav
authors.initials: M
authors.lastname: Dhodapkar
authors.affiliation: Department of Hematology, Mayo Clinic Hospital, Rochester, Minnesota.
authors.forename: Neil E
authors.initials: NE
authors.lastname: Kay
authors.affiliation: Department of Hematology, Mayo Clinic Hospital, Phoenix, Arizona.
authors.forename: Esteban
authors.initials: E
authors.lastname: Braggio
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Vilar
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.|Department of Pathology and Bioinformatics, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Mazzilli
authors.affiliation: Division of Hematology and Oncology, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Rebbeck
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Judy E
authors.initials: JE
authors.lastname: Garber
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.|Department of Pathology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
authors.forename: Victor E
authors.initials: VE
authors.lastname: Velculescu
authors.affiliation: Department of Medicine, Center for Translational Medicine in Women's Health, University of Washington, Seattle, Washington.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Disis
authors.affiliation: Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania.|Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Wallace
authors.affiliation: Department of Medicine, Moores Cancer Center, University of California San Diego, La Jolla, California. slippman@ucsd.edu.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lippman
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology; D060833:Cellular Microenvironment; D004272:DNA, Mitochondrial / Q000235:genetics; D044127:Epigenesis, Genetic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008928:Mitochondria / Q000502:physiology; D009369:Neoplasms / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D011230:Precancerous Conditions / Q000209:etiology*; D057285:Precision Medicine; D059010:Single-Cell Analysis
chemical_list: D019496:Cancer Vaccines; D004272:DNA, Mitochondrial