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Title: Precancer Atlas to Drive Precision Prevention Trials

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. Here, 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 hostmore » 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. In conclusion, 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.« less
Authors:
 [1] ;  [2] ; ORCiD logo [3] ;  [4] ;  [5] ;  [2] ;  [2] ;  [6] ;  [7] ;  [8] ;  [9] ;  [10] ;  [11] ;  [1] ;  [12] ;  [2] ;  [13] ;  [14] ;  [15] ;  [5]
  1. Boston University School of Medicine, MA (United States)
  2. Dana-Farber Cancer Institute, Boston, MA (United States)
  3. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  4. La Jolla Institute for Allergy and Immunology, CA (United States)
  5. University of California San Diego, La Jolla, CA (United States)
  6. Northwestern University Feinberg School of Medicine, Chicago, IL (United States)
  7. University of Pittsburgh, PA (United States)
  8. Yale Cancer Center, New Haven, CT (United States)
  9. Mayo Clinic Hospital, Rochester, MN (United States)
  10. Mayo Clinic Hospital, Phoenix, AZ (United States)
  11. The University of Texas MD Anderson Cancer Center, Houston, TX (United States)
  12. Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA (United States)
  13. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD (United States)
  14. Univ. of Washington, Seattle, WA (United States)
  15. Univ. of Pennsylvania, Philadelphia, PA (United States)
Publication Date:
Report Number(s):
LA-UR-17-20424
Journal ID: ISSN 0008-5472
Grant/Contract Number:
AC52-06NA25396
Type:
Accepted Manuscript
Journal Name:
Cancer Research
Additional Journal Information:
Journal Volume: 77; Journal Issue: 7; Journal ID: ISSN 0008-5472
Publisher:
American Association for Cancer Research
Research Org:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org:
USDOE Laboratory Directed Research and Development (LDRD) Program
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Biological Science
OSTI Identifier:
1356146