The Hallmarks of Precancer

Mary M Stangis^#^{1

2

3}, Zhengyi Chen^#^{4

5}, Jimin Min^#^{6

7}, Sarah E Glass^#^{5

8}, Jordan O Jackson^#^{9

10}, Megan D Radyk^#¹¹, Xen Ping Hoi^{12

13}, W Nathaniel Brennen^{14

15

16}, Ming Yu^{10

17

18}, Huy Q Dinh^{1

19}, Robert J Coffey^{5

8

20

21}, Martha J Shrubsole^{21

22}, Keith S Chan^{12

13}, William M Grady^{10

17

18}, Srinivasan Yegnasubramanian^{14

23

24

25}, Costas A Lyssiotis^{11

26

27}, Anirban Maitra^{6

7}, Richard B Halberg^{1

2

3}, Neelendu Dey^{10

17}, Ken S Lau^{4

5

8

21

28}

Affiliations

¹ McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, Madison, Wisconsin.
² Gastroenterology Division, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin.
³ Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin.
⁴ Chemical and Physical Biology Program, Vanderbilt University School of Medicine, Nashville, Tennessee.
⁵ Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee.
⁶ Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas.
⁷ Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, Texas.
⁸ Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
⁹ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington.
¹⁰ Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington.
¹¹ Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan.
¹² Department of Urology, Houston Methodist Research Institute, Houston, Texas.
¹³ Neal Cancer Center, Houston Methodist Research Institute, Houston, Texas.
¹⁴ Genitourinary Cancer Disease Division, Department of Oncology, Johns Hopkins Medicine, Baltimore, Maryland.
¹⁵ Department of Pharmacology and Molecular Sciences, Johns Hopkins Medicine, Baltimore, Maryland.
¹⁶ Department of Urology, Johns Hopkins Medicine, Baltimore, Maryland.
¹⁷ Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, Washington.
¹⁸ Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington.
¹⁹ Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin.
²⁰ Division of Gastroenterology, Hepatology, & Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
²¹ Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
²² Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
²³ Molecular Radiation Science Division, Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins Medicine, Baltimore, Maryland.
²⁴ Kidney-Urologic Pathology Division, Department of Pathology, Johns Hopkins Medicine, Baltimore, Maryland.
²⁵ Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medicine, Baltimore, Maryland.
²⁶ Division of Gastroenterology, Internal Medicine, University of Washington, Seattle, Washington.
²⁷ Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan.
²⁸ Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.

^# Contributed equally.

PMID: 38571435
PMCID: PMC11170686
DOI: 10.1158/2159-8290.CD-23-1550

The Hallmarks of Precancer

Mary M Stangis et al. Cancer Discov. 2024.

. 2024 Apr 4;14(4):683-689.

doi: 10.1158/2159-8290.CD-23-1550.

Authors

Affiliations

¹ McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, Madison, Wisconsin.
² Gastroenterology Division, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin.
³ Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin.
⁴ Chemical and Physical Biology Program, Vanderbilt University School of Medicine, Nashville, Tennessee.
⁵ Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee.
⁶ Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas.
⁷ Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, Texas.
⁸ Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
⁹ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington.
¹⁰ Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington.
¹¹ Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan.
¹² Department of Urology, Houston Methodist Research Institute, Houston, Texas.
¹³ Neal Cancer Center, Houston Methodist Research Institute, Houston, Texas.
¹⁴ Genitourinary Cancer Disease Division, Department of Oncology, Johns Hopkins Medicine, Baltimore, Maryland.
¹⁵ Department of Pharmacology and Molecular Sciences, Johns Hopkins Medicine, Baltimore, Maryland.
¹⁶ Department of Urology, Johns Hopkins Medicine, Baltimore, Maryland.
¹⁷ Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, Washington.
¹⁸ Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington.
¹⁹ Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin.
²⁰ Division of Gastroenterology, Hepatology, & Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
²¹ Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
²² Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
²³ Molecular Radiation Science Division, Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins Medicine, Baltimore, Maryland.
²⁴ Kidney-Urologic Pathology Division, Department of Pathology, Johns Hopkins Medicine, Baltimore, Maryland.
²⁵ Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medicine, Baltimore, Maryland.
²⁶ Division of Gastroenterology, Internal Medicine, University of Washington, Seattle, Washington.
²⁷ Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan.
²⁸ Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.

^# Contributed equally.

PMID: 38571435
PMCID: PMC11170686
DOI: 10.1158/2159-8290.CD-23-1550

Abstract

Research on precancers, as defined as at-risk tissues and early lesions, is of high significance given the effectiveness of early intervention. We discuss the need for risk stratification to prevent overtreatment, an emphasis on the role of genetic and epigenetic aging when considering risk, and the importance of integrating macroenvironmental risk factors with molecules and cells in lesions and at-risk normal tissues for developing effective intervention and health policy strategies.

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Conflict of interest statement

Conflict of Interest Disclosure Statement: In the past three years, C.A.L. has consulted for Astellas Pharmaceuticals, Odyssey Therapeutics, Third Rock Ventures, and T-Knife Therapeutics, and is an inventor on patents pertaining to Kras regulated metabolic pathways, redox control pathways in pancreatic cancer, and targeting the GOT1-ME1 pathway as a therapeutic approach (US Patent No: 2015126580-A1, 05/07/2015; US Patent No: 20190136238, 05/09/2019; International Patent No: WO2013177426-A2, 04/23/2015). W. M. G. is a scientific advisory board member for Freenome, Guardant Health, and SEngine and consultant for DiaCarta, Natera, Karius, Guidepoint and GLG. He receives research support from LucidDx. A.M. is a consultant for Tezcat Bioscience. A. M. is listed on a patent that had been licensed by Thrive Earlier Detection (an Exact Sciences Company).

Figures

**Figure 1.. The hallmarks of precancer.**
Studies on precancers have identified a set of 6 cellular/molecular traits consistently observed across various tissue types. Starting at the top center wedge of the ring and proceeding clockwise, these are: 1) age-related genetic alterations including telomere shortening and somatic mutations; 2) epigenetic changes resulting from aberrant methylation at specific sites; 3) metabolic alterations; 4) hijacking of regenerative cell state transitions; 5) disruption of immune surveillance and “inflammaging”; and 6) remodeling of the tissue microenvironment mediated by senescent fibroblasts.

**Figure 2.. Integration of multiomics analyses with patient metadata to understand how macroscopic risk factors influence molecular pathways.**
Advancing our knowledge of the cellular and molecular interactions that contribute to the formation and progression of precancers is essential as we build towards a cancer-free world. We propose integrative analysis of patient metadata with next-generation multiomics to enhance our understanding of how macroenvironmental exposures molecularly affect cells and biological pathways.

See this image and copyright information in PMC

References

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The Hallmarks of Precancer

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The Hallmarks of Precancer

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Conflict of interest statement

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