Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Jan 14;35(1):10-15.
doi: 10.1016/j.ccell.2018.11.009.

The Roles of Initiating Truncal Mutations in Human Cancers: The Order of Mutations and Tumor Cell Type Matters

Arnold J Levine  1 , Nancy A Jenkins  2 , Neal G Copeland  2
Affiliations
Review

The Roles of Initiating Truncal Mutations in Human Cancers: The Order of Mutations and Tumor Cell Type Matters

Arnold J Levine et al. Cancer Cell. .

Abstract

We propose that initiating truncal mutations plays a special role in tumor formation by both enhancing the survival of the initiating cancer cell and by selecting for secondary mutations that contribute to tumor progression, and that these mutations often act in a tissue-preferred fashion. Here, we explain why inherited mutations often have different tissue specificities compared with spontaneous mutations in the same gene. Initiating truncal mutations make excellent neo-antigens for immunotherapy, and understanding why one mutation selects for a second mutation in a particular tissue type could one day aid in the design of gene-targeted combination therapies.

Keywords: inherited mutations; initiating truncal mutations; mutational order; tissue specificity; tumor evolution.

PubMed Disclaimer

Conflict of interest statement

Declaration of Interests

AJL is a founder and member of the board of directors of PMV Pharmaceuticals, which develops small molecules that are structural correctors for different mutant p53 alleles. He is also a member of the board of Adaptive Biotechnologies, which develops diagnostics for measuring minimal residual disease and identifies B and T cell receptor sequences.

NAJ and NGC declare no competing interests.

References

    1. Armitage P, Doll R (1954). The age distribution of cancer and a multi-stage theory of carcinogenesis. Br. J. Cancer 8:1–12. - PMC - PubMed
    1. Baker SJ, Preisingrer AC, Jessup JM, Paraskeva C, Markowitz S, Willson JK, Hamilton S, Vogelstein B (1990). p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis. Cancer Res. 50(23):7717–22. - PubMed
    1. Baker SJ, Markowitz S, Fearon ER, Willson JK, Vogelstein B (1990). Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 249(4971):912–5. - PubMed
    1. Balachandran VP, Łuksza M, Zhao JN, Makarov V, Moral JA, Remark R, Herbst B, Askan G, Bhanot U, Senbabaoglu Y, Wells DK, Cary CIO, Grbovic-Huezo O, Attiyeh M, Medina B, Zhang J, Loo J, Saglimbeni J, Abu-Akeel M, Zappasodi R, Riaz N, Smoragiewicz M, Kelley ZL, Basturk O, Gönen M, Levine AJ, Allen PJ, Fearon DT, Merad M, Gnjatic S, Iacobuzio-Donahue CA, Wolchok JD, DeMatteo RP, Chan TA, Greenbaum BD, Merghoub T, Leach SD (2017). Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature 551(7681):512–516. - PMC - PubMed
    1. Bowman RL, Busque L, Levine RL (2018). Clonal Hematopoiesis and Evolution to Hematopoietic Malignancies. Cell Stem Cell 22(2):157–170. - PMC - PubMed

Publication types

LinkOut - more resources