Landscape of genetic alterations underlying hallmark signature changes in cancer reveals TP53 aneuploidy-driven metabolic reprogramming
Name:
36860655.pdf
Size:
10.21Mb
Format:
PDF
Description:
Identified with Open Access button
Authors
McClure, M. B.Kogure, Y.
Ansari-Pour, N.
Saito, Y.
Chao, H. H.
Shepherd, J.
Tabata, M.
Olopade, O. I.
Wedge, David C
Hoadley, K. A.
Perou, C. M.
Kataoka, K.
Affiliation
Division of Molecular Oncology, National Cancer Center Research Institute, Tokyo, JapanIssue Date
2023
Metadata
Show full item recordAbstract
The hallmark signatures based on gene expression capture core cancer processes. Through a pan-cancer analysis, we describe the overview of hallmark signatures across tumor types/subtypes and reveal significant relationships between these signatures and genetic alterations. TP53 mutation exerts diverse changes, including increased proliferation and glycolysis, which are closely mimicked by widespread copy-number alterations. Hallmark signature and copy-number clustering identify a cluster of squamous tumors and basal-like breast and bladder cancers with elevated proliferation signatures, frequent TP53 mutation, and high aneuploidy. In these basal-like/squamous TP53-mutated tumors, a specific and consistent spectrum of copy-number alterations is preferentially selected prior to whole-genome duplication. Within Trp53-null breast cancer mouse models, these copy-number alterations spontaneously occur and recapitulate the hallmark signature changes observed in the human condition. Together, our analysis reveals intertumor and intratumor heterogeneity of the hallmark signatures, uncovering an oncogenic program induced by TP53 mutation and select aneuploidy events to drive a worsened prognosis. Significance: Our data demonstrate that TP53 mutation and a resultant selected pattern of aneuploidies cause an aggressive transcriptional program including upregulation of glycolysis signature with prognostic implications. Importantly, basal-like breast cancer demonstrates genetic and/or phenotypic changes closely related to squamous tumors including 5q deletion that reveal alterations that could offer therapeutic options across tumor types regardless of tissue of origin.Citation
McClure MB, Kogure Y, Ansari-Pour N, Saito Y, Chao HH, Shepherd J, et al. Landscape of Genetic Alterations Underlying Hallmark Signature Changes in Cancer Reveals TP53 Aneuploidy-driven Metabolic Reprogramming. Cancer research communications. 2023 Feb;3(2):281-96. PubMed PMID: 36860655. Pubmed Central PMCID: PMC9973382. Epub 2023/03/03. eng.Journal
Cancer Research CommunicationsDOI
10.1158/2767-9764.crc-22-0073PubMed ID
36860655Additional Links
https://dx.doi.org/10.1158/2767-9764.crc-22-0073Type
ArticleLanguage
enae974a485f413a2113503eed53cd6c53
10.1158/2767-9764.crc-22-0073
Scopus Count
Collections
Related articles
- Aneuploidy, TP53 mutation, and amplification of MYC correlate with increased intratumor heterogeneity and poor prognosis of breast cancer patients.
- Authors: Oltmann J, Heselmeyer-Haddad K, Hernandez LS, Meyer R, Torres I, Hu Y, Doberstein N, Killian JK, Petersen D, Zhu YJ, Edelman DC, Meltzer PS, Schwartz R, Gertz EM, Schäffer AA, Auer G, Habermann JK, Ried T
- Issue date: 2018 Apr
- p53 in breast cancer subtypes and new insights into response to chemotherapy.
- Authors: Bertheau P, Lehmann-Che J, Varna M, Dumay A, Poirot B, Porcher R, Turpin E, Plassa LF, de Roquancourt A, Bourstyn E, de Cremoux P, Janin A, Giacchetti S, Espié M, de Thé H
- Issue date: 2013 Aug
- RB1 and TP53 co-mutations correlate strongly with genomic biomarkers of response to immunity checkpoint inhibitors in urothelial bladder cancer.
- Authors: Manzano RG, Catalan-Latorre A, Brugarolas A
- Issue date: 2021 Apr 20
- BRCA1-mutated and basal-like breast cancers have similar aCGH profiles and a high incidence of protein truncating TP53 mutations.
- Authors: Holstege H, Horlings HM, Velds A, Langerød A, Børresen-Dale AL, van de Vijver MJ, Nederlof PM, Jonkers J
- Issue date: 2010 Nov 30
- A mouse model featuring tissue-specific deletion of p53 and Brca1 gives rise to mammary tumors with genomic and transcriptomic similarities to human basal-like breast cancer.
- Authors: Hollern DP, Contreras CM, Dance-Barnes S, Silva GO, Pfefferle AD, Xiong J, Darr DB, Usary J, Mott KR, Perou CM
- Issue date: 2019 Feb