University of Oulu

Holstein, Elisa; Dittmann, Annalena; Kääriäinen, Anni; Pesola, Vilma; Koivunen, Jarkko; Pihlajaniemi, Taina; Naba, Alexandra; Izzi, Valerio. 2021. "The Burden of Post-Translational Modification (PTM)—Disrupting Mutations in the Tumor Matrisome" Cancers 13, no. 5: 1081.

The burden of post-translational modification (PTM) : disrupting mutations in the tumor matrisome

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Author: Holstein, Elisa1; Dittmann, Annalena1; Kääriäinen, Anni1;
Organizations: 1Faculty of Biochemistry and Molecular Medicine, University of Oulu, FI-90014 Oulu, Finland
2Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA
3University of Illinois Cancer Center, Chicago, IL 60612, USA
4Faculty of Medicine, University of Oulu, FI-90014 Oulu, Finland
5Finnish Cancer Institute, 00130 Helsinki, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 4 MB)
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Language: English
Published: Multidisciplinary Digital Publishing Institute, 2021
Publish Date: 2021-04-16


Background: To evaluate the occurrence of mutations affecting post-translational modification (PTM) sites in matrisome genes across different tumor types, in light of their genomic and functional contexts and in comparison with the rest of the genome.

Methods: This study spans 9075 tumor samples and 32 tumor types from The Cancer Genome Atlas (TCGA) Pan-Cancer cohort and identifies 151,088 non-silent mutations in the coding regions of the matrisome, of which 1811 affecting known sites of hydroxylation, phosphorylation, N- and O-glycosylation, acetylation, ubiquitylation, sumoylation and methylation PTM.

Results: PTM-disruptive mutations (PTMmut) in the matrisome are less frequent than in the rest of the genome, seem independent of cell-of-origin patterns but show dependence on the nature of the matrisome protein affected and the background PTM types it generally harbors. Also, matrisome PTMmut are often found among structural and functional protein regions and in proteins involved in homo- and heterotypic interactions, suggesting potential disruption of matrisome functions.

Conclusions: Though quantitatively minoritarian in the spectrum of matrisome mutations, PTMmut show distinctive features and damaging potential which might concur to deregulated structural, functional, and signaling networks in the tumor microenvironment.

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Simple Summary

Mutations are the driving force of the oncogenic process, altering regulatory pathways and leading to uncontrolled cell proliferation. Understanding the occurrence and patterns of mutations is necessary to identify the sequence of events enabling tumor growth and diffusion. Yet, while much is known about mutations in proteins whose actions are exerted inside the cells, much less is known about the extracellular matrix (ECM) and ECM-associated proteins (collectively known as the “matrisome”) whose actions are exerted outside the cells. In particular, while post-translational modifications (PTMs) are critical for the functions of many proteins, both intracellular and in the matrisome, there are no studies evaluating the mutations impacting known PTM sites within matrisome proteins. Here we report on a large Pan-Cancer cohort spanning 32 tumor types and demonstrate the specificities of matrisome PTM-affecting mutations over the rest of the genome, also evidencing features and findings that might be relevant for prognostication and mechanistic understanding of the supportive role of the tumor microenvironment in the tumorigenic process.

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Series: Cancers
ISSN: 2072-6694
ISSN-E: 2072-6694
ISSN-L: 2072-6694
Volume: 13
Issue: 5
Article number: 1081
DOI: 10.3390/cancers13051081
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
Funding: This research was funded by: ACADEMY OF FINLAND, grant number 329742; FINNISH CANCER INSTITUTE, K. Albin Johansson Cancer Research Fellowship; UNIVERSITY OF OULU, Profi-5 tenure track fund.
Academy of Finland Grant Number: 329742
Detailed Information: 329742 (Academy of Finland Funding decision)
Dataset Reference: The R code sustaining this submission is available at and The necessary data for the code are stored in a freely accessible Zenodo repository ( All data were deposited on 2 February 2021.
Copyright information: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (