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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., 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.

The expression and regulation of matrisome genes—the ensemble of extracellular matrix, ECM, ECM-associated proteins and regulators as well as cytokines, chemokines and growth factors—is of paramount importance for many biological processes and signals within the tumor microenvironment. The availability of large and diverse multi-omics data enables mapping and understanding of the regulatory circuitry governing the tumor matrisome to an unprecedented level, though such a volume of information requires robust approaches to data analysis and integration. In this study, we show that combining Pan-Cancer expression data from The Cancer Genome Atlas (TCGA) with genomics, epigenomics and microenvironmental features from TCGA and other sources enables the identification of “landmark” matrisome genes and machine learning-based reconstruction of their regulatory networks in 74 clinical and molecular subtypes of human cancers and approx. 6700 patients. These results, enriched for prognostic genes and cross-validated markers at the protein level, unravel the role of genetic and epigenetic programs in governing the tumor matrisome and allow the prioritization of tumor-specific matrisome genes (and their regulators) for the development of novel therapeutic approaches.

Tiivistelmä. Akuutti myelooinen leukemia on varhaisesta myelooisesta veren kantasolusta lähtoisin oleva pahanlaatuinen verisairaus. Blastitasoisten, epäkypsien valkosolujen kerääntyminen ja leviäminen elimistössä häiritsee normaalien verisolujen tuotantoa, mikä johtaa oireisiin, kuten anemiaan, väsymykseen, mustelma-alttiuteen, luukipuihin, veren hyytymisongelmiin ja lisääntyneisiin infektioihin. Hoitamattomana tauti johtaa nopeasti kuolemaan. Suomessa AML diagnosoidaan noin 150 aikuisella vuodessa. Koska AML:n ennuste on huono ja taudin uusiutuminen yleistä rankoista solunsalpaajahoidoista huolimatta, on uusien terapiamuotojen kehittäminen tärkeää. Tässä tutkielmassa tarkastellaan akuutin myelooisen leukemian patogeneesiä sekä geeni- ja kromosomimuutoksia taudin taustalla. Lisäksi käsitellään akuutin myelooisen leukemian hoitomenetelmiä.

The microenvironment plays a central role in cancer, and neoplastic cells actively shape it to their needs by complex arrays of extracellular matrix (ECM) proteins, enzymes, cytokines and growth factors collectively referred to as the matrisome. Studies on the cancer matrisome have been performed for single or few neoplasms, but a more systematic analysis is still missing. Here we present a Pan-Cancer study of matrisome gene expression in 10,487 patients across 32 tumor types, supplemented with transcription factors (TFs) and driver genes/pathways regulating each tumor’s matrisome. We report on 919 TF-target pairs, either used specifically or shared across tumor types, and their prognostic significance, 40 master regulators, 31 overarching regulatory pathways and the potential for druggability with FDA-approved cancer drugs. These results provide a comprehensive transcriptional architecture of the cancer matrisome and suggest the need for development of specific matrisome-targeting approaches for future therapies.