Pan-Cancer Mutational and Transcriptional Analysis of the Integrator Complex

Abstract

The integrator complex has been recently identified as a key regulator of RNA Polymerase II-mediated transcription, with many functions including the processing of small nuclear RNAs, the pause-release and elongation of polymerase during the transcription of protein coding genes, and the biogenesis of enhancer derived transcripts. Moreover, some of its components also play a role in genome maintenance. Thus, it is reasonable to hypothesize that their functional impairment or altered expression can contribute to malignancies. Indeed, several studies have described the mutations or transcriptional alteration of some Integrator genes in different cancers. Here, to draw a comprehensive pan-cancer picture of the genomic and transcriptomic alterations for the members of the complex, we reanalyzed public data from The Cancer Genome Atlas. Somatic mutations affecting Integrator subunit genes and their transcriptional profiles have been investigated in about 11,000 patients and 31 tumor types. A general heterogeneity in the mutation frequencies was observed, mostly depending on tumor type. Despite the fact that we could not establish them as cancer drivers, INTS7 and INTS8 genes were highly mutated in specific cancers. A transcriptome analysis of paired (normal and tumor) samples revealed that the transcription of INTS7, INTS8, and INTS13 is significantly altered in several cancers. Experimental validation performed on primary tumors confirmed these findings.

Integrator Subunit 4 is a ‘Symplekin-like’ Scaffold that Associates with INTS9/11 to Form the Integrator Cleavage Module

“…Several INT subunits have been found to play important roles in adipose tissue differentiation, embryonic development, ciliogenesis, lung homeostasis, structural integrity of a major nuclear feature, the Cajal body (CB), as well as in the formation of herpesvirus microRNA 3'-end formation (8)(9)(10)(11)(12)(13)(14)(15)(16). More recently, mutations of Integrator subunits 1 (INTS1) and INTS8 have been implicated in disrupted human brain development and a large-scale analysis of TCGA database data reveals significant misexpression of INT subunits in a spectrum of human tumor types (17,18).…”

Comparative Proteome Profiling and Mutant Protein Identification in Metastatic Prostate Cancer Cells by Quantitative Mass Spectrometry-based Proteogenomics

“…INTS7 is an RNA polymerase II complex subunit, important for transcriptional regulation. A recent study has shown that INTS7 is highly mutated and is significantly overexpressed in a diverse number of cancers including PCa (35). According to the human protein atlas, the mRNA levels of INTS7 are significantly higher in testis compared with its levels in other tissues (36).…”

Network-aware mutation clustering of cancer

“…The IC clique contains 15 members of the Integrator Complex, a major component of the RNA polymerase II mediated transcription machinery (Rienzo and Casamassimi, 2016) . The Integrator Complex is believed to mediate post-transcriptional control of developmental genes and transduction cascades in response to stress, growth factors or other stimuli (Gaertner and Zeitlinger, 2014) , and has been identified as a common target for mutation in cancer (Federico et al , 2017) . The correlation between these cliques and biological modules linked to cancer processes suggests that other novel cancer cliques will be fertile ground for further investigation.…”