Germline genetic polymorphisms influence tumor gene expression and immune cell infiltration

Lim, Yoong Wearn; Chen-Harris, Haiyin; Mayba, Oleg; Lianoglou, Steve; Wüster, Arthur; Bhangale, Tushar; Khan, Zia; Mariathasan, Sanjeev; Daemen, Anneleen; Reeder, Jens; Haverty, Peter M.; Forrest, William F.; Brauer, Matthew J.; Mellman, Ira; Albert, Matthew L.

doi:10.1073/pnas.1804506115

Cited by 100 publications

(118 citation statements)

References 58 publications

(76 reference statements)

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“…Specifically, deletion of ERAP1 in mouse tumors was reported to increase the efficiency of anti-PD-1 immunotherapy. 52,53) Furthermore, low levels of ERAP2 were found to be associated with improved response to anti-PD-L1 in human patients with bladder cancer. 54) On the other hand, besides acting as a processing enzyme, ERAP1 secreted into the extracellular milieu activates immune cells such as macrophages and NK cells, and stimulates the production of pro-inflammatory cytokines.…”

Section: Resultsmentioning

confidence: 99%

Endoplasmic Reticulum Aminopeptidase 1 beyond Antigenic Peptide-Processing Enzyme in the Endoplasmic Reticulum

Tsujimoto

Aoki

Ohnishi

et al. 2020

Biological & Pharmaceutical Bulletin

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Endoplasmic reticulum aminopeptidase 1 (ERAP1) is well known as a processing enzyme of antigenic peptides, which are presented to major histocompatibility complex (MHC) class I molecules in the lumen of endoplasmic reticulum. Besides antigen processing, ERAP1 performs multiple functions in various cells depending on its intracellular and extracellular localization. Of note is the secretion of ERAP1 into the extracellular milieu in response to inflammatory stimuli, which further activates immune cells including macrophages and natural killer cells. Furthermore, secreted ERAP1 enhances the expression of pro-inflammatory cytokines like tumor necrosis factor-α, interleukin-1β, and interleukin-6. Such findings indicate that ERAP1 plays a significant role in the field of innate and acquired immunity. This review summarizes the functional analyses of ERAP1 that support our current understanding of its role as more than an antigenic peptideprocessing enzyme, specifically emphasizing on its secretory form.

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Section: Resultsmentioning

confidence: 99%

Endoplasmic Reticulum Aminopeptidase 1 beyond Antigenic Peptide-Processing Enzyme in the Endoplasmic Reticulum

Tsujimoto

Aoki

Ohnishi

et al. 2020

Biological & Pharmaceutical Bulletin

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“…One prior study identified many eQTLs in TCGA, some of which may be related to immune signatures (Lim et al, 2018). However, this study focused mostly on eQTLs, including eQTLs that may affect immune related genes.…”

Section: Rare Variants Analyses Demonstrated Intriguing Associationsmentioning

confidence: 99%

Germline genetic contribution to the immune landscape of cancer

Sayaman

Saad

Thórsson

et al. 2020

Preprint

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SummaryThe role of germline genetics in shaping the tumor immune landscape is largely unknown. Using genotypes from >9,000 individuals in The Cancer Genome Atlas, we investigated the association of common and rare variants with 139 well-defined immune traits. Our analysis of common variants identified 10 immune traits with significant heritability estimates, and an additional 23 with suggestive heritability, including estimates of T-cell subset abundance and interferon signaling. We performed genome-wide association on the 33 heritable traits and identified 23 genome-wide significant loci associated with at least one immune trait, including SNPs in the IFIH1 locus previously associated with several autoimmune diseases. We also found significant associations between immune traits and pathogenic or likely-pathogenic rare variants in BRCA1 and in genes functionally linked to telomere stabilization, and Wnt/Beta-catenin signaling. We conclude that germline genetic variants significantly impact the composition and functional orientation of the tumor immune microenvironment.

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“…To aid prioritisation of HiChIP target genes, we interrogated expression quantitative trait locus (eQTL) data from the largest study of whole blood gene expression [17] and TCGA endometrial tumors [18]. Using these data, we evaluated the overlap between endometrial cancer risk CVs and the top eQTL variants for each HiChIP target gene.…”

Section: Hichip Target Gene Expression Associates With Cvsmentioning

confidence: 99%

Analysis of promoter-associated chromatin interactions reveals biologically relevant candidate target genes at endometrial cancer risk loci

O’Mara

Spurdle

Glubb

2019

Preprint

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The identification of target genes at genome-wide association study (GWAS) loci is a major obstacle for GWAS follow-up. To identify candidate target genes at the 16 known endometrial cancer GWAS risk loci, we performed HiChIP chromatin looping analysis of endometrial cell lines. To enrich for enhancer-promoter interactions, a mechanism through which GWAS variation may target genes, we captured loops associated with H3K27Ac histone, characteristic of promoters and enhancers. Analysis of HiChIP loops contacting promoters revealed enrichment for endometrial cancer GWAS heritability and intersection with endometrial cancer risk variation identified 103 HiChIP target genes at 13 risk loci. Expression of four HiChIP target genes (SNX11, SRP14, HOXB2 and BCL11A) was associated with risk variation, providing further evidence for their regulation. Network analysis functionally prioritized a set of proteins that interact with those encoded by HiChIP target genes, and this set was enriched for pan-cancer and endometrial cancer drivers. Lastly, HiChIP target genes and prioritized interacting proteins were over-represented in pathways related to endometrial cancer development. In summary, we have generated the first global chromatin looping data from endometrial cells, enabling analysis of all known endometrial cancer risk loci and identifying biologically relevant candidate target genes.

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Germline genetic polymorphisms influence tumor gene expression and immune cell infiltration

Cited by 100 publications

References 58 publications

Endoplasmic Reticulum Aminopeptidase 1 beyond Antigenic Peptide-Processing Enzyme in the Endoplasmic Reticulum

Endoplasmic Reticulum Aminopeptidase 1 beyond Antigenic Peptide-Processing Enzyme in the Endoplasmic Reticulum

Germline genetic contribution to the immune landscape of cancer

Analysis of promoter-associated chromatin interactions reveals biologically relevant candidate target genes at endometrial cancer risk loci

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