Biology subjects

Lyng, H.

Publications and source records attributed to Lyng, H..

4 recordsLinked to original sources

bioRxiv2025

Analysis of patient data reveals novel cancer-relevant functions for GCN2/eIF2αK4

Numerous studies have shown that high GCN2 levels correlate with poor survival in a number of cancers. GCN2 has been known for over thirty years as a stress-response kinase, which phosphorylates the translation-initiation factor eIF2, and thereby contributes to reprogramming of translation. Here we performed correlation analyses of GCN2 expression and that of other genes in a patient-derived sample set of cervical cancer samples. We found correlations not only with genes involved in stress responses, but also with genes involved in mitosis and cell migration. Our functional analyses confirmed that these correlations indeed reveal novel functions. Furthermore, our analyses of growth benefits associated with elevated GCN2 levels suggest that the novel functions can contribute to aggressive disease in cancers with high GCN2 levels.

cell biology↗

bioRxiv2024

A Deep Learning Framework for Predicting Prognostically Relevant Consensus Molecular Subtypes in HPV-Positive Cervical Squamous Cell Carcinoma from Routine Histology Images

Despite efforts in human papillomavirus (HPV) prevention and screening, cervical cancer remains the fourth most prevalent cancer among women globally. In this study, we propose an end-to-end deep learning framework to investigate histological correlates of the two consensus molecu-lar subtype (CMS) of HPV-positive cervical squamous cell carcinoma (CSCC) patients. Analysing three international CSCC cohorts (n=545 patients), we demonstrate that the genomically determined CMS can be predicted from routine haematoxylin and eosin (H&E)-stained histology slides, with our Digital-CMS scores achieving significant patient stratifications in terms of disease-specific survival (TCGA p=0.0022, Oslo p=0.0495) and disease-free survival (TCGA p=0.0495, Oslo p=0.0282). In addition, our extensive analyses reveal distinct tumour microenvironment (TME) differences between the two CMS subtypes of the CSCC cohorts. Notably, CMS-C1 CSCC subgroup has markedly increased lymphocyte presence, whereas CMS-C2 subgroup has high nuclear pleomor-phism, an elevated neutrophil-to-lymphocyte ratio, and increased neutrophil density. Analysis of representative histological regions reveals higher degree of malignancy in CMS-C2 patients, as-sociated with poor prognosis. This study introduces a potentially clinically advantageous Digital-CMS score derived from digitised WSIs of routine H&E-stained tissue sections, offers new insights into TME differences impacting patient prognosis and potential therapeutic targets, and identifies histological patterns serving as potential surrogate markers of the two CMS subtypes for clinical application.

pathology↗

bioRxiv2020

Pro-metastatic gene expression, immune evasion and an altered HPV spectrum characterize an aggressive subtype of cervical cancer

Human papillomavirus (HPV)-associated cervical cancer represents one of the leading causes of cancer death worldwide. Although low-middle income countries are disproportionately affected, our knowledge of the disease predominantly originates from populations in high-income countries. Using the largest multi-omic analysis of cervical squamous cell carcinoma (CSCC) to date, totalling 643 tumours and representing patient populations from the USA, Europe and Sub-Saharan Africa, we identify two CSCC subtypes (C1 and C2) with differing prognosis. C1 tumours are largely HPV16-driven, display increased cytotoxic T-lymphocyte infiltration and frequently harbour PIK3CA and EP300 mutations. C2 tumours are associated with shorter overall survival, are frequently driven by HPVs from the HPV18-containing alpha-7 clade, harbour alterations in the Hippo signalling pathway and increased expression of immune checkpoint genes, B7-H3 (also known as CD276) and NT5E (also known as CD73) and PD-L2 (also known as PDCD1LG2). In conclusion, we identify two novel, therapy-relevant CSCC subtypes that share the same defining characteristics across three geographically diverse cohorts.

cancer biology↗

bioRxiv2018

Integrated Genomic Analysis of Hypoxia Genes across Cancer Types Identifies Significant Associations with Cancer Hallmarks

Hypoxia is a generic micro-environmental factor in most solid tumours. While most published literature focused on in vitro or single tumour type investigations, we carried out the first multi-omics pan cancer analysis of hypoxia with the aim of gaining a comprehensive understanding of its implication in tumour biology. A core set of 52 mRNAs were curated based on experimentally validated hypoxia gene sets from multiple cancer types. The 52 mRNAs collectively stratified high- and low-hypoxia tumours from The Cancer Genome Atlas (TCGA) database (9698 primary tumours) in each of the 32 cancer types available. High- hypoxia tumours had high expression of not only mRNA but also protein and microRNA markers of hypoxia. In a pan cancer transcriptomic analysis, [≥]70% of the known cancer hallmark pathways were enriched in high-hypoxia tumours, most notably epithelial mesenchymal transition potential, proliferation (G2M checkpoint, E2F targets, MYC targets) and immunology response. In a multi-omics analysis, gene expression-determined high- hypoxia tumours had a higher non-silent mutation rate, DNA damage repair deficiency and leukocyte infiltration. The associations largely remained significant after correcting for confounding factors, showing a profound impact of hypoxia in tumour evolution across cancer types. High-hypoxia tumours determined using the core gene set had a poor prognosis in 16/32 cancer types, with statistical significances remaining in five after adjusting for tumour stage and omics biomarkers. In summary, this first comprehensive in vivo map of hypoxia in cancers highlights the importance of this micro-environmental factor in driving tumour progression.

cancer biology↗