ABSTRACT
Certain breast and ovarian cancers are characterised by high levels of chromosomal instability. We established a suite of eleven SNP array-based signatures of various forms of chromosomal instability. To understand what biological mechanisms might underpin these signatures, we generated and assembled genetic-feature data including allele-specific expression, fusion genes, gene expression, methylation, somatic coding mutations and protein expression. For each signature, we extracted a compendium of significantly associated genetic features using machine learning. We established an association between subchromosomal allelic imbalance-based measures and DNA repair genes. Numerical chromosomal instability and chromothripsis were found to have distinct genetic associations but shared a relationship to mitotic processes, while whole-genome doubling was characterised by TP53 mutation, and high AURKA and GINS1 expression. Furthermore, we identified two genetically distinct forms of tandem duplicator phenotypes. These findings identify potentially novel genomic targets for validation and drug development for specific subsets of breast and ovarian cancer.
Subject(s)
Chromosomal Instability/genetics , Genes, Neoplasm/genetics , Neoplasms/genetics , Alleles , Biomarkers, Tumor , Breast Neoplasms/genetics , DNA Methylation , DNA Repair/genetics , Female , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/genetics , Genetic Predisposition to Disease , Genomics , Humans , Machine Learning , Mitosis/genetics , Mutation/genetics , Ovarian Neoplasms/genetics , Phenotype , Polymorphism, Single NucleotideABSTRACT
BACKGROUND: Invasive fungal disease (IFD) is a disease of immunocompromised hosts. Cytokines are important mediators of innate and adaptive immune system. The aim of this study was to identify cytokine profiles that correlate with increased risk of IFD. METHODS: We prospectively enrolled 172 adult haematology patients undergoing intensive chemotherapy, immunosuppressive therapy, and haematopoietic stem cell transplantation. Pro-inflammatory cytokine profiling using 30-plex Luminex assay was performed at baseline and during treatment. Nine single nucleotide polymorphisms (TLR1, TLR2, TLR3, TLR4.1, TLR4.2, TLR6, CLEC7A, CARD9, and INFG) were investigated among transplant recipients and donors. FINDINGS: The incidence of IFD in this cohort was 16.9% (29/172). Median baseline serum concentrations of IL-15, IL-2R, CCL2, and MIP-1α were significantly higher whilst IL-4 was lower in patients with proven/probable IFD compared to those with no evidence of IFD. Baseline high IL-2R and CCL2 were associated with increased risk of IFD in the multivariate analysis (adjusted hazard ratio 2.3 [95% CI 1.1-5.1; P = 0.037], and hazard ratio 2.7 [95% CI 1.2-6.1; P = 0.016], respectively). However, these differences were not significant in follow up measurements. Similarly, no significant independent prognostic value was associated with baseline cytokine profile. INTERPRETATION: High baseline IL-2R and CCL2 concentrations were independent indicators of the risk of developing IFD and could be used to identify patients for enhanced prophylaxis and early antifungal therapy.
