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    Tumor mutational burden is a determinant of immune-mediated survival in breast cancer
    (Taylor and Francis, England, 2018-07-30) Thomas A; Routh ED; Pullikuth A; Jin G; Su J; Chou JW; Hoadley KA; Print C; Knowlton N; Black MA; Demaria S; Wang E; Bedognetti D; Jones WD; Mehta GA; Gatza ML; Perou CM; Page DB; Triozzi P; Miller LD
    Mounting evidence supports a role for the immune system in breast cancer outcomes. The ability to distinguish highly immunogenic tumors susceptible to anti-tumor immunity from weakly immunogenic or inherently immune-resistant tumors would guide development of therapeutic strategies in breast cancer. Genomic, transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohorts were used to examine statistical associations between tumor mutational burden (TMB) and the survival of patients whose tumors were assigned to previously-described prognostic immune subclasses reflecting favorable, weak or poor immune-infiltrate dispositions (FID, WID or PID, respectively). Tumor immune subclasses were associated with survival in patients with high TMB (TMB-Hi, P < 0.001) but not in those with low TMB (TMB-Lo, P = 0.44). This statistical relationship was confirmed in the METABRIC cohort (TMB-Hi, P = 0.047; TMB-Lo, P = 0.39), and also found to hold true in the more-indolent Luminal A tumor subtype (TMB-Hi, P = 0.011; TMB-Lo, P = 0.91). In TMB-Hi tumors, the FID subclass was associated with prolonged survival independent of tumor stage, molecular subtype, age and treatment. Copy number analysis revealed the reproducible, preferential amplification of chromosome 1q immune-regulatory genes in the PID immune subclass. These findings demonstrate a previously unappreciated role for TMB as a determinant of immune-mediated survival of breast cancer patients and identify candidate immune-regulatory mechanisms associated with immunologically cold tumors. Immune subtyping of breast cancers may offer opportunities for therapeutic stratification.
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    Evaluation of genetic and plasma markers of VEGF levels for prognosis in coronary heart disease : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Health Sciences at Massey University, Wellington, New Zealand
    (Massey University, 2024-12-13) Meza Alvarado, Juan Carlos
    Cardiovascular disease (CVD) is the leading cause of death. CVD risk assessment is complicated by the multifactorial nature of disease onset and the lack of predictive biomarkers in patients. The vascular endothelial growth factor (VEGF-A), involved in blood vessel formation, could be considered a novel biomarker since increased levels have been observed in CVD aetiologies. Genetic variants, such as single nucleotide polymorphisms (SNPs), influence circulating VEGF-A levels and have been linked to CVD risk. SNPs are biomarkers that are independent of age that can be link to molecular mechanisms involved in CVD. The identification of clinically relevant SNPs will complement the existing CVD risk framework and further our understanding on the role of VEGF-A in CVD. Imputed genotype data was obtained for 47 SNPs located at the VEGFA locus (human chromosome 6, n = 30), the VEGF receptor 2 (VEGFR2) locus (human chromosome 4, n = 13) and the very low-density lipoprotein receptor (VLDLR) locus (human chromosome 9, n = 4). Imputed genotype data for 1935 patients from the Coronary Disease Cohort Study (CDCS) and 1183 individuals from the Canterbury Healthy Volunteers Study (HVOL) was assessed. Association between genotype groups with cardiometabolic parameters was tested using one-way ANOVA tests. Association of genotypes with clinical endpoints was examined by Kaplan-Meir analyses and multivariate regression models. Candidate SNPs were selected from among all the imputed SNPs if data was p < 0.1 for any of the analyses. Manual genotyping, using predesigned TaqMan assays, was performed for SNPs with multiple significant associations (p < 0.05). Validation of imputed findings with manual genotyping data was possible for rs6921438, rs7767396, rs2305948 and rs1870377. VEGF-A levels for 227 HVOL participants were measured by an ELISA immunoassay to compare with previously reported levels from 549 CDCS patients. SNPs identified that influence circulating VEGF-A levels included five at the VEGFA locus (rs6921438. rs7767396, rs45137773, rs7763440 and rs11757868), seven at the VEGFR2 locus (rs2305948, rs1870377, rs1870378, rs1870379, rs7677779, rs13136007 and rs10016064) and four at the VLDLR locus (rs7043199, rs10738760. rs7030781 and rs2375981). The homozygote minor allele genotypes for each SNP were associated with lower VEGF-A levels. Manual genotyped data for VEGFA locus variants rs6921438 and rs7767396 showed: a) rs6921438 AA was associated with increased all-cause death (p = 0.03), non ST-elevated myocardial infarction (NSTEMI, p = 0.0003), heart failure (HF, p = 0.035) and major adverse cardiovascular event (MACE, p = 0.032) risk b) rs7767396 GG was associated with increased NSTEMI (p = 0.001) HF (p = 0.023) risk c) rs6921438 AA (Hazard Ratio (HR) = 6.6 p = 0.016) and VEGF-A (HR = 2.64, p = 0.014) were independent HF admission risk predictors, along with established predictors. Manual genotyped data for VEGFR2 locus variants rs2305948 and rs1870377 showed a) rs2305948 CC was associated with higher all-cause mortality (p = 0.045) and shorter time to first cardiovascular readmission risk (p = 0.045) b) rs1870377 was an independent predictor for cardiovascular death when adjusting for NTproBNP, hypertension, creatinine, and beta blocker treatment (TT vs TA+AA, p = 0.048, HR = 1.125). Lastly, analyses showed that VLDLR locus variant rs10738760 AA genotype was associated with increased risk of cardiovascular death (p = 0.047, HR = 1.50). The use of imputation data can facilitate the identification of clinically relevant SNPs by observing the amount and statistical significance of associations. In total, 11 imputed variants were identified as expression quantitative trait loci (eQTL) SNPs that affect circulating VEGF-A levels. Validation by genotyping confirmed that rs6921438 and rs7767396, at the VEGFA locus, are associated with VEGF-A levels and CVD risk. Additional data supported that VEGFR2 exonic variants rs2305948 and rs1870377 have an impact on increased outcome risk. Moreover, the VLDLR variant rs10738760 can interact with molecular mechanisms that exacerbate CVD risk. Overall, these five SNPs are promising genetic markers for CVD risk profiling assessments before outcome occurrence.
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    Development of a Nomogram to Predict the Outcome for Patients with Soft Tissue Sarcoma.
    (MDPI (Basel, Switzerland), 2023-03-29) Bray JP; Munday JS; Dobson J; Hayes A; Hughes K
    Soft tissue sarcomas (STSs) are common cutaneous or subcutaneous neoplasms in dogs. Most STSs are initially treated by surgical excision, and local recurrence may develop in almost 20% of patients. Currently, it is difficult to predict which STS will recur after excision, but this ability would greatly assist patient management. In recent years, the nomogram has emerged as a tool to allow oncologists to predict an outcome from a combination of risk factors. The aim of this study was to develop a nomogram for canine STSs and determine if the nomogram could predict patient outcomes better than individual tumour characteristics. The current study provides the first evidence in veterinary oncology to support a role for the nomogram to assist with predicting the outcome for patients after surgery for STSs. The nomogram developed in this study accurately predicted tumour-free survival in 25 patients but failed to predict recurrence in 1 patient. Overall, the sensitivity, specificity, positive predictive, and negative predictive values for the nomogram were 96%, 45%, 45%, and 96%, respectively (area under the curve: AUC = 0.84). This study suggests a nomogram could play an important role in helping to identify patients who could benefit from revision surgery or adjuvant therapy for an STS.
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    Immunostaining for VEGF and Decorin Predicts Poor Survival and Recurrence in Canine Soft Tissue Sarcoma.
    (MDPI (Basel, Switzerland), 2023-03-28) Bray JP; Perrott MR; Munday JS; van der Weyden L
    The aim of this study was to investigate whether using immunohistochemistry to detect the angiogenic proteins vascular endothelial growth factor (VEGF) and decorin can help predict the risk of local recurrence of, or death from, canine soft tissue sarcoma (STS). VEGF and decorin were detected using validated immunohistochemical methods on 100 formalin-fixed paraffin-embedded samples of canine STS. The tumours had been resected previously, with clinical outcome determined by questionnaire. Each slide was assessed by light microscopy and the pattern of immunostaining with VEGF and decorin determined. Patterns of immunostaining were then analysed to detect associations with outcome measures of local recurrence and tumour-related death. High VEGF immunostaining was significantly (p < 0.001) associated with both increased local recurrence and reduced survival time. The distribution of decorin immunostaining within the tumour was significantly associated with survival time (p = 0.04) and local tumour recurrence (p = 0.02). When VEGF and decorin scores were combined, STS with both high VEGF and low decorin immunostaining were more likely to recur or cause patient death (p < 0.001). The results of this study suggest that immunostaining of VEGF and decorin may help predict the risk of local recurrence of canine STS.