Molecular subtype, biological sex and age shape melanoma tumour evolution.

BACKGROUND: Many cancer types display sex and age disparity in incidence and outcome. The mutational load of tumours, including melanoma, varies according to sex and age. However, there are no tools to explore systematically whether clinical variables such as age and sex determine the genomic landscape of cancer. OBJECTIVES: To establish a mathematical approach using melanoma mutational data to analyse how sex and age shape the tumour genome. METHODS: We model how age-related (clock-like) somatic mutations that arise during cell division, and extrinsic (environmental ultraviolet radiation) mutations accumulate in cancer genomes. RESULTS: Melanoma is driven primarily by cell-intrinsic age-related mutations and extrinsic ultraviolet radiation-induced mutations, and we show that these mutation types differ in magnitude and chronology and by sex in the distinct molecular melanoma subtypes. Our model confirms that age and sex are determinants of cellular mutation rate, shaping the final mutation composition. We show mathematically for the first time how, similarly to noncancer tissues, melanoma genomes reflect a decline in cell division during ageing. We find that clock-like mutations strongly correlate with the acquisition of ultraviolet-induced mutations, but critically, men present a higher number and rate of cell-division-linked mutations. CONCLUSIONS: These data indicate that the contribution of environmental damage to melanoma likely extends beyond genetic damage to affect cell division. Sex and age determine the final mutational composition of melanoma.

Prognostic gene expression signature for high-grade serous ovarian cancer.

BACKGROUND: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC. PATIENTS AND METHODS: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies. RESULTS: Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years. CONCLUSION: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.

NFAT1 protects articular cartilage against osteoarthritic degradation by directly regulating transcription of specific anabolic and catabolic genes.

OBJECTIVES: Adult mice lacking the transcription factor NFAT1 exhibit osteoarthritis (OA). The precise molecular mechanism for NFAT1 deficiency-induced osteoarthritic cartilage degradation remains to be clarified. This study aimed to investigate if NFAT1 protects articular cartilage (AC) against OA by directly regulating the transcription of specific catabolic and anabolic genes in articular chondrocytes. METHODS: Through a combined approach of gene expression analysis and web-based searching of NFAT1 binding sequences, 25 candidate target genes that displayed aberrant expression in Nfat1 -/- AC at the initiation stage of OA, and possessed at least four NFAT1 binding sites in the promoter of each gene, were selected and tested for NFAT1 transcriptional activities by chromatin immunoprecipitation (ChIP) and promoter luciferase reporter assays using chondrocytes isolated from the AC of three- to four-month-old wild-type mice or Nfat1 -/- mice with early OA phenotype. RESULTS: Chromatin immunoprecipitation assays revealed that NFAT1 bound directly to the promoter of 21 of the 25 tested genes encoding cartilage-matrix proteins, growth factors, inflammatory cytokines, matrix-degrading proteinases, and specific transcription factors. Promoter luciferase reporter assays of representative anabolic and catabolic genes demonstrated that NFAT1-DNA binding functionally regulated the luciferase activity of specific target genes in wild-type chondrocytes, but not in Nfat1 -/- chondrocytes or in wild-type chondrocytes transfected with plasmids containing mutated NFAT1 binding sequences. CONCLUSION: NFAT1 protects AC against degradation by directly regulating the transcription of target genes in articular chondrocytes. NFAT1 deficiency causes defective transcription of specific anabolic and catabolic genes in articular chondrocytes, leading to increased matrix catabolism and osteoarthritic cartilage degradation.Cite this article: M. Zhang, Q. Lu, T. Budden, J. Wang. NFAT1 protects articular cartilage against osteoarthritic degradation by directly regulating transcription of specific anabolic and catabolic genes. Bone Joint Res 2019;8:90-100. DOI: 10.1302/2046-3758.82.BJR-2018-0114.R1.