Overcoming intra-tumoral heterogeneity for biomarker discovery in the High-Grade Serous Ovarian Cancer proteome
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ABSTRACT:
PROVIDER: PRJNA1160805 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR30656915_1.fastq.gz | Fastqsanger.gz | |||
| SRR30656915_2.fastq.gz | Fastqsanger.gz | |||
| SRR30656916_1.fastq.gz | Fastqsanger.gz | |||
| SRR30656916_2.fastq.gz | Fastqsanger.gz |
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Project description:Improved biomarkers of treatment response are needed for patients with High-Grade Serous Ovarian Cancer (HGSC). A challenge is substantial anatomical site-to-site variation in expression. We completed Data Independent Acquisition – Mass Spectrometry (DIA-MS) analysis of over 404 fresh frozen and 78 formalin fixed, paraffin-embedded HGSC tissue samples from ovary (adnexal) and a common secondary site (omentum) in 11 patients. This was compared with mutation testing, gene expression and whole genome copy number profiling. Proteins with relatively stable intra-, and variable inter-individual expression (n=1,651), included a 52-protein module reflecting interferon mediated tissue inflammation indicative of a cGAS-STING pathway cytosolic double-stranded (ds) DNA response. The dsDNA sensing / inflammation (DSI) score was higher in omentum compared with ovary. Ovarian HGSC samples showed marked inter-individual differences in inflammatory and immune responses to DNA damage. Stable discriminative features of the HGSC proteome, a prerequisite for clinical predictive biomarkers, are detectable in ovary (adnexal) tissue samples.
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Project description:Intra-individual tumoral heterogeneity (ITH) is a hallmark of solid tumors and impedes accurate genomic diagnosis and selection of proper therapy. The purpose of this study was to identify ITH of ovarian serous adenocarcinomas (OSAs) and to determine the utility of ascitic cancer cells as a resource for mutation profiling in spite of ITH. We performed whole-exome sequencing, copy number profiling, and DNA methylation profiling of four OSA genomes using multiregional biopsies from 13 intraovarian lesions, 12 extraovarian tumor lesions (omentum/peritoneum), and ascitic cells. We observed substantial levels of heterogeneity in mutations and copy number alterations (CNAs) of the OSAs. We categorized the mutations into 'common', 'shared' and 'private' according to the regional distribution. Six common, 8 shared, and 24 private mutations were observed in known cancer-related genes,. but common mutations had a higher mutant allele frequency and included TP53 mutations in all four OSAs. Region-specific chromosomal amplifications and deletions involving BRCA1, PIK3CA, and RB1 were also identified. Of note, the mutations detected in ascitic cancer cells represented 92.3-100% of overall somatic mutations in the given case. Phylogenetic analyses of ascitic genomes predicted a polyseeding origin of somatic mutations in ascitic cells. Our results demonstrate that despite ITH, somatic mutations, CNAs, and DNA methylations in both â??commonâ?? category and cancer-related genes were highly conserved in ascitic cells of OSAs, highlighting the clinical relevance of genome analysis of ascitic cells. Ascitic tumor cells may serve as a potential resource to discover somatic mutations of primary OSA with diagnostic and therapeutic relevance. Genome wide DNA methylation profiling of ascitic cells as well as biopsies from ovarian serous adenocarcinomas cases obtained by Illumina Infinium 450k Human DNA methylation Beadchip Bisulphite converted DNA from the 16 samples were hybridized to the Illumina Infinium 450k Human Methylation Beadchip
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Project description:High-grade serous ovarian cancer (HGSC) has a disproportionate impact on cancer-related mortality in women. There is an urgent need to improve treatment options for HGSC. This includes better selection of patients who will benefit from existing treatments, including HRD targeted therapy, and discovery of new targeted therapeutic options. Reliable tissue-based biomarkers that can guide treatment selection are key to progress in this area. A challenge for their definition is the large volume of disease that is characteristically present at HGSC diagnosis and that can show considerable heterogeneity within and between anatomical sites. In order to address this issue, we carried out a detailed study of the HGSC proteome in eleven individuals by comparing genomic and gene-expression features with multiple independent proteomic results derived from fresh frozen (FF) and formalin fixed paraffin embedded (FFPE) samples from both ovary and a common metastatic site, omentum. Our findings gave emphasis to the influence of sample site of origin on biomarker expression, and revealed opportunities to detect mechanisms shaping the HGSC tumour immune microenvironment from tissue proteomics. The dataset also forms a useful resource to investigate molecular heterogeneity in HGSC.
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Project description:Intra-individual tumoral heterogeneity (ITH) is a hallmark of solid tumors and impedes accurate genomic diagnosis and selection of proper therapy. The purpose of this study was to identify ITH of ovarian serous adenocarcinomas (OSAs) and to determine the utility of ascitic cancer cells as a resource for mutation profiling in spite of ITH. We performed whole-exome sequencing, copy number profiling, and DNA methylation profiling of four OSA genomes using multiregional biopsies from 13 intraovarian lesions, 12 extraovarian tumor lesions (omentum/peritoneum), and ascitic cells. We observed substantial levels of heterogeneity in mutations and copy number alterations (CNAs) of the OSAs. We categorized the mutations into 'common', 'shared' and 'private' according to the regional distribution. Six common, 8 shared, and 24 private mutations were observed in known cancer-related genes,. but common mutations had a higher mutant allele frequency and included TP53 mutations in all four OSAs. Region-specific chromosomal amplifications and deletions involving BRCA1, PIK3CA, and RB1 were also identified. Of note, the mutations detected in ascitic cancer cells represented 92.3-100% of overall somatic mutations in the given case. Phylogenetic analyses of ascitic genomes predicted a polyseeding origin of somatic mutations in ascitic cells. Our results demonstrate that despite ITH, somatic mutations, CNAs, and DNA methylations in both “common” category and cancer-related genes were highly conserved in ascitic cells of OSAs, highlighting the clinical relevance of genome analysis of ascitic cells. Ascitic tumor cells may serve as a potential resource to discover somatic mutations of primary OSA with diagnostic and therapeutic relevance.
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Project description:Glioblastoma (GBM) is an aggressive form of brain cancer with well-established patterns of intra-tumoral heterogeneity implicated in treatment resistance, recurrence and progression. While regional and single cell transcriptomic variations of GBM have been recently resolved, downstream phenotype-level proteomic programs have yet to be assigned to specific niches. Here, we leverage mass spectrometry to spatially align abundance levels of 4,794 proteins to GBM’s hallmark histomorphologic niches across 20 patients and define distinct molecular programs operational within these regional tumor compartments. Using machine learning, we overlay concordant transcriptional information, and define two distinct proteogenomic programs, MYC- and KRAS-axis hereon, that cooperate with hypoxia to produce a tri-dimensional model of intra-tumoral heterogeneity. Importantly, we show using multiple cohorts, that GBMs with an enhanced KRAS component harbor a more clinically aggressive and infiltrative phenotype. Conversely, tumor cells enriched along the MYC axis where mutually exclusive and had a distinct proliferative program. Moreover, by applying both experimental and computational approaches to link each of these distinct molecular axes with potential pharmacological therapies, we highlight differential drug sensitivities and a notable relative chemoresistance in GBM cell lines with enhanced KRAS programs. Importantly, pharmacological differences were less evident when using traditional expression-based subgroups supporting thattopographic phenotypic mapping ofGBM, and the proposed axes may provide new insights for targeting heterogeneity and overcoming therapy resistance in this aggressive disease.
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Project description:Intra-individual tumoral heterogeneity (ITH) is a hallmark of solid tumors and impedes accurate genomic diagnosis and selection of proper therapy. The purpose of this study was to identify ITH of ovarian serous adenocarcinomas (OSAs) and to determine the utility of ascitic cancer cells as a resource for mutation profiling in spite of ITH. We performed whole-exome sequencing, copy number profiling, and DNA methylation profiling of four OSA genomes using multiregional biopsies from 13 intraovarian lesions, 12 extraovarian tumor lesions (omentum/peritoneum), and ascitic cells. We observed substantial levels of heterogeneity in mutations and copy number alterations (CNAs) of the OSAs. We categorized the mutations into 'common', 'shared' and 'private' according to the regional distribution. Six common, 8 shared, and 24 private mutations were observed in known cancer-related genes,. but common mutations had a higher mutant allele frequency and included TP53 mutations in all four OSAs. Region-specific chromosomal amplifications and deletions involving BRCA1, PIK3CA, and RB1 were also identified. Of note, the mutations detected in ascitic cancer cells represented 92.3-100% of overall somatic mutations in the given case. Phylogenetic analyses of ascitic genomes predicted a polyseeding origin of somatic mutations in ascitic cells. Our results demonstrate that despite ITH, somatic mutations, CNAs, and DNA methylations in both âcommonâ category and cancer-related genes were highly conserved in ascitic cells of OSAs, highlighting the clinical relevance of genome analysis of ascitic cells. Ascitic tumor cells may serve as a potential resource to discover somatic mutations of primary OSA with diagnostic and therapeutic relevance. The purpose of this study was to identify intra-individual tumor heterogenety of ovarian serous adenocarcinomas Four to nine different ovarian cancer areas from intraovarian and extra-ovarian lesions that were at least 1cm apart as well as 50 ml ascites were collected from the four OSA patients. Genomic DNA from tumor and matched normal samples were simultaneously hybridized onto the array. Total 29 array experiments were conducted.
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