Dataset Information

Microvesicle Proteomic profiling of Uterine Liquid Biopsy for Ovarian Cancer Early Detection

ABSTRACT: High-grade ovarian cancer (HGOC) is the leading cause of mortality from gynecological malignancies, due to diagnosis at a metastatic stage. Current screening options fail to improve mortality due to the absence of early-stage-specific biomarkers. We postulated that a liquid biopsy, such as utero-tubal lavage (UtL), may identify localized lesions better than systemic approaches of serum/plasma analysis. Furthermore, while mutation-based assays are challenged by the rarity of tumor DNA within non-mutated DNA, analyzing the proteomic profile, is expected to enable earlier detection, as it reveals perturbations in both the tumor as well as in its microenvironment. To attain deep proteomic coverage and overcome the high dynamic range of this body fluid, we applied our method for microvesicle proteomics to the UtL samples. Liquid biopsies from HGOC patients (n=49), controls (n=127) and healthy BRCA mutation carriers (n=25), were divided into a discovery and validation sets. Data-dependent analysis of the samples on the Q-Exactive mass spectrometer provided depth of 8,578 UtL proteins in total, and on average ~3,000 proteins per sample. We used support vector machine algorithms for sample classification, and crossed three feature-selection algorithms, to construct and validate a 9-protein classifier with 70% sensitivity and 76.2% specificity. The signature correctly identified all Stage I lesions and highlighted increased risk in healthy BRCA carriers. These results demonstrate the potential power of microvesicle-based proteomic biomarkers for early cancer diagnosis.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Malignant Neoplasm Of Ovary

SUBMITTER: Tamar Geiger

LAB HEAD: Tamar Geiger

PROVIDER: PXD009655 | Pride | 2019-02-16

REPOSITORIES: Pride

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Publications

Microvesicle Proteomic Profiling of Uterine Liquid Biopsy for Ovarian Cancer Early Detection.

Barnabas Georgina D GD Bahar-Shany Keren K Sapoznik Stav S Helpman Limor L Kadan Yfat Y Beiner Mario M Weitzner Omer O Arbib Nissim N Korach Jacob J Perri Tamar T Katz Guy G Blecher Anna A Brandt Benny B Friedman Eitan E Stockheim David D Jakobson-Setton Ariella A Eitan Ram R Armon Shunit S Brand Hadar H Zadok Oranit O Aviel-Ronen Sarit S Harel Michal M Geiger Tamar T Levanon Keren K

Molecular & cellular proteomics : MCP 20190213 5

High-grade ovarian cancer (HGOC) is the leading cause of mortality from gynecological malignancies, because of diagnosis at a metastatic stage. Current screening options fail to improve mortality because of the absence of early-stage-specific biomarkers. We postulated that a liquid biopsy, such as utero-tubal lavage (UtL), may identify localized lesions better than systemic approaches of serum/plasma analysis. Further, while mutation-based assays are challenged by the rarity of tumor DNA within ...[more]

PMID: 30760538

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Project description:The development of non-invasive primary cancer preventive measures in humans require a thorough understanding of the initial cancer-driving molecular mechanisms. High grade serous extra-uterine M llerian cancers (HGSEMC; formerly classified as ovarian/tubal/peritoneal cancer) present at a very late stage and less than 40% of women survive 5 years. Although the recent TCGA initiatives revealed key molecular changes in established cancers, very little is known about the initial molecular alterations in cancer development. Analysis of normal tissue at extensively high risk prior to the development of any microscopic alterations is critical. BRCA1/2 mutation carriers have an up to 30 40 fold increased risk to develop ovarian cancer, preferentially HGSEMC. Despite a plethora of evidence linking mutations in BRCA1 or BRCA2 to cancer development the core components such as organ specificity (i.e. to breast and Fallopian Tube) are still missing. The Fallopian Tube of BRCA mutation carriers offers a unique opportunity to study carcinogenesis because these cancers originate only from the distal (i.e. fimbrial) end of the Fallopian Tube (which is in close proximity to the ovary), and not from the proximal end (which is close to the uterus). The ovary which is in extreme close proximity to the fimbriae provides an excellent soil for cancer cells which are likely shed from the fimbriae and once the cancer has been discovered the big bulk of tumour is usually present on the ovary and hence the majority of HGSEMC are also referred to as ovarian cancer . To study the earliest steps of human carcinogenesis we performed epigenome-wide DNA methylation (DNAme) analyses (using the Illumina 450k DNA methylation bead-array assay assessing DNAme at ~480 000 CpG sites) in 215 microscopic normal Fallopian Tube samples of BRCA1/2 mutation carriers (n=56) and controls (n=59) who had their tubes/ovaries removed for prophylactic or other reasons, respectively (for 52 and 49 individuals respectively we analysed both fimbrial and proximal Fallopian Tubes). In order to adjust for any epigenetic effects which are not of immediate importance to the carcinogenic process, for each volunteer we analysed both the fimbrial (at risk) and the proximal (non at risk) portion of the tubes separately. Formalin fixed paraffin embedded (FFPE) tissue blocks were retrieved from UCL Biobank (NC09.13). Histopathological features of fimbrial and proximal section of Fallopian Tube from BRCA carriers and control cases were carefully examined. Cases negative for serous tubal intraepithelial carcinoma (STIC) lesions were chosen for DNA isolation to characterize pre-cancer epigenetic changes. For DNA isolation, a core of 3 x 0.6 mm was taken from each block representing fimbrial and proximal end of fallopian tubes from both BRCA carriers and matched control cases. The DNA was isolated using QIAamp(r) DNA FFPE Tissue Kit as per manufacturer's protocol with minor modifications (Dewaxing for 4 hours in xylene and proteinase digestion performed overnight, other procedures were as per the instructions). DNA was quantified using Nandrop and restored using the Infinium FFPE DNA Restore Kit and then 200 nanogram of DNA was bisulfite converted using the EZ DNA Methylation-Gold(tm) and subjected to methylation analysis on the Illumina Infinium Human Methylation450 BeadChip.

Dataset Information

Microvesicle Proteomic profiling of Uterine Liquid Biopsy for Ovarian Cancer Early Detection

Publications

Microvesicle Proteomic Profiling of Uterine Liquid Biopsy for Ovarian Cancer Early Detection.

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