Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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ABSTRACT: We hypothesised that in esophagogastric junction adenocarcinomas combining molecular predictive biomarkers with FDG-PET would optimise response prediction. Changes in FDG uptake in tumours meaured by PET scans after 14 days of chemotherapy define metabolic responders and non-responders. However while <5% of metabolic non-responders will go onto have a response to the full 9-12 week chemotherapy protocol providing a high negative predictive value for FDG-PET, the positive predictive value of metabolic response is more limited. Only 50% of those patients that have a metabolic response determined by FDG PET at day 14 will go on to subsequently have a response to the full 9-12 week chemotherapy protocol . We used global gene expression profiling to identify molecular biomarkers that when combined with FDG-PET would improve predictive accuracy, in particular we aimed to identify molecular biomarkers that could sub-classify FDG PET defined metabolic responders into those that did and did not subsequently go on to have a radiological response and hence clinical benefit from the full chemotherapy protocol. Patients with stage IB-IV esophagogastric junction adenocarcinomas(n=28) received platinum combination chemotherapy .FDG-PET CT scans were performed at baseline and day 14 and expression profiling (Affymetrix ST1.0 Exon Genechips) on baseline tumour biopsies. 14 patients were classified as FDG-PET metabolic responders and gene expression was analysed in these tumour specimens to determine differences between those that did subsequently go on to have a radiological response (n=10) or did not have a radiological response (n=4) to the full 9-12 week chemotherapy protocol. A tissue microarray(n=154 esophagogastric adenocarcinomas who underwent surgery+/-neoadjuvant chemotherapy)was used with immunohistochemistry for qualification of gene expression profiling results. Radiological response was assessed after 3or4 cycles of chemotherapy by RECISTv1.1.

ORGANISM(S): Homo sapiens

SUBMITTER: Russell Petty

PROVIDER: E-MEXP-3730 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Fluorine-18-fluoro-2-deoxy-D-glucose (FDG) is widely used as positron-emission-tomography (PET) radiotracer for the detection and staging of human cancer. Tumor uptake of FDG varies substantially between different cancer types and between patients with the same tumor type. The molecular basis for this heterogeneity is unknown. Using cancer cell lines and primary human tumors of distinct histologic origins, we here show that increased FDG uptake is universally associated with coordinate upregulation of genes within the glycolysis, pentose-phosphate, and other related metabolic pathways. In primary human breast cancers, this FDG signature shows significant overlap with established breast cancer signatures for the “basal-like” disease subtype and “poor prognosis”. FDG high breast cancer showed significantly more gene copy number alterations genome wide than FDG low cancers. About 50 % of primary breast cancers with high FDG uptake and FDG gene expression signature show DNA copy gain encompassing the c-myc gene locus and express gene sets regulated by the transcription factor MYC. Our data shows that FDG-PET marks a distinct subset of “basal-like” human breast cancer which is characterized by MYC and prognostically unfavorable gene expression signatures, suggesting that FDG-PET imaging may be useful to risk-stratify patients with locally advanced breast cancer. Our general strategy to identify molecular determinants of FDG-retention through a genome-wide approach consisted of FDG uptake measurements in cancer cell lines and primary human tumors, the selection of samples with particularly high versus low FDG-retention, and subsequent pathway-based analysis of RNA expression data collected from these samples. Cell line RNA was extracted from a 10 cm plate seeded simultaneously and at the same density as the wells for FDG-uptake assays. For primary human tumor samples, RNA was extracted from macrodissected frozen tumor tissue. All cell line RNA samples and the astrocytoma RNA aliquots were hybridized to Affymetrix U133 Plus 2.0 arrays. All primary breast cancer RNA samples were hybridized to Affymetrix U133A arrays.

Project description:Using Human WG CodeLink microarrays, we established the expression profiling of 26 LARC without metastasis to gain insight into the molecular signatures associated with response to treatment after CRT. The study initially included a total of 35 consecutive patients with locally advanced rectal cancer (LARC) treated at Virgen de las Nieves Hospital from 2008 until 2010. Written informed consent was obtained from all the patients, and the study protocol was approved by the local Clinical Research (Ethics) Committee. They were distributed in two subgroups following a histological classification of response to treatment. Pretherapeutic staging was performed, including complete medical history and physical evaluation, digital rectal examination, endorectal ultrasound, rigid rectoscopy, colonoscopy, PET/TC and chest x-ray. Tumor samples were prospectively obtained during the rectoscopy. All patients subsequently received a total dose of 50.4Gy of radiatio (28 fractions of 1.8Gy) associated with capecitabine or capecitabine and oxaliplatine. Standardized surgery was performed, including total mesorectal excision, after an interval of 8 weeks after chemoradiotherapy. Tumor response was assessed in surgical specimen by semi-quantitative pathological examination (regression grade) including UICC stage. Histopathological tumor regression was graded based on the semiquantitative 5 point tumor regression grading (TRG) system: TRG1 or a TRG2 scores were considered Responders, whereas TRG3, TRG4, and TRG5 scores were classified as Non-Responders. In addition, the tumor regression or radiotherapy effects were assessed by positron emission tomography (18F-FDG PET). Tumor samples of LARC were collected from 35 patients. Nine patients were finally excluded due to the poor quality of the RNA or contradictory results of MandardM-BM-4s criteria and histopathological downstaging, resulting a total of 26 patients. Complete clinical data regarding, age, sex, stage of disease, response to therapy, and overall survival from 26 patients (10 responders and 16 non-responders) was provided in the sample characteristics field. CRT: Chemoradiation; Cap: Capecitabine; Capox: Capecitabine and Oxaliplatine; cTN: clinical stage; Surg: surgical technique; LAR: Low anterior resection; APR: Abdmino-perineal resection; HART: Hartmann, TRG: Tumor Regression Grade; Downst: Downstaging; Downs: downsizing, Resp: response, CPR: complete pathologic response

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