Dataset Information

18F-fluorodeoxy-glucose positron emission tomography marks MYC-overexpressing human basal-like breast cancers.

ABSTRACT: In contrast to normal cells, cancer cells avidly take up glucose and metabolize it to lactate even when oxygen is abundant, a phenomenon referred to as the Warburg effect. This fundamental alteration in glucose metabolism in cancer cells enables their specific detection by positron emission tomography (PET) following i.v. injection of the glucose analogue (18)F-fluorodeoxy-glucose ((18)FDG). However, this useful imaging technique is limited by the fact that not all cancers avidly take up FDG. To identify molecular determinants of (18)FDG retention, we interrogated the transcriptomes of human-cancer cell lines and primary tumors for metabolic pathways associated with (18)FDG radiotracer uptake. From ninety-five metabolic pathways that were interrogated, the glycolysis, and several glycolysis-related pathways (pentose phosphate, carbon fixation, aminoacyl-tRNA biosynthesis, one-carbon-pool by folate) showed the greatest transcriptional enrichment. This "FDG signature" predicted FDG uptake in breast cancer cell lines and overlapped with established gene expression signatures for the "basal-like" breast cancer subtype and MYC-induced tumorigenesis in mice. Human breast cancers with nuclear MYC staining and high RNA expression of MYC target genes showed high (18)FDG-PET uptake (P < 0.005). Presence of the FDG signature was similarly associated with MYC gene copy gain, increased MYC transcript levels, and elevated expression of metabolic MYC target genes in a human breast cancer genomic dataset. Together, our findings link clinical observations of glucose uptake with a pathologic and molecular subtype of human breast cancer. Furthermore, they suggest related approaches to derive molecular determinants of radiotracer retention for other PET-imaging probes.

SUBMITTER: Palaskas N

PROVIDER: S-EPMC3148325 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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18F-fluorodeoxy-glucose positron emission tomography marks MYC-overexpressing human basal-like breast cancers.

Palaskas Nicolaos N Larson Steven M SM Schultz Nikolaus N Komisopoulou Evangelia E Wong Justin J Rohle Dan D Campos Carl C Yannuzzi Nicolas N Osborne Joseph R JR Linkov Irina I Kastenhuber Edward R ER Taschereau Richard R Plaisier Seema B SB Tran Chris C Heguy Adriana A Wu Hong H Sander Chris C Phelps Michael E ME Brennan Cameron C Port Elisa E Huse Jason T JT Graeber Thomas G TG Mellinghoff Ingo K IK

Cancer research 20110606 15

In contrast to normal cells, cancer cells avidly take up glucose and metabolize it to lactate even when oxygen is abundant, a phenomenon referred to as the Warburg effect. This fundamental alteration in glucose metabolism in cancer cells enables their specific detection by positron emission tomography (PET) following i.v. injection of the glucose analogue (18)F-fluorodeoxy-glucose ((18)FDG). However, this useful imaging technique is limited by the fact that not all cancers avidly take up FDG. To ...[more]

PMID: 21646475

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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:Background and objectiveNumerous previous studies have assessed the prognostic role of 18F-fluorodeoxyglucose positron-emission tomography (18F FDG PET) in patients with biliary tract cancer (BTC), but those results were inconsistent. The present study aims to determine the predictive value of 18F FDG PET in BTC patients via a meta-analysis.MethodsThe underlying studies related to 18F FDG PET and BTC patients` outcomes were searched and identified in the online databases. The interested parameters include total lesion glycolysis (TLG), metabolic tumor volume (MTV), primary tumor and metastatic lymph node (LN) maximum standardized uptake value (SUVmax), as well as change of SUVmax (ΔSUVmax) during treatment. Overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS) were considered as the primary endpoints. Hazard ratio (HR) and corresponding 95% confidence intervals (CIs) were defined as the effective measure and calculated by a pooled analysis. Publication bias was assessed by funnel plot, Bagg's and Egger's tests.ResultsTotally, 23 studies involving 1478 patients were included in the present meta-analysis. After a pooled analysis, it revealed that a high SUVmax was significantly associated with a poor OS (HR:2.07, 95%CI: 1.74-2.46, P = 0.000) and DFS (HR: 2.28, 95%CI: 1.53-3.41, P = 0.000). In addition, an increased TLG level contributed to a shorter OS (HR:1.91, 95%CI: 1.26-2.90, P = 0.002) and DFS (HR: 4.34, 95%CI: 1.42-13.27, P = 0.01). Moreover, we confirmed that an elevated MTV was significantly associated with increased mortality (HR:2.04, 95%CI:1.26-3.31, P = 0.004) and disease relapse (HR: 3.88, 95%CI:1.25-12.09, P = 0.019) risks. Besides, the present study uncovered that increased ΔSUVmax could predict poor OS (HR:1.26, 95%CI:1.06-1.50, P = 0.008) instead of PFS (HR: 1.96, 95%CI: 0.82-4.72, P = 0.280). Lastly, we found that LN SUVmax did not link to OS (HR: 1.49, 95%CI: 0.83-2.68, P = 0.178). No obvious publication bias was detected in the present study.Conclusion18F FDG PET parameters, including SUVmax, TLG, MTV, and ΔSUVmax, could be applied as convenient and reliable factors for predicting BTC patients` outcomes.

Dataset Information

18F-fluorodeoxy-glucose positron emission tomography marks MYC-overexpressing human basal-like breast cancers.

Publications

18F-fluorodeoxy-glucose positron emission tomography marks MYC-overexpressing human basal-like breast cancers.

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