Abstract
The standardized uptake value (SUV), an indicator of the degree of glucose uptake in 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), has been used for predicting the clinical behavior of malignant tumors. However, its characteristics have been insufficiently explored at the genomics level. Here, we aim to identify genomic signatures reflecting prognostic SUV characteristics in breast cancer (BRC). Through integrative genomic profiling of 3710 BRC patients, including 254 patients who underwent preoperative FDG-PET, we identified an SUV signature, which showed independent clinical utility for predicting BRC prognosis (hazard ratio [HR] 1.27, 95% confidence interval [CI] = 1.12 to 1.45, p = 2.23 × 10−4). The risk subgroups classified by the signature exhibited mutually exclusive mutation patterns of TP53 and PIK3CA and showed significantly different responsiveness to immunotherapy. Experimental assays revealed that a signaling axis defined by TP53–FOXM1 and its downstream effectors in glycolysis–gluconeogenesis, including LDHA, might be important mediators in the FDG-PET process. Our molecular characterizations support an understanding of glucose metabolism and poor prognosis in BRC with a high SUV, utilizable in clinical practice to assist other diagnostic tools.
Highlights
18 F-fluorodexoyglucose positron emission tomography (FDG-PET) is utilized for predicting tumor behavior molecularly and clinically, because this imaging modality accurately reflects tumor biology [1,2,3,4]
Hierarchical clustering analysis with 1424 genes divided the breast cancer (BRC) patients into two subgroups according to the standardized uptake value (SUV): an SUV-high cluster (SHC) and an SUV-low cluster (SLC) (Figure S1A)
When comparing sample clusters divided by SUV-correlated genes and subgroups dichotomized by an SUV cut-off (SUV of ≤ 4 or > 4), as used in our previous studies [1,4], we observed that two criteria demonstrated significantly similar BRC patient classifications (Fisher’s exact test; p = 1.71 × 10−4 ; Figure S1A)
Summary
18 F-fluorodexoyglucose positron emission tomography (FDG-PET) is utilized for predicting tumor behavior molecularly and clinically, because this imaging modality accurately reflects tumor biology [1,2,3,4]. In breast cancer (BRC), numerous investigations have shown the contribution of tumor biology to increased glucose uptake in FDG-PET [5,6] and have demonstrated that the degree of glucose uptake is associated with aggressive tumor characteristics [7,8]. Cancers 2020, 12, 497 which represents the degree of glucose uptake in FDG-PET, has been recognized as a prognostic and predictive factor. Previous investigations showed a significant association between the SUV and prognostic indicators such as estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER2), or histologic grade in BRC [1,4,5,10,11], indicating a close relationship between tumor aggressiveness and FDG-PET.
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