Department of Urology, Massachusetts General Hospital, Boston, MA; Division of Urology, Department of Surgery, Western University, London, Ontario, Canada.
Department of Urology, Massachusetts General Hospital, Boston, MA.
Urol Oncol. 2023 Nov;41(11):459.e9-459.e16. doi: 10.1016/j.urolonc.2023.09.005. Epub 2023 Oct 19.
Renal cell carcinoma (RCC) is a metabolic disease, with subtypes exhibiting aberrations in different metabolic pathways. Metabolomics may offer greater sensitivity for revealing disease biology. We investigated the metabolomic profile of RCC using high-resolution magic angle spinning (HRMAS) proton magnetic resonance spectroscopy (HMRS).
Surgical tissue samples were obtained from our frozen tissue bank, collected from radical or partial nephrectomy. Specimens were fresh-frozen, then stored at -80 °C until analysis. Tissue HRMAS-HMRS was performed. A MatLab-based curve fitting program was used to process the spectra to produce relative intensities for 59 spectral regions of interest (ROIs). Comparisons of the metabolomic profiles of various RCC histologies and benign tumors, angiomyolipoma, and oncocytoma, were performed. False discovery rates (FDR) were used from the response screening to account for multiple testing; ROIs with FDR p < 0.05 were considered potential predictors of RCC. Wilcoxon rank sum test was used to compare median HMRS relative intensities for those metabolites that may differentiate between RCC and benign tumor. Logistic regression determined odds ratios for risk of malignancy based on the abundance of each metabolite.
Thirty-eight RCC (16 clear cell, 11 papillary, 11 chromophobe), 10 oncocytomas, 7 angiomyolipomas, and 13 adjacent normal tissue specimens (matched pairs) were analyzed. Candidate metabolites for predictors of malignancy based on FDR p-values include histidine, phenylalanine, phosphocholine, serine, phosphocreatine, creatine, glycerophosphocholine, valine, glycine, myo-inositol, scyllo-inositol, taurine, glutamine, spermine, acetoacetate, and lactate. Higher levels of spermine, histidine, and phenylalanine at 3.15 to 3.13 parts per million (ppm) were associated with decreased risk of RCC (OR 4 × 10, 95% CI 7.42 × 10, 0.02), while 2.84 to 2.82 ppm increased the risk of malignant pathology (OR 7158.67, 95% CI 6.3, 8.3 × 10). The specific metabolites characterizing this region remain to be identified. Tumor stage did not affect metabolomic profile of malignant tumors, suggesting that metabolites are dependent on histologic subtype.
HRMAS-HMRS identified metabolites that may predict RCC. We demonstrated that those in the 3.14 to 3.13 ppm ROI were present in lower levels in RCC, while higher levels of metabolites in the 2.84 to 2.82 ppm ROI were associated with substantially increased risk of RCC. Further research in a larger population is required to validate these findings.
肾细胞癌（RCC）是一种代谢疾病，其亚型表现出不同代谢途径的异常。代谢组学可能提供更高的灵敏度来揭示疾病生物学。我们使用高分辨率魔角旋转（HRMAS）质子磁共振波谱（HMRS）研究了 RCC 的代谢组学特征。
从我们的冷冻组织库中获取手术组织样本，取自根治性或部分肾切除术。标本新鲜冷冻，然后储存在-80°C 直到分析。进行组织 HRMAS-HMRS。使用基于 MatLab 的曲线拟合程序处理光谱，以产生 59 个感兴趣的光谱区域（ROI）的相对强度。比较各种 RCC 组织学和良性肿瘤、血管平滑肌脂肪瘤和嗜酸细胞瘤的代谢组学特征。使用错误发现率（FDR）从响应筛选中进行，以考虑多次测试；FDR p 值<0.05 的 ROI 被认为是 RCC 的潜在预测因子。Wilcoxon 秩和检验用于比较可能区分 RCC 和良性肿瘤的代谢物的 HMRS 相对强度中位数。基于每种代谢物的丰度，逻辑回归确定恶性肿瘤风险的优势比。
分析了 38 个 RCC（16 个透明细胞癌、11 个乳头状癌、11 个嫌色细胞癌）、10 个嗜酸细胞瘤、7 个血管平滑肌脂肪瘤和 13 个相邻正常组织标本（配对）。基于 FDR p 值的恶性肿瘤预测候选代谢物包括组氨酸、苯丙氨酸、磷酸胆碱、丝氨酸、磷酸肌酸、肌酸、甘油磷酸胆碱、缬氨酸、甘氨酸、肌醇、scyllo-肌醇、牛磺酸、谷氨酰胺、精胺、乙酰乙酸盐和乳酸。在 3.15 至 3.13 ppm 处，精胺、组氨酸和苯丙氨酸水平较高与 RCC 风险降低相关（OR 4×10，95%CI 7.42×10，0.02），而 2.84 至 2.82 ppm 处增加了恶性病理的风险（OR 7158.67，95%CI 6.3，8.3×10）。表征该区域的特定代谢物仍有待确定。肿瘤分期不影响恶性肿瘤的代谢组学特征，这表明代谢物依赖于组织学亚型。
HRMAS-HMRS 鉴定出可能预测 RCC 的代谢物。我们证明，3.14 至 3.13 ppm ROI 中的代谢物水平较低，而 2.84 至 2.82 ppm ROI 中的代谢物水平较高与 RCC 的风险显著增加相关。需要在更大的人群中进行进一步的研究来验证这些发现。
