Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA.
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.
Sci Rep. 2020 Mar 17;10(1):4905. doi: 10.1038/s41598-020-61851-0.
Women have a lower incidence of colorectal cancer (CRC) than men, however, they have a higher incidence of right-sided colon cancer (RCC). This is of concern as patients with RCC have the poorest clinical outcomes among all CRC patients. Aberrant metabolism is a known hallmark and therapeutic target for cancer. We propose that metabolic subphenotypes exist between CRCs due to intertumoral molecular and genomic variation, and differences in environmental milieu of the colon which vary between the sexes. Metabolomics analysis of patient colon tumors (n = 197) and normal tissues (n = 39) revealed sex-specific metabolic subphenotypes dependent on anatomic location. Tumors from women with RCC were nutrient-deplete, showing enhanced energy production to fuel asparagine synthesis and amino acid uptake. The clinical importance of our findings were further investigated in an independent data set from The Cancer Genomic Atlas, and demonstrated that high asparagine synthetase (ASNS) expression correlated with poorer survival for women. This is the first study to show a unique, nutrient-deplete metabolic subphenotype in women with RCC, with implications for tumor progression and outcomes in CRC patients.
女性的结直肠癌（CRC）发病率低于男性，但她们右侧结肠癌（RCC）的发病率较高。这令人担忧，因为 RCC 患者的临床预后在所有 CRC 患者中最差。代谢异常是癌症的一个已知特征和治疗靶点。我们假设由于肿瘤间的分子和基因组变异以及男女之间结肠环境的差异，CRC 之间存在代谢亚表型。对 197 名患者结肠癌肿瘤（n=197）和正常组织（n=39）的代谢组学分析显示，依赖于解剖位置存在性别特异性的代谢亚表型。女性 RCC 患者的肿瘤营养匮乏，表现出增强的能量产生以提供天冬酰胺合成和氨基酸摄取的燃料。我们的研究结果在癌症基因组图谱（The Cancer Genomic Atlas）的独立数据集进一步进行了临床重要性研究，表明高天冬酰胺合成酶（ASNS）表达与女性患者的生存率较差相关。这是第一项显示女性 RCC 中存在独特的、营养匮乏的代谢亚表型的研究，对 CRC 患者的肿瘤进展和结局具有重要意义。
