Sex Differences in Colon Cancer Metabolism Reveal A Novel Subphenotype

Yuping Cai, Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA.Follow
Nicholas J. Rattray, Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA.Follow
Qian Zhang, Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA.Follow
Varvara Mironova, Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA.Follow
Alvaro Santos-Neto, Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA.Follow
Kuo-Shun Hsu, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Zahra Rattray, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.Follow
Justin R. Cross, Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.Follow
Yawei Zhang, Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA.Follow
Philip B. Paty, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.Follow
Sajid A. Khan, Department of Surgery, Division of Surgical Oncology, Yale University School of Medicine, New Haven, CT, USA. sajid.khan@yale.edu.Follow
Caroline H. Johnson, Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA. caroline.johnson@yale.edu.Follow

Document Type

Article

Publication Title

Scientific reports

Abstract

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.

First Page

4905

DOI

10.1038/s41598-020-61851-0

Publication Date

3-17-2020

Identifier

32184446 (pubmed); PMC7078199 (pmc); 10.1038/s41598-020-61851-0 (doi); 10.1038/s41598-020-61851-0 (pii)

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