Sex Differences in Colon Cancer Metabolism Reveal A Novel Subphenotype

Yuping Cai,Kuo-Shun Hsu,Philip B Paty,Zahra Rattray,Caroline H Johnson,Alvaro Santos-Neto,Justin R Cross,Yawei Zhang,Varvara Mironova,Qian Zhang,Nicholas J W Rattray,Sajid A Khan

doi:10.1038/s41598-020-61851-0

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.

Highlights

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the United States, and the second leading cause of cancer-related deaths for cancers that affect both men and women[1]
Women have a much lower overall incidence of colorectal cancer (CRC), yet they are more frequently diagnosed with right-sided colon cancer (RCC), it is highly plausible that RCCs have a unique biology in women shaped by differences in life-course exposures which promotes their growth in this location and affects therapeutic response
When comparing normal colon tissues to tumors stratified by sex, the 82 metabolites that were altered in tumor tissues were represented in the following pathways: glycolysis, pentose phosphate pathway (PPP), amino acid metabolism, nucleotide metabolism, methionine metabolism, and lysophospholipid synthesis

Summary

Introduction

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the United States, and the second leading cause of cancer-related deaths for cancers that affect both men and women[1]. Tumors in different anatomic locations have differing clinical outcomes, and recent epidemiologic studies have shown that patients with RCC have the poorest survival, even when adjusted for confounding factors, including clinical stage[4,5,6]. There have been no studies investigating sex-associated differences in colon cancer metabolism It is not known if men and women have metabolic phenotypes specific to the anatomic location of the colon tumor. We correlated our findings to clinical outcomes of patients with colon cancer using The Cancer Genome Atlas (TCGA) database, and identified a positive association of high asparagine synthesis and poorer survival in women with colon cancer To our knowledge, this is the first high-throughput metabolomic study to identify sex differences in colon cancer metabolism. We have revealed novel insights into the biological differences in tumor metabolism within population groups, and identified asparagine metabolism as potential future therapeutic target for women with RCC

Methods

Results

Conclusion