Sex Differences in Colon Cancer Metabolism Reveal A Novel Subphenotype

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, nutrientdeplete metabolic subphenotype in women with RCC, with implications for tumor progression and outcomes in CRC patients. 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. In 2019, there will be an estimated 145,600 new cases and 51,020 deaths attributed to the disease 2. Cancers of the colorectum can be categorized by anatomic location. Right-sided colon cancers (RCCs) occur in the cecum, ascending colon and hepatic flexure, and left-sided colon cancers (LCCs) occur in the splenic flexure, descending, sigmoid and rectosigmoid colon. Mid and lower rectal cancers are sometimes grouped as LCCs 3. 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 4-6. This suggests that differences exist in the underlying tumor biology based on anatomic location. Distinguishing molecular features of RCCs include high microsatellite instability (MSI-H), valine to glutamate BRAF mutations at codon 600, cytosine-guanosine (CpG) island methylation phenotype (CIMP) 7,8 , and diploid cells 9. In contradistinction, patients with LCCs more frequently have chromosomal instability, mutations in the TP53 and APC genes, and aneuploidy 10. Recently, expression arrays have revealed four molecular subtypes of CRCs, called "consensus molecular subtypes" which tend to occur more frequently in either the right-or left-sides of the colon. Consensus molecular subtype 1, for example, has a 77% frequency in RCCs and is enriched for high MSI, CIMP, and BRAF mutations. In addition, gene set enrichment analysis shows molecular pathways related to immune infiltration and PD-1 activation for this subtype 10,11. In addition to genetic variance in colorectal subsites, RCCs ...

The Importance of Sex in the Discovery of Colorectal Cancer Prognostic Biomarkers

“…However, very few studies consider sex differences in the analysis of tumors and biomarkers. Recently, Cai et al demonstrated that there are sex-specific metabolic sub-phenotypes dependent on tumor location [ 20 ]. However, no studies have evaluated sex-specific CRC biomarkers at a large scale.…”

Future Prospects of Colorectal Cancer Screening: Characterizing Interval Cancers

“…By contrast, previous studies have suggested that right-sided CRCs occur more frequently in women [ 52 , 53 , 54 ]. Hormonal factors and genetic changes [ 55 , 56 , 57 ], such as sporadic microsatellite instability that occurs with ageing [ 58 , 59 ], may contribute to a higher prevalence of right-sided CRC. Finally, these sex differences in sensitivity could also be explained by the slower colonic transit time in women [ 60 , 61 , 62 ].…”

The metabolome and lipidome of colorectal adenomas and cancers

“…Most of the previously published studies were undertaken to identify diagnostic CRC biomarkers in body fluids (e.g., plasma, serum, stool, or urine), and 42 of these were included in the systematic review and meta-analysis recently conducted by Tian J. et al 33 . A smaller, but still impressive, number of studies have been focused on levels of compounds in colorectal tissues 34–63 . Somewhat surprisingly, there is substantial overlap between the temporal distributions of the two study types in the literature published over the past 15 years.…”