Project description: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. UPLC-MS HILIC POS assay is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS1122' rel='noopener noreferrer' target='_blank'>MTBLS1122</a>.UPLC-MS HILIC NEG assay is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS1124' rel='noopener noreferrer' target='_blank'>MTBLS1124</a>.UPLC-MS RP POS assay is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS1129' rel='noopener noreferrer' target='_blank'>MTBLS1129</a>.UPLC-MS RP NEG assay is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS1130' rel='noopener noreferrer' target='_blank'>MTBLS1130</a>.

Project description:Understanding sex differences in colon cancer is essential to advance disease prevention, diagnosis, and treatment. Males have a higher risk of developing colon cancer and a lower survival rate than women. However, the molecular features that drive these sex differences are poorly understood. In this study, we use both transcript-based and gene regulatory network methods to analyze RNA-seq data from The Cancer Genome Atlas for 445 patients with colon cancer. We compared gene expression between tumors in men and women and observed significant sex differences in sex chromosome genes only. We then inferred patient-specific gene regulatory networks and found significant regulatory differences between males and females, with drug and xenobiotics metabolism via cytochrome P450 pathways more strongly targeted in females. This finding was validated in a dataset of 1,193 patients from five independent studies. While targeting, the drug metabolism pathway did not change overall survival for males treated with adjuvant chemotherapy, females with greater targeting showed an increase in 10-year overall survival probability, 89% [95% confidence interval (CI), 78-100] survival compared with 61% (95% CI, 45-82) for women with lower targeting, respectively (P = 0.034). Our network analysis uncovers patterns of transcriptional regulation that differentiate male and female colon cancer and identifies differences in regulatory processes involving the drug metabolism pathway associated with survival in women who receive adjuvant chemotherapy. This approach can be used to investigate the molecular features that drive sex differences in other cancers and complex diseases.Significance: A network-based approach reveals that sex-specific patterns of gene targeting by transcriptional regulators are associated with survival outcome in colon cancer. This approach can be used to understand how sex influences progression and response to therapies in other cancers. Cancer Res; 78(19); 5538-47. ©2018 AACR.

Dataset Information

Sex Differences in Colon Cancer Metabolism Reveal A Novel Subphenotype.

Publications

Sex Differences in Colon Cancer Metabolism Reveal A Novel Subphenotype.

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