Yuping Cai1,2, Xinyi Shen1, Lingeng Lu3, Hong Yan1, Huang Huang1,4, Patricia Gaule5, Engjel Muca6, Casey M Theriot7, Zahra Rattray8, Nicholas J W Rattray8, Jun Lu9,10, Nita Ahuja5,11, Yawei Zhang1,4, Philip B Paty6, Sajid A Khan12, Caroline H Johnson13. 1. Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, 06510, USA. 2. Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China. 3. Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale University, New Haven, CT, 06510, USA. 4. National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. 5. Department of Pathology, Yale University School of Medicine, New Haven, CT, 06510, USA. 6. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 7. North Caroline State University, Raleigh, NC, USA. 8. Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, G4 0RE, UK. 9. Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, 06520, USA. 10. Department of Genetics, Yale University School of Medicine, New Haven, CT, 06520, USA. 11. Department of Surgery, Division of Surgical Oncology, Yale University School of Medicine, New Haven, CT, 06510, USA. 12. Department of Surgery, Division of Surgical Oncology, Yale University School of Medicine, New Haven, CT, 06510, USA. sajid.khan@yale.edu. 13. Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, 06510, USA. caroline.johnson@yale.edu.
Abstract
BACKGROUND: Bile acids are known to be genotoxic and contribute to colorectal cancer (CRC). However, the link between CRC tumor bile acids to tumor location, patient sex, microbiome, immune-regulatory cells, and prognosis is not clear. METHODS: We conducted bile acid analysis using targeted liquid chromatography-mass spectrometry (LC-MS) on tumor tissues from CRC patients (n = 228) with survival analysis. We performed quantitative immunofluorescence (QIF) on tumors to examine immune cells. RESULTS: Twelve of the bile acids were significantly higher in right-sided colon tumors compared to left-sided colon tumors. Furthermore, in male patients, right-sided colon tumors had elevated secondary bile acids (deoxycholic acid, lithocholic acid, ursodeoxycholic acid) compared to left-sided colon tumors, but this difference between tumors by location was not observed in females. A high ratio of glycoursodeoxycholic to ursodeoxycholic was associated with 5-year overall survival (HR = 3.76, 95% CI = 1.17 to 12.1, P = 0.026), and a high ratio of glycochenodeoxycholic acid to chenodeoxycholic acid was associated with 5-year recurrence-free survival (HR = 3.61, 95% CI = 1.10 to 11.84, P = 0.034). We also show correlation between these bile acids and FoxP3 + T regulatory cells. CONCLUSIONS: This study revealed that the distribution of bile acid abundances in colon cancer patients is tumor location-, age- and sex-specific, and are linked to patient prognosis. This study provides new implications for targeting bile acid metabolism, microbiome, and immune responses for colon cancer patients by taking into account primary tumor location and sex.
BACKGROUND: Bile acids are known to be genotoxic and contribute to colorectal cancer (CRC). However, the link between CRC tumor bile acids to tumor location, patient sex, microbiome, immune-regulatory cells, and prognosis is not clear. METHODS: We conducted bile acid analysis using targeted liquid chromatography-mass spectrometry (LC-MS) on tumor tissues from CRC patients (n = 228) with survival analysis. We performed quantitative immunofluorescence (QIF) on tumors to examine immune cells. RESULTS: Twelve of the bile acids were significantly higher in right-sided colon tumors compared to left-sided colon tumors. Furthermore, in male patients, right-sided colon tumors had elevated secondary bile acids (deoxycholic acid, lithocholic acid, ursodeoxycholic acid) compared to left-sided colon tumors, but this difference between tumors by location was not observed in females. A high ratio of glycoursodeoxycholic to ursodeoxycholic was associated with 5-year overall survival (HR = 3.76, 95% CI = 1.17 to 12.1, P = 0.026), and a high ratio of glycochenodeoxycholic acid to chenodeoxycholic acid was associated with 5-year recurrence-free survival (HR = 3.61, 95% CI = 1.10 to 11.84, P = 0.034). We also show correlation between these bile acids and FoxP3 + T regulatory cells. CONCLUSIONS: This study revealed that the distribution of bile acid abundances in colon cancer patients is tumor location-, age- and sex-specific, and are linked to patient prognosis. This study provides new implications for targeting bile acid metabolism, microbiome, and immune responses for colon cancer patients by taking into account primary tumor location and sex.
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