The metabolic profile of colorectal cancer tumors may give clues to a patient’s prognosis, suggests a tissue analysis that found asparagine production within the tumor is associated with poor overall and recurrence-free survival, but only in women.
“Sex-specific tumor metabolism is an important factor for understanding differences in patient prognosis and potentially differences in treatment responses,” wrote Xinyi Shen, MPH, Yale School of Public Health, Yale University, New Haven, Connecticut, and colleagues in a study published November 1 on the preprint server medRxiv. It has not yet been peer-reviewed.
“Accordingly, we recommend that the design of precision medicine approaches consider both tumor metabolism and sex to obtain more robust findings in clinical trials and improve patient outcomes,” the authors wrote.
The prognosis of colorectal cancer — the third leading cause of cancer deaths in the United States — is dependent upon key factors, such as stage at presentation, primary tumor location, body mass index, and comorbid diabetes, as well as gene mutations and other genetic alterations. Sex-related differences in prognosis have also emerged in recent years, although patients do not yet receive sex-specific therapies.
In addition, the metabolic profile of a tumor, as measured via urine and tissue samples, has been shown to be associated with cancer survival and recurrence. A previous study by the researchers revealed sex-specific metabolic subphenotypes within colorectal cancer tumors that could affect tumor progression and treatment response.
To investigate further, they studied frozen tissue samples after curative intent colectomy from 197 patients with right-sided or left-sided stage I–III colon cancer treated between 1991 and 2000.
Information on patient age, sex, anatomic primary tumor location, chemotherapy history, and clinical stage was gathered, and the presence of 91 metabolite was determined via hydrophilic interaction liquid chromatography mass spectrometry and reverse phase liquid chromatography mass spectrometry.
The study showed that over a follow-up of 74.8 months, 5-year overall survival was inversely related to older age, advanced clinical stage, and the administration of chemotherapy. There were no significant overall sex-related differences in overall survival, at 74.3 months in men and 83.2 months in women (P = .18).
Only the administration of chemotherapy was significantly associated with 5-year recurrence-free survival, with — again — no significant sex-related differences at 77.5 months in men and 84.0 months in women (P = .48).
Eleven of the studied tumor metabolites had significant sex differences in their association with 5-year overall survival, while five metabolites were associated with sex differences in recurrence-free survival (P < .05 for interaction). Common to both overall survival and recurrence-free survival were sex-related interactions with asparagine and serine.
Further analysis showed there were significant associations between the asparagine synthetase (ASNS)-catalyzed asparagine synthesis pathway and colorectal cancer prognosis with the abundance of asparagine significantly linked to both overall survival and recurrence-free survival after adjusting for clinical stage, chemotherapy history, age, anatomic location, and metabolites involved in ASNS expression.
In women, increasing asparagine abundance was associated with markedly reduced overall survival at a hazard ratio for death of 6.39 (P = .04) and recurrence-free survival at a hazard ratio for progression of 4.36 (P = .01). In men, increasing asparagine levels were conversely associated with better overall survival at a hazard ratio of 0.57 (P = .02).
Similar relationships between tumor metabolism and worse colorectal cancer prognosis were seen in women for lysophospholipid and polyamine synthesis.
Limitations of the study, the authors note, include the number of events relative to the sample size, and patients being in multiple categories, such as clinical stage and anatomic locations. Moreover, some potential confounders were not available for analysis in the clinical records.
CITATION: Xinyi Shen, Yuping Cai, Lingeng Lu, et al. “Asparagine metabolism in tumors is linked to poor survival in females with colorectal cancer: A cohort study,” Nov. 1, 2021. medRxiv. https://www.medrxiv.org/content/10.1101/2021.10.30.21265637v1
This study was published as a preprint on the preprint server medRxiv A preprint is a preliminary version of a manuscript that has not undergone peer review. The posting of a preprint study should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
The research featured in this article was funded by a grant from the National Institutes of Health and an American Cancer Society Research scholar grant. The publication of the study was also made possible by a CTSA Grant from the National Center for Advancing Translational Science and the NIH roadmap for Medical Research. No relevant financial relationships declared.
No relevant financial relationships declared.
Xinyi Shen, Yuping Cai, Lingeng Lu, et al. “Asparagine metabolism in tumors is linked to poor survival in females with colorectal cancer: A cohort study,” Nov. 1, 2021. medRxiv. https://www.medrxiv.org/content/10.1101/2021.10.30.21265637v1
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