Succinyl-CoA and Cobalamin Are Biomarkers That Improve Anal Cancer Screening

A high risk of anal cancer is observed in men who have sex with men (MSM) that live with human immunodeficiency virus (HIV). High-grade squamous intraepithelial lesions (HSIL) are precursors to anal cancer, and screening for and treating these HSILs can reduce anal cancer risk, but current screening tests for HSILs are lacking in specificity. Serrano-Villar and colleagues sought to investigate if the anal microbiome could be used to improve HSIL screening and showed that, in 213 individuals (n = 167 in the discovery cohort and n = 46 in the validation cohort) of whom 94% were cisgender MSM with HIV, microbiome composition did not differ between the HSIL and no-HSIL groups. However, proteomic signatures were altered in patients with HSIL, with ribosomal structure and biogenesis, carbohydrate transport and metabolism, as well as energy production and metabolism being the most represented functions in the proteome. Moreover, 11 proteins that have been associated with cancer were found to be overexpressed in the HSIL versus the non-HSIL group, while evaluation of differences in protein expression between low-grade intraepithelial lesions or HSIL indicated that proteins related to acyl-CoA metabolism, branched-chain amino acids, cobalamin biosynthesis and transport, and ATP synthesis, which converge on methylmalonic acid production, a precursor for succinyl-CoA and gluconeogenesis, were overexpressed in patients with HSIL and have also been shown to be related to tumor progression. Patients with HSIL had higher levels of succinyl-CoA and cobalamin than those without HSIL, and use of succinyl-CoA and cobalamin levels improved the accuracy in diagnosing HSIL as compared to anal cytology, with the sensitivity increasing from 91.2% to 96.6% and the specificity increasing from 34.1% to 81.8%. Reclassification of 82% false-positive results as true negatives also occurred upon measurement of these biomarkers in anal cytobrushes. In summary, these results indicate that use of the microbiome-associated biomarkers succinyl-CoA and cobalamin can better stratify anal cancer risk and suggest that use of these biomarkers could improve screening methods in high-risk patient populations.

Serrano-Villar S, Tincati C, Raju SC, Sáenz JS, Moreno E, Bargiela R, et al. Microbiome-derived cobalamin and succinyl-CoA as biomarkers for improved screening of anal cancer. Nat Med 2023;29:1738–49.

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