Background: A common pathway where carcinogenic chemicals exert their biological influence is the generation of oxidative stress resulting from the production of reactive electrophiles. These electrophiles often form adducts with nucleophilic Cys34 of human serum albumin, which can be quantified to assess in vivo oxidative stress and other biological processes. Here, we aimed to examine the associations of Cys34 albumin adducts with acute myeloid leukemia (AML), the most common adult myeloid leukemia, which has strong links with exposure to certain chemicals and ionizing radiation.

Methods: This nested case-control study included data from 52 incident AML cases and 103 controls matched on age, sex, and race from two prospective cohorts: the CLUE study (24 cases and 48 controls) and the PLCO Trial (28 cases and 55 controls) and 42 untargeted serum Cys34 albumin adducts measured by liquid chromatography-high resolution mass spectrometry. We calculated odds ratios (OR) and 95% confidence intervals (CI) for AML risk for each albumin adduct on a continuous scale and across tertiles of exposure in combined samples as well as stratified by the median years of follow-up.

Results: The median (range) follow-up from phlebotomy at enrollment was 5.47 (1.02 - 29.93) years. Several Cys34 albumin adducts were significantly associated with incident AML risk. For example, higher serum levels of S-γ-Glu-Cys adduct (894.44) were associated with lower risk of AML (ORcontinuous= 0.18; 95% CI: 0.37-0.92; p-value= 0.04). Similarly, the ORs for the 2nd and 3rd tertiles of adduct levels compared to the lowest tertile were 0.65 (95% CI: 0.31-1.36) and 0.31 (95% CI: 0.12-0.80), respectively (p-trend = 0.01). Stratification by median years of follow-up showed that the association was largely driven by effects present among cases diagnosed ≥5.47 years of follow-up; the ORcontinuous was 0.06 (95% CI: 0.01-0.61; p-value = 0.02) and ORs by tertile were 0.32 (95% CI: 0.09-1.16) and 0.22 (95% CI: 0.06-0.89) for the 2nd and 3rd tertiles, respectively compared to the lowest tertile (p-trend= 0.04). In contrast, there was no association for cases diagnosed within 5.47 years of follow-up (ORcontinuous= 0.78; 95% CI: 0.07-8.95; p-value= 0.84).

Conclusion: Higher serum levels of Cys34 adduct of S-γ-Glu-Cys, which is a substrate for the biosynthesis of L-glutathione, a key antioxidant in humans, were associated with a lower risk of AML. Modified Cys34 adducts of human serum albumin could potentially help to understand the underlying mechanisms of leukemogenesis.

Citation Format: Mohammad L. Rahman, Bryan Bassig, Hasmik Grigoryan, Wei Hu, Dean Hosgood, Wen-Yi Huang, Jason Wong, Paul Strickland, Stephen Rappaport, Qing Lan, Nathaniel Rothman. A nested case-control study of untargeted serum protein adductomics and the risk of AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 225.