Endogenous aldehyde accumulation generates genotoxicity and exhaled biomarkers in esophageal adenocarcinoma

Abstract

Volatile aldehydes are enriched in esophageal adenocarcinoma (EAC) patients’ breath and could improve early diagnosis, however the mechanisms of their production are unknown. Here, we show that weak aldehyde detoxification characterizes EAC, which is sufficient to cause endogenous aldehyde accumulation in vitro. Two aldehyde groups are significantly enriched in EAC biopsies and adjacent tissue: (i) short-chain alkanals, and (ii) medium-chain alkanals, including decanal. The short-chain alkanals form DNA-adducts, which demonstrates genotoxicity and confirms inadequate detoxification. Metformin, a putative aldehyde scavenger, reduces this toxicity. Tissue and breath concentrations of the medium-chain alkanal decanal are correlated, and increased decanal is linked to reduced ALDH3A2 expression, TP53 deletion, and adverse clinical features. Thus, we present a model for increased exhaled aldehydes based on endogenous accumulation from reduced detoxification, which also causes therapeutically actionable genotoxicity. These results support EAC early diagnosis trials using exhaled aldehyde analysis.

Elevation of fatty acid desaturase 2 in esophageal adenocarcinoma increases polyunsaturated lipids and may exacerbate bile acid‐induced DNA damage

“… 26 We have found that ALDHs are variably affected in BE and EAC patients compared to NE (protein: Figure S4L–Q , transcript: Figure S5 J–M ). Consistent with a recent study, 10 ALDH4A1 and ALDH9A1 proteins were down‐regulated in BE and EAC relative to NE, yet ALDH1A1, ALDH1B1, ALDH16A1 were elevated (Figures S4 and S5 ). ALDH3A1 appeared to have a transient decrease in BE (Figure S4 ), before a return to healthy levels in EAC, and a previous study confirmed a decrease in ALDH3A1 in EAC by immunostaining, 10 suggesting that these changes may not necessarily be linear throughout disease stages, and changes are protein‐specific.…”

“…Genotoxic aldehydes 10 and exhaled aldehydes are increased in EAC patients, 10 likely as a result of peroxidation of the elevated polyunsaturated fatty acids and reduced aldehyde detoxification. ALDHs, including ALDH1A1, ALDH1B1, ALDH2, and ALDH6A1, as well as glutathione S‐transferases, convert genotoxic aldehydes to acetyl‐CoA 40 : this can feed into the TCA cycle 41 or the ketogenic pathway, 42 both of which are upregulated in our study.…”

“… 8 Oxidative DNA damage along with evasion of apoptosis/ferroptosis leads to extensive genomic mutations in BE and EAC. 9 Evidence for the accumulation of genotoxic lipid aldehydes in EAC was recently reported by Antonowicz et al.. 10 However, there has only been a single study reporting lipidomics profiles for BE and EAC tissues. 11 Desorption electrospray ionization‐mass spectrometry imaging identified a progressive increase in polyunsaturated long‐chain glycerophospholipids and the lipid class phosphatidylglycerol (PG) in the stages of EAC development, with a significant increase in glycerophospholipids with four double bonds and 38 total acyl chains, and a parallel decrease in monounsaturated glycerophospholipids and 34 total acyl chains.…”

Identification of lung cancer breath biomarkers based on perioperative breathomics testing: A prospective observational study

“…Furthermore, reduced ALDH3A2 expression, which is associated with TP53 depletion, has been demonstrated to cause reduced detoxification and endogenous accumulation of aldehyde. 37 However, changes in lipidomics profiles and regulator enzymes could occur in multiple cancers. This supports the mentioned speculations that most VOCs could correspond to broad spectrum cancers.…”

Genotoxic aldehydes in the hematopoietic system

“…In acute myeloid leukemia, ALDH3A2 has been implicated to protect against fatty aldehydes generated by ferroptosis 102 . In non-hematological malignancies, reduced expression of ALDH3A2 along with several other ALDH family members has also been observed in human oesophageal adenocarcinomas; this correlated with accumulation of medium-chain aldehydes including nonanal (C9), and decanal (C10), increased markers of DNA damage, and worse overall survival 103 .…”