Metabolic perturbations prior to hepatocellular carcinoma diagnosis: Findings from a prospective observational cohort study

Abstract

Hepatocellular carcinoma (HCC) development entails changes in liver metabolism. Current knowledge on metabolic perturbations in HCC is derived mostly from case‐control designs, with sparse information from prospective cohorts. Our objective was to apply comprehensive metabolite profiling to detect metabolites whose serum concentrations are associated with HCC development, using biological samples from within the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (>520 000 participants), where we identified 129 HCC cases matched 1:1 to controls. We conducted high‐resolution untargeted liquid chromatography‐mass spectrometry‐based metabolomics on serum samples collected at recruitment prior to cancer diagnosis. Multivariable conditional logistic regression was applied controlling for dietary habits, alcohol consumption, smoking, body size, hepatitis infection and liver dysfunction. Corrections for multiple comparisons were applied. Of 9206 molecular features detected, 220 discriminated HCC cases from controls. Detailed feature annotation revealed 92 metabolites associated with HCC risk, of which 14 were unambiguously identified using pure reference standards. Positive HCC‐risk associations were observed for N1‐acetylspermidine, isatin, p‐hydroxyphenyllactic acid, tyrosine, sphingosine, l,l‐cyclo(leucylprolyl), glycochenodeoxycholic acid, glycocholic acid and 7‐methylguanine. Inverse risk associations were observed for retinol, dehydroepiandrosterone sulfate, glycerophosphocholine, γ‐carboxyethyl hydroxychroman and creatine. Discernible differences for these metabolites were observed between cases and controls up to 10 years prior to diagnosis. Our observations highlight the diversity of metabolic perturbations involved in HCC development and replicate previous observations (metabolism of bile acids, amino acids and phospholipids) made in Asian and Scandinavian populations. These findings emphasize the role of metabolic pathways associated with steroid metabolism and immunity and specific dietary and environmental exposures in HCC development.

Data Processing Thresholds for Abundance and Sparsity and Missed Biological Insights in an Untargeted Chemical Analysis of Blood Specimens for Exposomics

“…Advanced and cost-effective nucleic acid sequencing methods can identify rare DNA variants, RNAs, and protein variants to improve our understanding about the development and spread of diseases (13)(14)(15). Similarly, untargeted chemical analyses using a high-resolution LC/MS instrument can detect thousands of small molecules in bio-fluid samples and can generate high quality and rich semi-quantitative data to identify and discover new metabolic hypotheses, biomarkers, and risk factors for diseases and biological phenotypes (16)(17)(18)(19)(20). In contrast to a targeted assay (21), an untargeted assay aims to detect in an unbiased manner as many possible chemicals present in a bio-fluid sample using a GC/LC-HRMS instrument (18) and such untargeted assays are key methods in exposome research to identify and discover new risk factors and biomarkers for chronic diseases (21)(22)(23).…”

Circulating acetylated polyamines correlate with Covid-19 severity in cancer patients

“…It is important to note that acetylated polyamine derivatives have previously been associated with the risk of developing hepatocellular carcinoma [ 53 ], poor prognosis triple-negative breast cancer [ 54 ], non-small cell lung cancer [ 55 , 56 ], colorectal cancer [ 57 ], pancreas carcinoma [ 58 ], lethal cardiovascular disease [ 59 , 60 ], Parkinson disease [ 61 ] and an elderly-type gut microbiota [ 62 ]. This contrasts with the observations that nutritional uptake of spermidine (and spermine but not putrescine) is epidemiologically linked to a decrease in the risk of lethal cancer, cardiovascular disease and cognitive decline [ 39 , 63 ] and that experimental spermidine supplementation has wide oncopreventive, cardioprotective and neuroprotective effects in preclinical models [ 64 – 68 ].…”

Novel biomarkers of habitual alcohol intake and associations with risk of pancreatic and liver cancers and liver disease mortality

“…The discovery set (n=454) was nested in the EPIC cross-sectional study [17, 18]. The first replication set included control subjects from two EPIC nested case-control studies of hepatocellular carcinoma (HCC; n=129) and pancreatic cancer (n=152) with untargeted metabolomics data [19-21]. Non-metastatic incident HCC (n=129) and pancreatic cancer (n=152) cases, were matched 1:1 with cancer-free controls on study center, sex, age at blood collection (□±□1 year), date (□±□6 months) and time of the day (□±□2□h) of blood collection, fasting status, and, for women, exogenous hormone use.…”