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Metabolomic profiles of hepatocellular carcinoma in a European prospective cohort.

Fages A, Duarte-Salles T, Stepien M, Ferrari P, Fedirko V, Pontoizeau C, Trichopoulou A, Aleksandrova K, Tjønneland A, Olsen A, Clavel-Chapelon F, Boutron-Ruault MC, Severi G, Kaaks R, Kuhn T, Floegel A, Boeing H, Lagiou P, Bamia C, Trichopoulos D, Palli D, Pala V, Panico S, Tumino R, Vineis P, Bueno-de-Mesquita HB, Peeters PH, Weiderpass E, Agudo A, Molina-Montes E, Huerta JM, Ardanaz E, Dorronsoro M, Sjöberg K, Ohlsson B, Khaw KT, Wareham N, Travis RC, Schmidt JA, Cross A, Gunter M, Riboli E, Scalbert A, Romieu I, Elena-Herrmann B, Jenab M - BMC Med (2015)

Bottom Line: A metabolic pattern associated with HCC risk comprised of perturbations in fatty acid oxidation and amino acid, lipid, and carbohydrate metabolism was observed.Sixteen metabolites of either endogenous or exogenous origin were found to be significantly associated with HCC risk.Our results show clear metabolic alterations from early stages of HCC development with application for better etiologic understanding, prevention, and early detection of this increasingly common cancer.

View Article: PubMed Central - PubMed

Affiliation: Institut des Sciences Analytiques, Centre de RMN à très hauts champs, CNRS/ENS Lyon/UCB Lyon-1, Université de Lyon, 5 rue de la Doua, 69100, Villeurbanne, France.

ABSTRACT

Background: Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer, is difficult to diagnose and has limited treatment options with a low survival rate. Aside from a few key risk factors, such as hepatitis, high alcohol consumption, smoking, obesity, and diabetes, there is incomplete etiologic understanding of the disease and little progress in identification of early risk biomarkers.

Methods: To address these aspects, an untargeted nuclear magnetic resonance metabolomic approach was applied to pre-diagnostic serum samples obtained from first incident, primary HCC cases (n = 114) and matched controls (n = 222) identified from amongst the participants of a large European prospective cohort.

Results: A metabolic pattern associated with HCC risk comprised of perturbations in fatty acid oxidation and amino acid, lipid, and carbohydrate metabolism was observed. Sixteen metabolites of either endogenous or exogenous origin were found to be significantly associated with HCC risk. The influence of hepatitis infection and potential liver damage was assessed, and further analyses were made to distinguish patterns of early or later diagnosis.

Conclusion: Our results show clear metabolic alterations from early stages of HCC development with application for better etiologic understanding, prevention, and early detection of this increasingly common cancer.

No MeSH data available.


Related in: MedlinePlus

Stratification of the analysis by hepatitis infection status and liver function score. (a) O-PLS score plot including HCC cases infected by HBV or HCV (n = 37) and matched controls (n = 72), R2 = 45 % and Q2 = 34 %, and the metabolic signature. (b) O-PLS score plot including HCC cases with HBV/HCV free (n = 77) and matched controls (n = 150), R2 = 28 % and Q2 = 12 %, and the metabolic signature colored for correlation after significance to ANOVA tests (Benjamini-Hochberg multiple corrected). (c) O-PLS score plot including HCC cases with liver function score ≥1 (n = 80) and matched controls (n = 155), R2 = 58 % and Q2 = 43 %, and the metabolic signature colored for correlation after significance to ANOVA tests (Benjamini-Hochberg multiple corrected). The validations of the O-PLS models are presented in Additional file 1: Figure S2. 1, CH3 bond of lipids mainly VLDL; 1’, CH3 bond of lipids, mainly LDL; 2, Leucine; 3, Isoleucine; 4, Valine; 5, Propylene glycol; 6, Ethanol; 7, CH2 bond of lipids; 8, CH2-CH2-COOC bond of lipids; 9, Acetate; 10, CH2-CH = bond of lipids; 11, N-acetyl glycoproteins; 12, Acetone and CH2-CH2-COOC bond of lipids; 13, Glutamate; 14, Glutamine; 15, citrate; 16 = CH-CH2-CH = bond of lipids; 17, Choline; 18, Glucose; 19, Lipid O-CH2; 20, mannose and lipids; 21, CH = CH bond of lipids; 22, Tyrosine; 23 Phenylalanine. Phc, Phosphocholine
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Fig3: Stratification of the analysis by hepatitis infection status and liver function score. (a) O-PLS score plot including HCC cases infected by HBV or HCV (n = 37) and matched controls (n = 72), R2 = 45 % and Q2 = 34 %, and the metabolic signature. (b) O-PLS score plot including HCC cases with HBV/HCV free (n = 77) and matched controls (n = 150), R2 = 28 % and Q2 = 12 %, and the metabolic signature colored for correlation after significance to ANOVA tests (Benjamini-Hochberg multiple corrected). (c) O-PLS score plot including HCC cases with liver function score ≥1 (n = 80) and matched controls (n = 155), R2 = 58 % and Q2 = 43 %, and the metabolic signature colored for correlation after significance to ANOVA tests (Benjamini-Hochberg multiple corrected). The validations of the O-PLS models are presented in Additional file 1: Figure S2. 1, CH3 bond of lipids mainly VLDL; 1’, CH3 bond of lipids, mainly LDL; 2, Leucine; 3, Isoleucine; 4, Valine; 5, Propylene glycol; 6, Ethanol; 7, CH2 bond of lipids; 8, CH2-CH2-COOC bond of lipids; 9, Acetate; 10, CH2-CH = bond of lipids; 11, N-acetyl glycoproteins; 12, Acetone and CH2-CH2-COOC bond of lipids; 13, Glutamate; 14, Glutamine; 15, citrate; 16 = CH-CH2-CH = bond of lipids; 17, Choline; 18, Glucose; 19, Lipid O-CH2; 20, mannose and lipids; 21, CH = CH bond of lipids; 22, Tyrosine; 23 Phenylalanine. Phc, Phosphocholine

Mentions: The O-PLS analyses stratified by hepatitis infection status of the cases (Fig. 3a,b) presented distinct metabolic signatures from hepatitis-infected HCC cases (R2 = 45 %, Q2 = 34 %) and hepatitis-free HCC cases (R2 = 28 %, Q2 = 12 %). Hepatitis-infected HCC cases presented (1) higher levels of AAA, glucose, and citrate and (2) lower VLDL and unsaturated lipids levels, while on the other hand HCC hepatitis-free cases were characterized by (1) higher levels in ethanol and glutamate and (2) lower levels in glutamine, BCAA, and choline. In hepatitis-free HCC cases, the risk associations of glutamine (OR = 0.56; 95 % CI, 0.34–0.92) and glutamate (OR = 2.06; 95 % CI, 1.18–3.61) were significantly different from matched controls (Table 4).Fig. 3


Metabolomic profiles of hepatocellular carcinoma in a European prospective cohort.

Fages A, Duarte-Salles T, Stepien M, Ferrari P, Fedirko V, Pontoizeau C, Trichopoulou A, Aleksandrova K, Tjønneland A, Olsen A, Clavel-Chapelon F, Boutron-Ruault MC, Severi G, Kaaks R, Kuhn T, Floegel A, Boeing H, Lagiou P, Bamia C, Trichopoulos D, Palli D, Pala V, Panico S, Tumino R, Vineis P, Bueno-de-Mesquita HB, Peeters PH, Weiderpass E, Agudo A, Molina-Montes E, Huerta JM, Ardanaz E, Dorronsoro M, Sjöberg K, Ohlsson B, Khaw KT, Wareham N, Travis RC, Schmidt JA, Cross A, Gunter M, Riboli E, Scalbert A, Romieu I, Elena-Herrmann B, Jenab M - BMC Med (2015)

Stratification of the analysis by hepatitis infection status and liver function score. (a) O-PLS score plot including HCC cases infected by HBV or HCV (n = 37) and matched controls (n = 72), R2 = 45 % and Q2 = 34 %, and the metabolic signature. (b) O-PLS score plot including HCC cases with HBV/HCV free (n = 77) and matched controls (n = 150), R2 = 28 % and Q2 = 12 %, and the metabolic signature colored for correlation after significance to ANOVA tests (Benjamini-Hochberg multiple corrected). (c) O-PLS score plot including HCC cases with liver function score ≥1 (n = 80) and matched controls (n = 155), R2 = 58 % and Q2 = 43 %, and the metabolic signature colored for correlation after significance to ANOVA tests (Benjamini-Hochberg multiple corrected). The validations of the O-PLS models are presented in Additional file 1: Figure S2. 1, CH3 bond of lipids mainly VLDL; 1’, CH3 bond of lipids, mainly LDL; 2, Leucine; 3, Isoleucine; 4, Valine; 5, Propylene glycol; 6, Ethanol; 7, CH2 bond of lipids; 8, CH2-CH2-COOC bond of lipids; 9, Acetate; 10, CH2-CH = bond of lipids; 11, N-acetyl glycoproteins; 12, Acetone and CH2-CH2-COOC bond of lipids; 13, Glutamate; 14, Glutamine; 15, citrate; 16 = CH-CH2-CH = bond of lipids; 17, Choline; 18, Glucose; 19, Lipid O-CH2; 20, mannose and lipids; 21, CH = CH bond of lipids; 22, Tyrosine; 23 Phenylalanine. Phc, Phosphocholine
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Fig3: Stratification of the analysis by hepatitis infection status and liver function score. (a) O-PLS score plot including HCC cases infected by HBV or HCV (n = 37) and matched controls (n = 72), R2 = 45 % and Q2 = 34 %, and the metabolic signature. (b) O-PLS score plot including HCC cases with HBV/HCV free (n = 77) and matched controls (n = 150), R2 = 28 % and Q2 = 12 %, and the metabolic signature colored for correlation after significance to ANOVA tests (Benjamini-Hochberg multiple corrected). (c) O-PLS score plot including HCC cases with liver function score ≥1 (n = 80) and matched controls (n = 155), R2 = 58 % and Q2 = 43 %, and the metabolic signature colored for correlation after significance to ANOVA tests (Benjamini-Hochberg multiple corrected). The validations of the O-PLS models are presented in Additional file 1: Figure S2. 1, CH3 bond of lipids mainly VLDL; 1’, CH3 bond of lipids, mainly LDL; 2, Leucine; 3, Isoleucine; 4, Valine; 5, Propylene glycol; 6, Ethanol; 7, CH2 bond of lipids; 8, CH2-CH2-COOC bond of lipids; 9, Acetate; 10, CH2-CH = bond of lipids; 11, N-acetyl glycoproteins; 12, Acetone and CH2-CH2-COOC bond of lipids; 13, Glutamate; 14, Glutamine; 15, citrate; 16 = CH-CH2-CH = bond of lipids; 17, Choline; 18, Glucose; 19, Lipid O-CH2; 20, mannose and lipids; 21, CH = CH bond of lipids; 22, Tyrosine; 23 Phenylalanine. Phc, Phosphocholine
Mentions: The O-PLS analyses stratified by hepatitis infection status of the cases (Fig. 3a,b) presented distinct metabolic signatures from hepatitis-infected HCC cases (R2 = 45 %, Q2 = 34 %) and hepatitis-free HCC cases (R2 = 28 %, Q2 = 12 %). Hepatitis-infected HCC cases presented (1) higher levels of AAA, glucose, and citrate and (2) lower VLDL and unsaturated lipids levels, while on the other hand HCC hepatitis-free cases were characterized by (1) higher levels in ethanol and glutamate and (2) lower levels in glutamine, BCAA, and choline. In hepatitis-free HCC cases, the risk associations of glutamine (OR = 0.56; 95 % CI, 0.34–0.92) and glutamate (OR = 2.06; 95 % CI, 1.18–3.61) were significantly different from matched controls (Table 4).Fig. 3

Bottom Line: A metabolic pattern associated with HCC risk comprised of perturbations in fatty acid oxidation and amino acid, lipid, and carbohydrate metabolism was observed.Sixteen metabolites of either endogenous or exogenous origin were found to be significantly associated with HCC risk.Our results show clear metabolic alterations from early stages of HCC development with application for better etiologic understanding, prevention, and early detection of this increasingly common cancer.

View Article: PubMed Central - PubMed

Affiliation: Institut des Sciences Analytiques, Centre de RMN à très hauts champs, CNRS/ENS Lyon/UCB Lyon-1, Université de Lyon, 5 rue de la Doua, 69100, Villeurbanne, France.

ABSTRACT

Background: Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer, is difficult to diagnose and has limited treatment options with a low survival rate. Aside from a few key risk factors, such as hepatitis, high alcohol consumption, smoking, obesity, and diabetes, there is incomplete etiologic understanding of the disease and little progress in identification of early risk biomarkers.

Methods: To address these aspects, an untargeted nuclear magnetic resonance metabolomic approach was applied to pre-diagnostic serum samples obtained from first incident, primary HCC cases (n = 114) and matched controls (n = 222) identified from amongst the participants of a large European prospective cohort.

Results: A metabolic pattern associated with HCC risk comprised of perturbations in fatty acid oxidation and amino acid, lipid, and carbohydrate metabolism was observed. Sixteen metabolites of either endogenous or exogenous origin were found to be significantly associated with HCC risk. The influence of hepatitis infection and potential liver damage was assessed, and further analyses were made to distinguish patterns of early or later diagnosis.

Conclusion: Our results show clear metabolic alterations from early stages of HCC development with application for better etiologic understanding, prevention, and early detection of this increasingly common cancer.

No MeSH data available.


Related in: MedlinePlus