Eleanor L. Watts

Background: Underlying metabolic perturbations may offer insight into etiological factors related to liver cancer development. The objective of this study was to explore associations between pre-diagnostic metabolites and risk of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Methods: We conducted a nested case-control study within 12 prospective US cohort studies, including 727 HCC cases and 126 ICC cases with matched controls. Metabolomic profiling was performed on pre-diagnostic blood samples using the Metabolon platform. Multivariable conditional logistic regression estimated adjusted odds ratios and 95% confidence intervals for associations between metabolites (per doubling in levels) and liver cancer risk. Elastic net regression selected metabolites predictive of HCC and ICC, with predictive performance assessed by area under the curve (AUC). Results: Median time from blood collection to diagnosis was 11.6 years. Of 1485 pre-diagnostic metabolites, 600 were associated with HCC risk after false discovery rate correction (366 positively, 234 negatively); no metabolites were significantly associated with ICC. Enriched pathways among HCC cases included methylhistidine metabolism, amino acid metabolism, and bile acid biosynthesis; ICC showed enrichment in valine, leucine, and isoleucine pathways. Elastic net models for HCC selected 38 metabolites with strong predictive performance (AUC = 0.87; 95% CI = 0.83 to 0.91), while 8 metabolites were selected for ICC with modest discrimination (AUC = 0.64; 95% CI = 0.49 to 0.80). Conclusions: Numerous pre-diagnostic metabolites were associated with HCC risk, potentially reflecting underlying liver dysfunction. Enrichment patterns suggest distinct metabolic perturbations between HCC and ICC. Larger studies are needed to characterize metabolic risk factors for ICC and evaluate metabolites as predictors of HCC risk.

Supplementary Figure S2 shows prediction performance of the lifestyle score.

Supplementary Figure S4 shows foods and lifestyles selected to derive the lifestyle score in the PLCO.

Supplementary Table S6 shows results for stratified analyses of endometrial cancer risk.

High endogenous estrogen levels contribute to the etiology of hormone-related cancers. 2-hydroxylation (2-OH) of estrogen exhibits potential antitumorigenic properties. We hypothesized that lifestyle patterns related to the ratio of 2-OH pathway estrogen metabolites (EM) to parent estrogens (2-OH EM/parent E ratio) might lower estrogen-related cancer risk. We applied elastic net regularized regression to derive lifestyle scores correlated with the 2-OH EM/parent E ratio separately using data from subsets of cancer-free, postmenopausal women in the Shanghai Women’s Health Study (SWHS, n = 723) and the Prostate, Lung, Colorectal and Ovarian Screening Trial (PLCO, n = 635), in which blood (PLCO) or urine (SWHS) samples collected at baseline were profiled for parent Es and EMs. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations of lifestyle scores with the risk of breast, endometrial, and ovarian cancers in SWHS (N = 35,453) and PLCO (N = 26,565). The lifestyle scores explained 10% to 11% of the total variance in the 2-OH EM/parent E ratio. In the SWHS, a higher score was associated with a 29% (HR = 0.71; 95% CI, 0.57–0.88; Ptrend < 0.001) and 61% (HR = 0.39; 95% CI, 0.21–0.71; Ptrend < 0.001) lower risk of breast and endometrial cancers when comparing the highest with the lowest quartile, respectively. The association was more apparent with estrogen receptor (ER)-positive than with ER-negative breast cancer. Similar inverse associations were observed in the PLCO. Lifestyle patterns linked to elevated 2-OH of estrogen were associated with a lower risk of postmenopausal breast and endometrial cancers. Our study provides evidence for lifestyle modifications for cancer prevention.Prevention Relevance:Elevated estrogen 2-OH has been linked to reduced breast cancer risk. We showed that lifestyle patterns increasing the 2-OH EM/parent E ratio were associated with lower postmenopausal breast and endometrial cancer risk. Our findings suggest that targeted lifestyle modifications may benefit postmenopausal women with a low 2-OH EM/parent E ratio.

Supplementary Table S1 shows selected baseline characteristics of study participants eligible for endometrial cancer analyses.

Supplementary Figure S3 shows foods and lifestyles selected to derive the lifestyle score in the SWHS.

Supplementary Table S4 shows foods and lifestyles selected to derive the lifestyle score in the PLCO.

Supplementary Table S5 shows results for stratified analyses of breast cancer risk.