Joyce Y. Huang

Dietary intake of one-carbon metabolism-related nutrients and pancreatic cancer risk: The Singapore Chinese Health Study

Background: Nutrients involved in one-carbon metabolism are hypothesized to protect against pancreatic cancer development. Methods: The Singapore Chinese Health Study database was used to prospectively examine the association between intake of one-carbon metabolism–related nutrients and pancreatic cancer risk. Between 1993 and 1998, 63,257 men and women ages 45 to 74 years were enrolled into the cohort. The daily intakes of the following one-carbon metabolism–related nutrients were assessed at enrollment using a 165-item food frequency questionnaire: betaine, choline, folate, and vitamins B2, B6, and B12. Multivariable HRs and 95% confidence intervals (CI) for pancreatic cancer risk associated with dietary intakes of one-carbon metabolism–related nutrients were calculated. Results: As of December 2013, 271 incident pancreatic cancer cases were identified during an average of 16.3 years of follow-up. Higher intakes of vitamin B6 and choline were associated with statistically significant decreases in the risk of developing pancreatic cancer. Compared with the lowest quartile, HRs (95% CIs) for the highest quartiles of vitamin B6 and choline were 0.52 (0.36–0.74; P trend = 0.001) and 0.67 (0.48–0.93; P trend = 0.04), respectively. There were no clear associations between the other one-carbon metabolism–related nutrients and pancreatic cancer risk. Conclusion: Our study suggests that higher intake of vitamin B6 and choline may lower the risk of pancreatic cancer. Impact: Our prospective findings are consistent with the in vivo evidence for protective roles of vitamin B6 and choline on pancreatic cancer development. Cancer Epidemiol Biomarkers Prev; 25(2); 417–24. ©2015 AACR.

Leukocyte telomere length in relation to risk of lung adenocarcinoma incidence: Findings from the Singapore Chinese Health Study: Telomere length and lung cancer

Telomeres are crucial in the maintenance of chromosome integrity and genomic stability. Critically short telomeres can trigger programed cell death while cells with longer telomeres may have increased likelihood of replicative errors, resulting in genetic mutations and chromosomal alterations, and ultimately promoting oncogenesis. Data on telomere length and lung cancer risk from large prospective cohort studies are spare. Relative telomere length in peripheral blood leukocytes was quantified using a validated monochrome multiplex quantitative polymerase chain reaction (qPCR) method in 26,540 participants of the Singapore Chinese Health Study. After a follow‐up of 12 years, 654 participants developed lung cancer including 288 adenocarcinoma, 113 squamous cell carcinoma and 253 other/unknown histological type. The Cox proportional hazard regression was used to estimate hazard ratio (HR) and 95% confidence interval (CI). HR of lung adenocarcinoma for individuals in the highest comparing the lowest 20 percentile of telomere length was 2.84 (95% CI 1.94–4.14, ptrend < 0.0001). This positive association was present in never smokers (ptrend < 0.0001), ever smokers (ptrend = 0.0010), men (ptrend = 0.0003), women (ptrend < 0.0001), and in shorter (ptrend = 0.0002) and longer (ptrend = 0.0001) duration of follow‐up. There was no association between telomere length and risk of squamous cell carcinoma or other histological type of lung cancer in all or subgroups of individuals. The agreement of results from this prospective cohort study with those of previous prospective studies and Mendelian randomization studies suggest a possible etiological role of telomere length in the development of lung adenocarcinoma.

ABO blood type and the risk of cancer – Findings from the Shanghai Cohort Study

ABO blood type is an inherited characteristic. The associations between ABO blood type and risk of all cancer and specific cancers were examined in a prospective cohort study of 18,244 Chinese men enrolled in 1986. During the 25 years of follow-up, 3,973 men developed cancer including 964 lung cancers, 624 colorectal cancers, 560 gastric cancers, 353 liver cancers, and 172 urinary bladder cancers. Hazard ratios (HR) for all cancer and specific cancers by ABO blood type were calculated using Cox proportional hazards models. Compared with blood type A, blood type B was associated with statistically significant reduced risk of all cancers (HR, 0.91, 95% CI:0.84, 0.99). Both blood types B and AB were associated with significantly lower risk of gastrointestinal cancer and colorectal cancer, respectively. Blood type B was also associated with significantly lower risk of stomach cancer and bladder cancer, while blood type AB was associated with significantly increased risk of liver cancer. By histological type, blood types B and AB were associated with lower risk of epidermoid carcinoma and adenocarcinoma, but were not associated with risk of sarcoma, lymphoma, leukemia or other cell types of cancer. The findings of this study support a role of genetic traits related to ABO blood type in the development of cancers in the gastrointestinal and urinary tracts.

A prospective evaluation of serum kynurenine metabolites and risk of pancreatic cancer

Background Serum pyridoxal 5’-phosphate (PLP), the active form of vitamin B6, is associated with reduced risk of pancreatic cancer. Data on functional measures of vitamin B6 status and risk of pancreatic cancer is lacking. Methods A nested case-control study involving 187 incident cases of pancreatic cancer and 362 individually matched controls were conducted within two prospective cohorts to evaluate the associations between kynurenine metabolites in pre-diagnostic serum samples and risk of pancreatic cancer. Results Higher serum concentrations of 3-hydroxyanthranilic acid (HAA) and the HAA:3-hydroxykynurenine (HK) ratio (a measure for in vivo functional status of PLP) were significantly associated with reduced risk of pancreatic cancer. Compared with the lowest tertile, odds ratios (95% confidence intervals) of pancreatic cancer for the highest tertile was 0.62 (0.39, 1.01) for HAA, and 0.59 (0.35–0.98) for the HAA:HK ratio, after adjustment for potential confounders and serum PLP (both Ps for trend<0.05). The kynurenine:tryptophan ratio or neopterin was not significantly associated with pancreatic cancer risk. Conclusions The inverse association between HAA or the HAA:HK ratio and risk of pancreatic cancer supports the notion that functional status of PLP may be a more important measure than circulating PLP alone for the development of pancreatic cancer.

Plasma fatty acids and risk of colon and rectal cancers in the Singapore Chinese Health Study

Fatty acid composition in plasma captures both dietary intake and endogenous synthesis. Prospective analyses of plasma fatty acid composition are needed to establish the role of monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) on risk of developing colorectal cancer. To evaluate associations between plasma fatty acid composition and colon or rectal cancer risk separately, a nested case-control study of 350 colorectal (211 colon and 139 rectal) cancer cases and an equal number of individually matched control subjects was conducted within the Singapore Chinese Health Study, a cohort of 63,257 men and women recruited between 1993 and 1998. Fatty acids in pre-diagnostic plasma were quantified using gas chromatography–tandem mass spectrometry. Conditional odds ratios (ORs) and 95% confidence intervals (CIs) comparing highest to lowest quartiles are presented. For colon cancer, inverse associations were reported with higher essential PUFAs, α-linolenic acid (OR = 0.41; 95% CI: 0.23, 0.73; Ptrend = 0.005) and linoleic acid (OR = 0.43; 95% CI: 0.23, 0.82; Ptrend = 0.008). Higher desaturase activity in the n-6 PUFA synthesis pathway estimated by the arachidonic:linoleic acid ratio was associated with increased colon cancer risk (OR = 3.53; 95% CI: 1.82, 6.85; Ptrend = 0.006), whereas higher desaturase activity in the MUFA synthesis pathway estimated by the oleic:stearic acid ratio was associated with decreased colon cancer risk (OR = 0.42; 95% CI: 0.19, 0.92; Ptrend = 0.024). There was no significant association between the essential fatty acids or the desaturase indices and rectal cancer risk. Endogenous synthesis of arachidonic and oleic acids has an impact on colon cancer development.Colorectal cancer: Dietary fat intake shapes colon cancer riskHigher consumption of “good fats,” or their natural creation by the body, may help protect people from colon cancer. Jian-Min Yuan from the University of Pittsburgh, USA, and colleagues used samples from the Singapore Chinese Health Study to examine fatty acids contained in blood plasma from 350 people who later developed colorectal cancer and an equal number of matched control individuals. They found that higher blood levels—which reflect dietary intake—of the essential polyunsaturated fatty acids linolenic acid and α-linolenic acid were associated with a lower risk of colon cancer. So was oleic acid, a monounsaturated fat created by the body, whereas conversion of linolenic acid to another fatty acid called arachidonic acid boosted colon cancer risk. No effect was seen on rectal cancer risk. Diets rich in linolenic acid may help prevent colon cancer.

Abstract 2273: Serum choline, methionine, betaine, dimethylglycine, and trimethylamine-N-oxide in relation to pancreatic cancer risk in two nested case-control studies in Asian populations

Background: Choline, methionine, and betaine are methyl group donors associated with DNA methylation. Diets deficient in choline and methionine have been shown to promote pancreatic carcinogenesis in experimental animals. We have previously reported an inverse association between dietary intake of choline and pancreatic cancer risk in a prospective cohort of Singapore Chinese. In the present study biomarkers of dietary choline and other methyl donor nutrients were evaluated in relation to pancreatic cancer risk. Method: Two case-control studies were nested within the Shanghai Cohort Study (129 cases and 258 matched controls) and the Singapore Chinese Health Study (58 cases and 104 matched controls). Concentrations of choline, methionine, betaine, dimethylglycine (DMG), and trimethylamine-N-oxide (TMAO) were measured by LC-MS/MS in pre-diagnostic serum samples. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression method with adjustment for potential confounders. Results: Choline, methionine, and betaine were moderately associated with each other (spearman correlation coefficient: 0.28 ~0.43). In the pooled analysis, serum choline, betaine, and methionine were inversely associated with risk of pancreatic cancer, while TMAO, an oxidative metabolite of choline produced by gut microbiota, was positively associated with risk of pancreatic cancer. Compared with the lowest quartile, ORs (95%CIs) of pancreatic cancer for the highest quartiles of choline, methionine, betaine, and TMAO were 0.37 (0.17-0.80), 0.39 (0.22-0.69), 0.49 (0.28-0.85), and 1.60 (0.94-2.74), respectively (all Ps for trend Conclusion: The novel inverse associations of serum choline, methionine, and betaine with risk of pancreatic cancer support the notion that methyl groups related to DNA methylation may modulate the risk of pancreatic cancer development. The positive association between TMAO and pancreatic cancer risk suggested gut microbiota may play an important role in pancreatic carcinogenesis. Citation Format: Joyce Huang, Lesley Butler, Oivind Midttun, Renwei Wang, Aizhen Jin, Yu-Tang Gao, Per Ueland, Woon-Puay Koh, Jian-Min Yuan. Serum choline, methionine, betaine, dimethylglycine, and trimethylamine-N-oxide in relation to pancreatic cancer risk in two nested case-control studies in Asian populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2273. doi:10.1158/1538-7445.AM2017-2273

Abstract 4297: Serum B6 vitamers (pyridoxal-5’-phosphate, pyridoxal, and 4’-pyridoxic acid) and pancreatic cancer risk: Two nested case-control studies in Asian populations

Background: Vitamin B6 is an important enzymatic cofactor in the synthesis of one-carbon units, amino acids, and carbohydrates. Epidemiological studies provided inconsistent results on the associations between circulating pyridoxal 5’-phosphate (PLP) and pancreatic cancer risk. Method: Two nested case-control studies were conducted within the Shanghai Cohort Study (SCS) (129 cases and 258 matched controls) and the Singapore Chinese Health Study (SCHS) (58 cases and 104 matched controls). Concentrations of B6 vitamers [PLP, pyridoxal (PL), and pyridoxic acid (PA)] were measured in serum samples that were collected an average of 12.5 years in SCS and 6.8 years in SCHS before pancreatic cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression with the adjustment for potential confounders. Restricted cubic splines were used to explore potential non-linear relationships between serum B6 vitamer levels and pancreatic cancer risk. Results: The median (5th-95th percentiles) levels of serum PLP were 25.7 (10.0-91.7) nmol/L among SCS controls and 58.1 (20.8-563.0) nmol/L among SCHS controls. There was a statistically significant inverse association between serum PLP levels and pancreatic cancer risk in SCS [comparing highest (g 95%CI: 0.21, 0.91; P for trend = 0.01]. A weaker, nonsignificant association was observed in SCHS [comparing highest (g 95%CI: 0.27, 2.25; P for trend = 0.64]. We combined the data from the two cohorts for the purpose of estimating the serum PLP-pancreatic cancer association using the widest PLP range available. Compared with PLP Citation Format: Joyce Y. Huang, Lesley M. Butler, Oivind Midttun, Per M. Ueland, Woon-Puay Koh, Yu-Tang Gao, Jian-Min Yuan. Serum B6 vitamers (pyridoxal-5’-phosphate, pyridoxal, and 4’-pyridoxic acid) and pancreatic cancer risk: Two nested case-control studies in Asian populations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4297.

Abstract 1882: Dietary intake of vitamin B6 and choline are inversely associated with pancreatic cancer risk: The Singapore Chinese Health Study

Background. Dietary nutrients involved in one-carbon metabolism, either as methyl donors or as enzyme co-factors are hypothesized to protect against pancreatic cancer development. Animal studies showed that diets deficient in one carbon metabolism-related nutrients, such as vitamin B6 and choline, were able to induce DNA damage in the pancreas and enhance the development of carcinogen-initiated pancreatic cancers in rodents. Although there is a strong rationale that one carbon metabolism-related nutrients may alter pancreatic cancer risk in human, prospective studies with well-characterized dietary intake that test the hypothesis are lacking. Methods. Between 1993 and 1998, 63,257 men and women aged 45-74 years were recruited into the Singapore Chinese Health Study. By the end of 2013, 271 incident pancreatic cancer cases were identified during up to 20 years of follow-up, after excluding individuals with extreme calorie intake or a history of cancer at enrollment (N = 2,959). The daily intakes of betaine, choline, folate, methionine, and vitamins B2, B6 & B12 were assessed at baseline by a 165-item semi-quantitative food frequency questionnaire that was developed for, and validated in the study population. Hazard ratios (HRs) and 95% confidence intervals (CIs) for pancreatic cancer risk associated with total calorie-adjusted intake levels of one carbon nutrients were calculated using the Cox-proportional hazard regression method with the adjustment for established risk factors for pancreatic cancer including age, sex, body mass index (BMI), smoking, alcohol drinking, and diabetes. Results. Higher intake of vitamin B6 and choline were associated with a statistically significant decrease in the risk of developing pancreatic cancer. Compared with the lowest quartile, HRs (95% CIs) for the 2nd, 3rd, and 4th quartiles of vitamin B6 were 0.71 (0.51-0.98), 0.80 (0.58-1.11), and 0.52 (0.36-0.74), respectively (P trend = 0.001). Similarly, the corresponding HRs (95% CIs) for choline were 0.57 (0.40-0.80), 0.72 (0.52-1.00), and 0.67 (0.48-0.93), respectively (P trend = 0.04). There was no overall statistically significant relationship between dietary intake of betaine, folate, methionine, vitamins B2 or B12 and pancreatic cancer risk. In stratified analyses by sex, the statistically significant, inverse associations between dietary choline and vitamin B6 and pancreatic cancer risk were present among men only (both P trend ≤0.02). Among men, these inverse associations were more apparent in smokers and nondrinkers of alcoholic beverages. Conclusion. Our prospective findings are consistent with in vivo evidence for protective roles of vitamin B6 and choline on pancreatic cancer development. These dietary compounds may be developed as potential chemopreventive agents against pancreatic cancer development in humans. Citation Format: Joyce Y. Huang, Lesley M. Butler, Renwei Wang, Ai Zhen Jin, Woon-Puay Koh, Jian-Min Yuan. Dietary intake of vitamin B6 and choline are inversely associated with pancreatic cancer risk: The Singapore Chinese Health Study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1882. doi:10.1158/1538-7445.AM2015-1882

Abstract 2212: Urinary biomarkers of catechins in relation to risk of hepatocellular carcinoma in the Shanghai Cohort Study

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Catechins from tea and non-tea sources are potential anti-carcinogenic compounds with potent antioxidant properties. Data supporting an effect of specific catechins on the risk of hepatocellular carcinoma (HCC) in humans are sparse. We examined the association between urinary biomarkers of catechins and their metabolites and risk of HCC. Methods: A nested case-control study of HCC (221 cases and 1072 matched controls) was conducted within the Shanghai Cohort Study, a cohort of 18,244 men who were enrolled in 1986-1989. Specific catechins and their metabolites including epicatechin (EC), epigallocatechin (EGC), 4′-O-methyl-epigallocatechin (4′-MeEGC), (-)-5-(3′, 4′, 5′-trihydroxyphenyl)-gamma-valerolactone (M4), and (-)-5-(3′, 4′-dihydroxyphenyl)-gamma-valerolactone (M6) were quantified in urine samples collected from study subjects at enrollment. Logistic regression methods were used to calculate odds ratios (OR) and 95% confidence intervals (CI) with adjustment for established risk factors for HCC, including hepatitis B surface antigen (HBsAg) serology status, self-reported physician-diagnosed cirrhosis, cigarette smoking, and alcohol drinking. Results: Compared with men who had no detectable EC, men with detectable levels of urinary EC had a statistically significant lower risk of HCC (OR=0.64; 95% CI: 0.45, 0.92). The inverse association between EC and HCC risk was not modified by smoking, alcohol intake or HBsAg/cirrhosis status. This inverse EC-HCC association strengthened in analyses restricted to cases that were diagnosed 10 or more years after specimen collection (OR=0.40; 95% CI: 0.22, 0.71). There was no association between urinary levels of EGC or other catechin metabolites and HCC risk. Conclusion: In our study population green tea is the sole source of dietary EGC while the major sources of EC include green tea, as well as apples, black grapes, soybeans, and broad beans. Thus, the findings of the present study support the notion that consumption of fruits and legumes may have a beneficial effect on HCC risk. Experimental studies are warranted to elucidate the biologic mechanisms of EC in hepatocarcinogenesis. Citation Format: Joyce Y. Huang, Lesley M. Butler, Renwei Wang, Chung S. Yang, Jian-Min Yuan, Yu-Tang Gao. Urinary biomarkers of catechins in relation to risk of hepatocellular carcinoma in the Shanghai Cohort Study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2212. doi:10.1158/1538-7445.AM2014-2212