Supplementary table 1.
1. (serum OR serum/ OR serol* OR plasma OR blood OR urin* OR saliv* OR biomarker* OR biomarker/ OR biological marker*).af 2. (Oesophag* OR esophag* OR esophagus/).af.
3. (Cancer* OR neoplas* OR neoplasm/ OR tumo$r* OR carcinoma* OR carcinoma/ OR adenocarcinoma* OR malignan*).af.
4. (Diagnosis OR risk OR detection).af.
5. 1 AND 2 AND 3 AND 4
6. Limit to 5 human studies
7. Limit 6 to review articles
8. 6 NOT 5
Supplementary table 2. Summary of study results for the association between lipid & glucose biomarkers and risk of oesophageal cancer.
Total cases n
Categorical Continuous Adjusted for/stratified by:
Total n Categories High Reference Units RR/HR (95% CI) RR/HR (95% CI)
Age Sex BMI/WHR Smoking Alcohol
Total oesophageal cancer
Cholesterol Ahn (2009) 29,093 117 Quintiles >7.16 <5.28 mmol /l 1.37 (0.73-2.57) not reported Y Y Y Y Y
Chyou (1992) 6,361 25 Tertiles >6.08 <5.18 mmol/l 0.67 (0.24-1.86) not reported Y Y Y Y
Wulaningsih (2012) 540,309 318 Quartiles >6.30 <4.70 mmol/l 0.79 (0.54-1.15) 0.63 (0.35-1.13) Y Y
Kitahara (2011)* 1,189,719 1,414 Quintile >6.21 <4.14 mmol/l 0.93 (0.77-1.11) 0.96 (0.94-0.99) Y Y Y Y Y Strohmaier (2013)* 577,330 295 Quintiles 7.4** 4.2** mmol/l 1.34 (0.90-2.01) 1.03 (0.91-1.17)
HDL Ahn (2009) 29,093 117 Quintiles >1.43 <0.94 mmol/l 1.60 (0.80-3.19) not reported
Wulaningsih (2012) 84,774 57 Quartiles >1.80 <1.25 mmol/l 2.04 (0.79-5.27) 3.66 (1.41-9.49) Y Y LDL Wulaningsih (2012) 84,774 57 Quartiles >4.25 <2.82 mmol/l 0.22 (0.06-0.86) 0.13 (0.03-0.49) Y Y LDL:HDL ratio Wulaningsih (2012) 84,774 57 Quartiles >3.16 <1.74 mmol/l 0.28 (0.12-0.66) 0.41 (0.20-0.81) Y Y Total:HDL ratio Wulaningsih (2012) 84,774 57 Quartiles >4.68 <2.95 mmol/l 0.42 (0.17-1.05) 0.18 (0.07-0.49) Y Y Triglycerides Wulaningsih (2012) 540,309 318 Quartiles >1.60 <0.70 mmol/l 2.29 (1.42-3.68) 1.62 (1.31-2.01) Y Y Triglyceride:HDL ratio Wulaningsih (2012) 84,774 57 Quartiles >1.23 <0.44 mmol/l 1.37 (0.43-4.42) 0.84 (0.47-1.50) Y Y ApoB Wulaningsih (2012) 84,774 57 Quartiles >1.42 <0.97 mmol/l 0.45 (0.14-1.44) 0.25 (0.06-1.01) Y Y ApoA Wulaningsih (2012) 84,774 57 Quartiles >1.56 <1.27 mmol/l 1.70 (0.78-3.70) 7.56 (1.58-36.1) Y Y ApoB:ApoA ratio Wulaningsih (2012) 84,774 57 Quartiles >0.85 <0.67 mmol/l 0.31 (0.13-0.74) 0.29 (0.12-0.70) Y Y
Glucose Jee (2005) 1,298,385 n/s Quintiles >7.78 <5.00 mmol/l 1.26 (0.89-1.52) not reported Y Y Y Y Y
Wulaningsih (2012) 540,309 318 Quartiles >5.20 <4.40 mmol/l 1.27 (0.89-1.87) 2.03 (0.45-9.12) Y Y
Stocks (2009) 549,944 246 Quintiles 6.7** 4.1** mmol/l 1.48 (0.41-5.33) 1.29 (0.92-1.8) Y Y Y Y OAC
Cholesterol Lindkvist (2014) 577,259 114 Quintiles 7.4** 4.2** mmol/l 1.22 (0.63-2.37) 0.95 (0.77-1.17) Y Y Y Y Triglycerides Lindkvist (2014) 577,259 114 Quintiles 3.12** 0.72** mmol/l 1.05 (0.54-2.05) 1.05 (0.85-1.30) Y Y Y Y
Glucose Lindkvist (2014) 577,259 114 Quintiles 6.8** 4.1** mmol/l 1.04 (0.57-1.90) 0.97 (0.80-1.17) Y Y Y Y
HOMA (Insulin*glucose) Duggan (2013) 392 43 Tertiles >2.15 <1.22 1.72 (0.75-3.98) 1.64 (1.08-2.48) Y Y Y Y OSCC
Cholesterol Lindkvist (2014) 577,259 184 Quintiles 7.4** 4.2** mmol/l 1.42 (0.85-2.37) 1.08 (0.92-1.26) Y Y Y Y Triglycerides Lindkvist (2014) 577,259 184 Quintiles 3.12** 0.72** mmol/l 1.45 (0.87-2.39) 1.05 (0.88-1.24) Y Y Y Y
Glucose Lindkvist (2014) 577,259 184 Quintiles 6.8** 4.1** mmol/l 1.44 (0.92-2.27) 1.11 (0.97-1.27) Y Y Y Y
* Results for men and women were combined in a preliminary meta-analysis
** Within-category means
Abbreviations: Apo: Apolipoportein; BMI: Body mass index; HDL: High-density lipoprotein; HOMA: Homeostatic model assessment; HR: Hazard ratio; LCI: Lower 95% confidence interval; LDL: Low-density lipoprotein; OAC: Oesophageal adenocarcinoma; OSCC: Oesophageal squamous cell carcinoma; OR: Odds ratio; RR: Relative risk; UCI: Upper 95% confidence interval; WHR: Waist-hip ratio.
Supplementary table 3. Summary of study results for the association between nutrition-related biomarkers and risk of oesophageal cancer
Categorical Continuous Adjusted for/stratified by:
Total n Cases n Categories High† Reference† Units OR/RR (95% CI) OR/RR (95% CI)
Age Sex BMI/WHR Smoking Alcohol
Total oesophageal cancer
Alpha-tocopherol Knekt (1991) 25 9 Continuous mg/l 0.39 (n/s-n/s) Y Y
Beta carotene Knekt (1991) 25 9 Continuous ug/l 1.64 (n/s-n/s) Y Y
Retinol Knekt (1991) 25 9 Continuous ug/l 1.09 (n/s-n/s) Y Y
Selenium Knekt (1991) 25 9 Continuous ug/l 0.41 (n/s-n/s) Y Y
25(OH)D Abnet (2010) 529 264 6 groups >100 50-75 * nmol/l 1.06 (0.37-3.05) Y Y Y Y Y
Calcium Wulaningsih (2013) 492,044 323 Quartiles >2.45 <2.32 mmol/l 1.31 (0.96-1.80) 1.16 (1.04-1.30) Y Y Y Phosphate Wulaningsih (2013) 397,292 271 Quartiles >1.14 <0.92 mmol/l 1.43 (0.94-2.18) 1.12 (0.98-1.28) Y Y
AST:ALT ratio Kimm (2010) 782,632 1,383 Quartiles >40 <20 U/l 3.20 (2.70-3.90) Y Y Y Y Y
urinary EGC Sun (2002) 772 42 High v negative >0.197 Negative mg/g cr 0.91 (0.36-2.31) Y Y Y Y
OAC
25(OH)D Abnet (2010) 207 103 6 groups >100 50-75 * nmol/l 1.17 (0.30-4.45) Y Y Y Y Y
Selenium Takata (2012)# 361 47 Tertiles >143.8 <126.3 ug/l 1.4 (0.65-3.02) 1.16 (0.60-2.28) Y Y Y Y
Riboflavin Fanidi (2015) 995 74 Quartiles >21.4 <9.4 nmol/l 1.95 (0.84-4.52) Y Y Y Y
Vitamin B6 Fanidi (2015) 995 74 Quartiles >47.7 <25.6 nmol/l 0.63 (0.30-1.33) Y Y Y Y
Folate Fanidi (2015) 995 74 Quartiles >18.2 <9.1 nmol/l 1.68 (0.79-3.56) Y Y Y Y
Vitamin B12 Fanidi (2015) 995 74 Quartiles >392 <265 pmol/l 1.17 (0.56-2.44) Y Y Y Y
Homocysteine Fanidi (2015) 995 74 Quartiles >12.5 <8.3 umol/l 1.19 (0.51-2.77) Y Y Y Y
Methionine Fanidi (2015) 995 74 Quartiles >29.4 <21.8 umol/l 1.32 (0.63-2.8) Y Y Y Y
OSCC
Alpha-tocopherol Taylor (2003) 1,643 590 Quartiles >955 <676 ug/dl 0.63 (0.44-0.91) 0.90 (0.83-0.98) Y Y Y Y Y Gamma tocopherol Taylor (2003) 1,643 590 Quartiles >75 <44 ug/dl 1.26 (0.89-1.77) 1.01 (0.95-1.08) Y Y Y Y Y
Beta carotene Abnet (2003) 1,643 590 Quartiles 7.3** 2.4** ug/dl 1.00 (0.74-1.40) 1 (0.95-1.10) Y Y Y Y Y
Lutein Abnet (2003) 1,643 590 Quartiles 52.6** 27.8** ug/dl 0.89 (0.66-1.20) 1 (0.9-1.10) Y Y Y Y Y
Beta Cryptoxanthin Abnet (2003) 1,643 590 Quartiles 6.6** 2** ug/dl 1.30 (0.93-1.70) 1 (0.98-1.10) Y Y Y Y Y
Retinol Abnet (2003) 1,643 590 Quartiles 42.1** 25.3** ug/dl 0.97 (0.71-1.3) 0.97 (0.91-10) Y Y Y Y Y
Vitamin C Lam (2013) 1,566 618 Quartiles >55.2 <13.5 umol/l 0.89 (0.66-1.2) 0.97 (0.86-1.09) Y Y Y Y
Selenium Mark (2000) 1,652 590 Quartiles 92**
(median)
52** ug/l 0.56 (0.44-0.71) 0.89 (0.83-0.95) Y Y Y Y
25(OH)D Abnet (2010) 284 142 6 groups >100 50-75 * nmol/l 0.68 (0.08-6.02) Y Y Y Y Y
25(OH)D Chen (2007) 1,105 545 Quartiles >75 <40 nmol/l 1.30 (0.97-1.73) 1.06 (1.01-1.13) Y Y Y Y
Riboflavin Fanidi (2015) 995 73 Quartiles >21.4 <9.4 nmol/l 1.21 (0.54-2.72) Y Y Y Y
Vitamin B6 Fanidi (2015) 995 73 Quartiles >47.7 <25.6 nmol/l 2.26 (1.06-4.84) Y Y Y Y
Folate Fanidi (2015) 995 73 Quartiles >18.2 <9.1 nmol/l 1.03 (0.47-2.24) Y Y Y Y
Vitamin B12 Fanidi (2015) 995 73 Quartiles >392 <265 pmol/l 1.07 (0.51-2.23) Y Y Y Y
Homocysteine Fanidi (2015) 995 73 Quartiles >12.5 <8.3 umol/l 1.69 (0.76-3.74) Y Y Y Y
Methionine Fanidi (2015) 995 73 Quartiles >29.4 <21.8 umol/l 1.29 (0.62-2.68) Y Y Y Y
Cysteine Murphy (2011) 1,445 498 Quartiles >216 <178 nmol/l 0.70 (0.51-0.98) 0.86 (0.79-0.93) Y Y Y Y Y
# Studies were within cohorts selected on basis of presence of precancerous condition (such as Barrett’s oesophagus).
* Reference category not lowest
** Within-category means/medians
Abbreviations: 25(OH)D: 25-hydroxyvitamin D; AST: Aspartate Aminotransferase; ALT: Alanine Aminotransferase; BMI: Body mass index; EC: Epicatechin;EGC: Epigallocatechin; HR: Hazard ratio; LCI: Lower 95%
confidence interval; m4: Epigallocatechin metabolite 4; m6: Epicatechin metabolite 6; n/s:Not stated OAC: Oesophageal adenocarcinoma; OR: Odds ratio; OSCC: Oesophageal squamous cell carcinoma; RR:
Relative risk; UCI: Upper 95% confidence interval; WHR: Waist-hip ratio.
Supplementary table 4. Summary of study results for the association between metabolism or inflammation related biomarkers and risk of oesophageal cancer.
Total n
Cases n
Categorical Continuous Adjusted for/stratified by:
Categories High† Reference† Units HR/OR/RR (95% CI) HR/OR/RR (95% CI)
Age Sex BMI/WHR Smoking Alcohol
OAC
Adinoponectin Duggan (2013) # 392 23 Tertiles >5.95 <3.84 ug/ml 0.87 (0.31-2.41) Y Y Y Y
Leptin Duggan (2013) # 392 23 Tertiles >63.6 <6.3 ng/ml 3.68 (0.94-14.45) 2.51 (1.09-5.81) Y Y Y Y
Ghrelin De Martel (2007) 110 31 2 groups >3200 <3200 pg/ml 0.21 (0.04-1.10) Y Y Y
C-reactive protein Hardikar (2014) # 386 43 Quartiles >3.6 <0.1 mg/l 1.55 (0.56-4.24) Y Y Y Y
Interleukin 6 Hardikar (2014) # 394 45 Quartiles >3.1 <0.4 pg/ml 1.17 (0.42-3.26) Y Y Y Y
Isoprostanes Hardikar (2014) # 394 45 Quartiles >74 <14 pg/ml 0.46 (0.18-1.20) Y Y Y Y
Tumour Necrosis Factor I Hardikar (2014) # 394 45 Quartiles >1.7 <0.3 ng/ml 0.68 (0.27-1.68) Y Y Y Y
Tumour Necrosis Factor 2 Hardikar (2014) # 377 45 Quartiles >6.4 <1.6 ng/ml 1.75 (0.68-4.49) Y Y Y Y
Insulin-like Growth Factor-1 Siahpush (2007) 344 38 Median 1.10 (0.60-2.30) Y Y Y Y
OSCC
Pepsinogen (PGI) Cook (2010) 173 79 2 groups <50
(lower)
>50* mg/l 3.68 (1.51-8.97) 1.49 (1.13-1.96) Y Y Y Y Y Ren (2009) 974 323 2 groups <50
(lower)
>50* mg/l 1.64 (0.89-3) Y Y Y Y Y
Xue (2013) 1501 10 2 groups <70 >70* mg/l 2.55 (0.51-12.78) Y Y
Pepsinogen ratio (PGI:PGII) Cook (2010) 173 79 2 groups <3 >3* ratio 4.32 (1.74-10.71) 1.48 (1.17-1.87) Y Y Y Y Y
Ren (2009) 974 323 2 groups <3 >3* ratio 1.1 (0.59-2.04) Y Y Y Y Y
Xue (2013) 1501 10 2 groups <3 >3* ratio 3.13 (0.38-25) Y Y
Ghrelin Murphy (2012) 164 82 Quartiles (Low) (High)* 6.83 (1.46-31.84) 1.49 (1.09-2.04) Y Y Y Y
Tumour Necrosis Factor I Keeley (2014) 81 36 Continuous 8.20 (2.66-25.31) Y Y Y
Tumour Necrosis Factor 2 Keeley (2014) 81 36 Continuous 5.00 (1.88-13.32) Y Y Y
MCP-3 Keeley (2014) 81 36 Continuous 10.94 (3.09-38.68) Y Y Y
Interleukin-1R Keeley (2014) 81 36 Continuous 35.88 (4.69-274.51) Y Y Y
Interleukin-13 Keeley (2014) 81 36 Continuous 10.67 (3.01-37.75) Y Y Y
GM-CSF Keeley (2014) 81 36 Continuous 17.43 (3.92-77.40) Y Y Y
# Studies were within cohorts selected on basis of presence of precancerous condition (such as Barrett’s oesophagus).
* Reference category not lowest
Abbreviations: BMI: Body mass index; GM-CSF: granulocyte⁄macrophage colony-stimulating factor; HR: Hazard ratio; LCI: Lower 95% confidence interval; MCP: Monocyte chemotactic protein; OAC: Oesophageal adenocarcinoma; OR: Odds ratio; OSCC: Oesophageal squamous cell carcinoma; RR: Relative risk; UCI: Upper 95% confidence interval; WHR: Waist-hip ratio.
Supplementary table 5. Summary of study results for the association between miscellaneous biomarkers and risk of oesophageal cancer.
Total n
Cases n
Categorical Continuous Adjusted for/stratified by:
Categories High† Reference† Units HR/OR/RR (95% CI) HR/OR/RR (95% CI)
Age Sex BMI/WHR Smoking Alcohol
Total oesophageal cancer
Smoking: Total NNN Hecht (2013) 223 77 Tertiles >66.5 <29.2 fmol/mg cr 17.00 (3.99-72.8) Y Y Y
Smoking: % NNN-N-Glucuronide Hecht (2013) 223 77 Tertiles >62.2 <50.5 % 0.27 (0.11-0.62) Y Y Y
Haemoglobin Edgren (2010) 1,110 106 Continuous Y 0.98 (0.74-1.30) Y Y
Gamma-glutamyltransferase Tsuboya (2012) 15,031 61 Quartiles >31 <13 IU/l 1.53 (0.58-4.03) Y Y Y Y Y
Trichloroethylene Hansen (2013) 3,975 12 Quartiles 5-25 <5 mg/l 0.48 (0.14-1.60) Y Y
Lead Gwini (2012) 2,612 8 High v low >30 <30 ug/dl 4.06 (0.97-16.95) Y Y
OAC
Leukocyte telomere length Risques (2007) # 300 38 Quartiles Shortest Longest 4.66 (1.28-16.93) 4.18 (1.6-10.94) Y Y Y Y Lymphocyte mutagen sensitivity Chao (2006) # 220 27 Quartiles >0.87 <0.44 Breaks/cell 1.98 (0.61-6.41) Y Y Y Y OSCC
Sphingosine Abnet (2001) 283 98 Quartiles nmol/l 0.71 (0.33-1.50) Y Y Y Y
Sphinganine Abnet (2001) 283 98 Quartiles nmol/l 0.83 (0.40-1.70) Y Y Y Y
Sphinganine:Sphingosine ratio Abnet (2001) 283 98 Quartiles Ratio 0.79 (0.37-1.70) Y Y Y Y
# Studies were within cohorts selected on basis of presence of precancerous condition (such as Barrett’s oesophagus).
Abbreviations: BMI: Body mass index; cr: Creatinine; HR: Hazard ratio; LCI: Lower 95% confidence interval; OAC: Oesophageal adenocarcinoma; OR: Odds ratio; OSCC: Oesophageal squamous cell carcinoma; RR:
Relative risk; NNN: N’-nitrosonornicotine; UCI: Upper 95% confidence interval; WHR: Waist:hip ratio.