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Selenium Exposure and Cancer Risk: An Updated Meta-analysis and Meta-regression

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The objective of this study was to investigate the associations between selenium exposure and cancer risk. We identified 69 studies and applied meta-analysis, meta-regression and dose-response analysis to obtain available evidence. The results indicated that high selenium exposure had a protective effect on cancer risk (pooled OR = 0.78; 95%CI: 0.73–0.83). The results of linear and nonlinear dose-response analysis indicated that high serum/plasma selenium and toenail selenium had the efficacy on cancer prevention. However, we did not find a protective efficacy of selenium supplement. High selenium exposure may have different effects on specific types of cancer. It decreased the risk of breast cancer, lung cancer, esophageal cancer, gastric cancer, and prostate cancer, but it was not associated with colorectal cancer, bladder cancer, and skin cancer.
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Scientific RepoRts | 6:19213 | DOI: 10.1038/srep19213
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Selenium Exposure and Cancer
Risk: an Updated Meta-analysis and
Meta-regression
Xianlei Cai1,2,*, Chen Wang3,*, Wanqi Yu4, Wenjie Fan4, Shan Wang4, Ning Shen3,
Pengcheng Wu3, Xiuyang Li1,4 & Fudi Wang5
The objective of this study was to investigate the associations between selenium exposure and cancer
risk. We identied 69 studies and applied meta-analysis, meta-regression and dose-response analysis
to obtain available evidence. The results indicated that high selenium exposure had a protective eect
on cancer risk (pooled OR = 0.78; 95%CI: 0.73–0.83). The results of linear and nonlinear dose-response
analysis indicated that high serum/plasma selenium and toenail selenium had the ecacy on cancer
prevention. However, we did not nd a protective ecacy of selenium supplement. High selenium
exposure may have dierent eects on specic types of cancer. It decreased the risk of breast cancer,
lung cancer, esophageal cancer, gastric cancer, and prostate cancer, but it was not associated with
colorectal cancer, bladder cancer, and skin cancer.
Selenium (Se) is an essential trace element having considerable and particular functions for human health
because it is genetically encoded for which incorporation into proteins, as the constitutive part of selenocyst-
eine, the 21st amino acid1. Most se-proteins have been shown to have a wide range of pleiotropic eects, ranging
from antioxidant to anti-inammatory eects2, particularly the families of glutathione peroxidases (GPxs) and
thioredoxin reductases (TrxRs)1, but their precise mechanism are not understood absolutely currently. Despite
the scarce knowledge of mechanism, a large number of laboratory and ecologic researches focused on the asso-
ciations between selenium and human health have been completed, showing that Se is associated with several
human diseases including cardiovascular disease3–5, central nervous system disease6, diabetes mellitus7–10, and
cancer, but the results are inconsistent.
We can see worldwide debates on the relation between selenium and cancer risk. Observational studies and
randomized controlled trials suggest dierent eects in human. A new meta-analysis11 published in Cochrane
2014 described the association between selenium and cancer prevention, and this article tended to analyze the
eect of selenium supplement based on random controlled trials. ere are other similar meta-analyses have been
published, few of them established dose-response or benecial range of selenium exposure associated with the
risk reduction or determined the shape of dose-response curve to nd whether it is a linear relation, saturation
or U-shaped curve relation between selenium exposure level and cancer risk. On the other hand, numerous new
studies have been reported in recent years, and we think it is meaningful to conduct an updated meta-analysis
including dierent types of cancer to provide comprehensive evidence and clarify the shape of dose-response
association between selenium status and cancer risk.
Methods
Search strategy. We carried out a systematic search for articles which described the relations between sele-
nium and cancer risk in the medical and biologic databases (Medline 1980-March 2014, via Pubmed; Embase
1980-March 2014; Science Citation Index, Web of Science 1980- March 2014; CAB Health 1980- March 2014),
using a comprehensive list of selenium/ selenium supplement/ serum/plasma selenium/ toenail selenium/ anti-
oxidant/ minerals And cancer/ breast cancer/ lung cancer/ esophageal cancer/ gastric/stomach cancer/ colorectal
cancer/ bladder cancer/ prostate cancer/skin cancer). We also searched references of relevant studies and reviews
1Institute of Environmental Medicine, Zhejiang University, P.R.China. 2Ningbo Medical Treatment Center Lihuili
Hospital, P.R.China. 3Department of Clinic Medicine, Zhejiang University, Hangzhou, P.R.China. 4Department of
Epidemiology & Biostatistics, Zhejiang University, Hangzhou, P.R.China. 5Department of Toxicology & Nutrition,
Zhejiang University, Hangzhou, P.R.China. *These authors contributed equally to this work. Correspondence and
requests for materials should be addressed to X.L. (email: lixiuyang@zju.edu.cn)
Received: 01 October 2015
Accepted: 08 December 2015
Published: 20 January 2016
OPEN
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Scientific RepoRts | 6:19213 | DOI: 10.1038/srep19213
to identify works which were not found in the database search. e rst two authors (Xianlei Cai and Chen Wang)
conducted the search work (as shown in Fig.1)
Inclusion and exclusion criteria. Inclusion criteria were as follows: (1) was a randomized controlled trial,
cohort or case-control study; (2) regarded selenium as baseline exposure, and cancer event (including incidence
and mortality) as outcome; (3) were original works in English language which were published and indexed from
January 1980 to March 2014; (4) had key date for meta-analysis or dose-response analysis.
Exclusion criteria were as follows: (1) was not involved with exposure-response associations between selenium
and cancer risk; (2) cytological studies, animal studies, reviews, comments, abstracts and reviews; (3) low quality
articles.
Data extraction. All the data were extracted independently by three reviewers (Xianlei Cai, Chen Wang and
Ning Shen) with a standardized data extraction form. e characteristics of the identied works were extracted
as follows: rst author name, year of publication, study country, design (RCT, cohort or case-control), num-
ber of subject (we extracted number of selenium exposure group and placebo group respectively from RCT
studies, number of cohort participants from cohort studies, and number of case group plus control group from
case-control studies), number of cases, age (mean or ranger), participants (men, women, both gender combined
or special participants described in original studies), follow-up (year), Measurements of selenium (serum/plasma
selenium, toenail selenium or selenium supplement), type of cancer, outcome, and estimates (odds ratio (OR),
relative risk (RR) or hazard ratio (HR) at the highest compared with the lowest selenium exposure, with 95% con-
dence interval (CI)); Table1 presents the summary data of each identied work in our meta-analysis.
Quality assessment. We applied the Newcastle-Ottawa scale12,13 to assess the quality of the cohort and
case-control studies. In this scale, one article was assessed on three perspectives: selection, comparability, out-
come by using a “star system. e maximum score was nine stars. We simply regarded scores of 0–3 stars as low
quality, scores of 4–6 stars as moderate quality, and scores of 7–9 stars as high quality. According to RCTs, we used
the Cochrane collaborations tool14 for assessing risk of bias from six domains: selection bias, performance bias,
detection bias, attrition bias, reporting bias and other bias. Results were presented as low risk of bias, unclear risk
of bias or high risk of bias.
Statistical analyses. We extracted the multivariate-adjusted RRs, HRs or ORs and 95% condence inter-
val (CI) from original works. If some studies only provided 2× 2 table data, we calculated the responding ORs.
We considered these estimates as ORs when took those studies with dierent designs into account, for RRs and
HRs were assumed to be the accurate estimates of ORs. Meta-regression analysis was conducted to gure out
whether the associations between selenium exposure and cancer risk were inuenced by some covariates (expo-
sure modes, area and design), and we could recognize the inuence factor with a positive meta-regression coe-
cient(P 0.05). We used Greenland and Longnecker15 method to conduct study-specic dose-response analyses
based on the estimates of each category of plasma/serum selenium (ug/L), toenail selenium (ug/g) and selenium
supplement (ug/d) respectively. We used mean or median of selenium exposure for each category when it was
Figure 1. Flowchart of search strategy.
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Scientific RepoRts | 6:19213 | DOI: 10.1038/srep19213
Study Countr y Design Subject Case age Gender Follow-up
Measurements of
selenium
Type of
cancer OR(95%CI) Quality sore
Not site specic cancer
Bleys J(2008) USA cohort 13887 457 20–90 M and F 12 Y Serum s elenium All cancer 0.69(0.53,0.90) 9
Akbaraly
NT(2005) France cohort 1387 45 59–71 M and F 9 Y Serum selenium All cancer 0.56(0.41,0.76) 8
Kornitzer M(2004) Belgium nested
case-control 539 139 25–74 Men 10 Y Serum selenium All cancer 0.45(0.27,0.77) 9
195 50 Wom e n 1.43(0.63,3.33)
Ujiie S(2002) Japan cohort 5019 2707 N/A M and F 5 Y Ser um selenium All cancer 0.40(0.35,0.46) 7
Persson-Moschos
ME(2000) Sweden nested
case-control 903 302 middle
age Men 6 Y S erum selenium All cancer 0.19(0.04,0.83) 8
Breast cancer
Harris H R(2012) Swedish cohort 66651 3146 mean 65 Wom e n 9Y Diet selenium Breast cancer 0.69(0.52,0.92) 9
Pan S Y(2011) Canada case-control 4824 866 20–76 Premen-
opausal N/A Diet selenium Breast cancer 1.10(0.75,1.61) 8
4824 1496 Postmen-
opausal 1.09(0.84,1.43)
Rejali L(2007) Malaysia matched
case-control 124 62 mean 49 Wom e n N/A Serum selenium Breast cancer 0.89(0.84,0.94) 8
Cui Y (2007) USA Nested
case-control 304 252 N/A Wom en N/A Breast t issue
selenium Breast cancer 1.06(0.70,1.62) 9
Singh P (2005) India case-control 320 160 mean 45 Wom e n N/A Serum selenium Breast cancer 0.93(0.72,1.22) 8
Mannisto S(2000) Finland case-control 280 112 25–75 Premen-
opausal N/A Toe n ai l Breast cancer 0.90(0.30,2.70) 9
442 177 Postmen-
opausal selenium 0.60(0.30,1.30)
Ghadirian P(2000) Canada case-control 1102 414 N/A Wo men N/A Toenail selenium Breast cancer 0.72(0.40,1.31) 8
Dorgan J F(1998) USA nested
case-control 315 105 mean 58 Wo m en N/A S erum selenium Breast cancer 0.90(0.40,1.80) 9
Strain J J(1997) Northern
Ireland case-control 204 99 mean 62 Postmen-
opausal N/A To enail selenium Breast cancer 0.75(0.35,1.57) 8
van T V P(1996) Europe case-control 605 266 50–74 Postmen-
opausal N/A To enail selenium Breast cancer 0.96(0.63,1.47) 8
van den Brandt P
A(1994) Netherlands cohort 62537 355 55–69 Postmen-
opausal 3.3 Y Toenail selenium Breast cancer 0.84(0.55,1.27) 9
Hardell L(1993) Sweden case-control 632 441 20–84 Wome n N/A Serum selenium Breast cancer 0.33(0.17,0.64) 7
van T V P(1990) Netherlands case-control 371 133 25–64 Wom e n N/A Diet selenium Breast cancer 0.63(0.29,1.25) 9
Serum selenium 0.50(0.23,1.11)
Toenail selenium 0.91(0.48,1.67)
Knekt P(1990) Finland cohort N/A 48 15–99 women N/A S erum selenium Breast cancer 1.03(0.43,2.50) 8
Lung cancer
Jaworska K(2013) Po land case-control 172 86 mean
61.6 M and F N/A Serum selenium Lung cancer 0.10(0.03,0.34) 8
Jablonska E(2008) Poland case-control 612 325 30–78 M and F N/A Serum selenium Lung cancer 1.21(0.67,2.20) 8
Gromadzinska
J(2003) Poland case-control 362 152 43–78 M and F N/A S erum selenium Lung cancer 0.33(0.18,0.60) 8
Hartman TJ(2002) Finland Nested
case-control 500 250 50–69 men N/A To enail selenium Lung cancer 0.20(0.09,0.44) 9
Goodman
GE(2001) USA case-control 712 356 45–74 men N/A Serum selenium Lung cancer 1.20(0.77,1.88) 9
Ratnasinghe
D(2000) China nested
case-control 324 108 35–74 men 6 Y Serum selenium Lung cancer 1.20(0.60,2.40) 9
Knekt P(1998) Finland nested
case-control 285 95 mean 57 M and F 19 Y Serum selenium Lung cancer 0.41(0.17,0.94) 9
Garland M(1995) USA nested
case-control 94 47 30–55 women 41 M Toenail selenium Lung cancer 1.95(0.41,9.28) 8
Kabuto, M(1994) Japan case-control 197 77 59–60 M and F 13 Y Serum selenium Lung cancer 0.56(0.20,5.88) 8
van den Brandt
PA(1993) Netherlands cohort 3345 384 55–69 M and F 3.3 Y Toenail selenium Lung cancer 0.40(0.27,0.97) 9
Knekt P(1990) Finland cohort N/A 153 15–99 men N/A Serum selenium Lung cancer 0.66(0.37,1.19) 8
Lippman
SM(2009)
USA, Canada,
Puerto Rico RCT P:8696,e:8752 P:67,e: 75 50 men 5.46 Y Selenium supple-
ment Lung cancer 1.12(0.73,1.72) low risk of
bias
Clark LC(1996) USA RCT P:659, e: 653 P:35, e: 13 mean 63 M and F 6.4 Y Selenium supple-
ment Lung cancer 0.56(0.31,1.01) low risk of
bias
Esophageal cancer
Continued
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Scientific RepoRts | 6:19213 | DOI: 10.1038/srep19213
Study Countr y Design Subject Case age Gender Follow-up
Measurements of
selenium
Type of
cancer OR(95%CI) Quality sore
Steevens J(2010) Netherlands case-cohort 3346 129 55–69 M and F 16.3 Y Toenail selenium EAC 0.76(0.41,1.40) 9
3346 71 ESCC 0.37(0.16,0.86)
Cai, L(2006) China case-cohort 633 218 N/A M and F 10+ Y Selenium intake ESCC 0.48(0.25,0.89) 9
Wei WQ(2004) China cohort 1103 75 40–69 M and F 15 Y Serum selenium ESCC death 0.83(0.71,0.98) 9
Mark SD(2000) China case-cohort 1464 402 40–69 M and F 4.5 Y Serum selenium Incidence 0.89(0.83,0.95) 9
morality 0.90(0.83,0.97)
Clark LC(1996) USA RCT P:659, e: 653 P:6, e: 2 mean 63 M and F 6.4 Y Selenium supple-
ment
esophageal
cancer 0.33(0.03,1.84) low risk of
bias
Gastric cancer
Steevens J(2010) Netherlands case-cohort 3346 114 55–69 M and F 16.3 Y Toenail selenium GCC 0.52(0.27,1.02) 9
Wei WQ(2004) China cohort 1103 36 40–69 M and F 15 Y Serum selenium GCC death 0.75(0.59,0.95) 9
Mark SD(2000) China case-cohort 1479 87 40–69 M and F 4.5 Y Serum selenium GNC onset 1.02(0.89,1.18) 9
1652 590 GCC onset 0.83(0.77,0.90)
1149 87 GNC death 1.02(0.88,1.20)
1652 590 GCC death 0.87(0.79,0.96)
Kabuto, M(1994) Japan case-control 428 202 59–60 M and F 13 Y Serum selenium gastric
cancer 1.00(0.50,1.90) 8
van den Brandt
PA(1993) Netherlands cohort 2459 92 55–69 M and F 3.3 Y Toenail selenium gastric
cancer 0.61(0.33,1.11) 9
Knekt P(1990) Finland cohort N/A 43 15–99 Men N/A Serum selenium gastric
cancer 0.24(0.09,0.69) 8
N/A 30 Wom e n 0.48(0.14,1.66)
Colorectal cancer
Takata Y(2011) USA nested
case-control 1449 648 50–79 Wom en N/A Serum selenium colon Ca 1.28(0.91,1.79) 9
950 149 rectal Ca 1.25(0.68,2.31)
Connelly-Frost
A(2009) USA case-control 1362 532 40–80 M and F N/A Serum selenium Colon cancer 0.40(0.20,0.60) 9
Ghadirian P(2000) Canada case-control 1090 402 N/A M and F N/A Toenailselenium colorectal
cancer 0.42(0.19,0.93) 8
Nelson RL(1995) USA case-control 163 25 26–87 M and F N/A Serum selenium colorectal
cancer 1.70(0.50,5.90) 7
Garland M(1995) USA nested
case-control 178 89 30–55 Wome n 41 M Toenailselenium colorectal
cancer 2.04(0.88,4.75) 8
van den Brandt
PA(1993) Netherlands cohort 2495 234 55–69 M and F 3.3 Y To e nai l colon Ca 0.77(0.49,1.19) 9
2495 113 selenium rectal Ca 1.01(0.55,1.84)
Knekt P(1990) Finland cohort N/A 29 15–99 Men N/A Serum selenium colorectal
cancer 1.01(0.18,5.65) 8
48 Wom e n 1.10(0.42,2.92)
Schober SE(1987) USA case-control 215 72 <75 M and F N/A Serum selenium colon cancer 0.71(0.29,1.67) 7
Lippman
SM(2009)
US, Canada,
Puerto Rico RCT P:8696,e: 8752 P:60, e: 63 50 men 5.46 Y Selenium supple-
ment
colorectal
cancer 1.09(0.69,1.73) low risk of
bias
Clark LC(1996) USA RCT P:659, e: 653 P:19, e: 8 mean 63 M and F 6.4 Y Selenium supple-
ment
colorectal
cancer 0.42(0.18,0.95) low risk of
bias
Bladder cancer
Hotaling JM(2011) USA cohor t 77050 330 50–76 M and F 6 Y Selenium supple-
ment
bladder
cancer 0.97(0.72,1.31) 8
Wallace K(2009) Ger many case-control 2048 857 25–74 M and F N/A Toenail selenium bladder
cancer 0.90(0.68,1.19) 9
Kellen E(2006) Belgium case-control 540 362 50 M and F N/A Serumselenium bladder
cancer 0.27(0.15,0.47) 9
Michaud DS(2005) US nested
case-control 446 222 mean 62 Men N/A Toenail selenium bladder
cancer 1.17(0.66,2.07) 9
233 116 Women 0.36(0.14,0.91)
Zeegers MP(2002) Netherlands case-cohort 2890 431 55–69 M and F 6.3 Y Toenail selenium bladder
cancer 0.67(0.47,0.97) 9
Michaud DS(2002) Finland nested
case-control 264 132 50–69 M and F N/A Toenail selenium bladder
cancer 0.90(0.45,1.78) 8
Helzlsouer
KJ(1989) USA case-control 95 35 mean 59 M and F N/A Serumselenium bladder
cancer 0.49(0.16,1.49) 9
Lotan Y(2012) US, Canada,
Puerto Rico RCT P:8696,e: 8752 P:35, e: 63 50 men 7.1 Y Selenium supple-
ment
bladder
cancer 1.13(0.70,1.84) low risk of
bias
Continued
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Scientific RepoRts | 6:19213 | DOI: 10.1038/srep19213
Study Countr y Design Subject Case age Gender Follow-up
Measurements of
selenium
Type of
cancer OR(95%CI) Quality sore
Clark LC(1996) USA RCT P:659, e: 653 P:6, e: 8 mean 63 M and F 6.4 Y Selenium supple-
ment
bladder
cancer 1.27(0.44,3.67) low risk of
bias
Prostate cancer
Geybels, M
S(2013) Netherlands Case-cohort 2074 898 55–69 Men 7 Y Toenail selenium prostate
cancer 0.37(0.27,0.51) 9
Grundmark,
B(2011) Sweden cohort 2045 208 50 Men 34 Y S erum selenium Prostate
cancer 0.83(0.60,1.16) 9
Steinbrecher,
A(2010) European Nested
case-control 734 244 40–64 Men N/A Serum selenium Prostate
cancer 0.78(0.49,1.22) 9
Gill, J K(2009) USA Nested
case-control 1403 467 45–75 Men N/A Serum selenium Prostate
cancer 0.82(0.59,1.14) 9
Allen, N E(2008) Europe Nested
case-control 2018 959 43–76 Men 2.6–9.2 Y Serum selenium Prostate
cancer 0.96(0.70,1.31) 9
Pourmand,
G(2008) Iran case-control 130 62 40–90 Men N/A Serum selenium Prostate
cancer 0.16(0.06,0.47) 8
Peters, U(2008) USA cohort 35242 693 50–76 men N/A selenium supple-
ment
Prostate
cancer 1.00(0.68,1.50) 9
Peters, U(2007) USA Nested
case-control 1603 724 55–74 men 8 Y Serum selenium Prostate
cancer 0.84(0.62,1.14) 9
Lipsky, K(2004) Austri a case-control 150 70 48–95 men N/A Toenail selenium Prostate
cancer 0.74(0.22,2.71) 8
Li H(2004) USA Nested
case-control 1143 586 40–84 men 13 Y Serum selenium Prostate
cancer 0.78(0.54,1.13) 9
Allen, N E(2004) Britain case-control 600 300 44–77 men N/A Toenail selenium Prostate
cancer 1.24(0.73,2.10) 9
van den Brandt, P
A(2003) Netherlands Cohort 1751 540 55–69 men 6.3 Y Toenail selenium Prostate
cancer 0.69(0.48,0.99) 9
Goodman, G
E(2001) USA case-control 691 235 45–74 men N/A Serum s elenium Prostate
cancer 1.02(0.65,1.60) 9
Brooks, J D(2001) USA case-control 148 52 68 men N/A Serum selenium Prostate
cancer 0.24(0.07,0.77) 9
Ghadirian, P(2000) Canada case-control 165 83 35–84 men N/A Toenail selenium Prostate
cancer 1.14(0.46,2.83) 8
Helzlsouer, K
J(2000) USA Nested
case-control 350 117 70 men N/A Serum selenium Prostate
cancer 0.38(0.17,0.85) 8
Nomura, A
M(2000) USA Nested
case-control 498 249 44–85 men N/A Serum selenium Prostate
cancer 0.50(0.30,0.90) 9
Hartman, T
J(1998) USA cohort 29460 317 61 men 9 Y Serum selenium Prostate
cancer 1.32(0.70,2.47) 9
Yoshizawa,
K(1998) USA Nested
case-control 362 181 40–75 men 7 Y Toenail selenium Prostate
cancer 0.35(0.16,0.78) 9
Hardell, L(1995) Sweden case-control 245 124 44–87 men N/A Serum selenium Prostate
cancer 0.30(0.10,0.70) 7
West, D W(1991) USA case-control 564 179 45–67 men N/A selenium Prostate
cancer 0.80(0.50,1.40) 9
473 179 68–74 supplement 1.60(1.00,2.80)
Knekt, P(1990) Finland cohort N/A 46 15–99 men N/A Serum selenium Prostate
cancer 1.00(0.42,2.4) 8
Lippman
SM(2009)
US, Canada,
Puerto Rico RCT P:8696,e: 8752 P:416 50 men 5.46 Y Selenium supple-
ment
Prostate
cancer 1.04(0.83,1.30) low risk of
bias
e:432
Dueld-Lillico, A
J(2003) USA RCT P:470; P: 42; 65 men 7.5 Y selenium Prostate
cancer 0.48(0.28,0.80) low risk of
bias
E:457 E: 22 supplement
Clark LC(1996) USA RCT P:659, e: 653 P:35, e: 13 mean 63 men 6.4 Y Selenium supple-
ment
Prostate
cancer 0.35(0.18,0.65) low risk of
bias
Skin cancer
Garland M(1995) USA nested
case-control 30–55 126 63 women 41 M Toenail selenium melanoma 1.66(0.71,3.85) 8
Knekt P(1990) USA cohort 15–99 N/A 54 Men N/A Serum selenium basal cell
carcinoma 0.86(0.35,2.12) 8
52 Wom e n 1.54(0.64,3.75)
Reid ME(2008) USA RCT P:210, e: 213 P:108e: 98 mean 63 M and F 6.4 Y Selenium supple-
ment
non-mela-
noma skin
cancer
0.91(0.69,1.20) low risk of
bias
Continued
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Scientific RepoRts | 6:19213 | DOI: 10.1038/srep19213
presented, and used midpoint when selenium exposure ranges were presented. When highest or lowest catego-
ries of selenium exposure were unbounded, we assumed the category width to be the same as the adjacent one.
Number of subjects or person-time and number of cases for at least three categories of selenium exposure were
also needed in dose-response analyses. We used restricted cubic splines method16 described by Orsini, N et al. to
test the possible nonlinear relations, applying three xed knots at 10%, 50% and 90% of selenium exposure level.
e dose-response analyses were produced when there were more than 2 studies with relevant data.
Pooled ORs of selenium exposure with 95% condence intervals (CI) for cancer risk were conducted by
using xed or random eects model. Heterogeneity was examined by using Q17 and I2 18 index. When Q-test
and I2 statistics does not presented a notable heterogeneity (P > 0.05 and I2 50%), we used a xed-eects anal-
ysis described by Mantel-Haenszel19. Otherwise, a random-eects analysis would be conducted described by
DerSimonian and Laird method20. Publication bias was tested by Begger’s test and a weighted Egger test21,22. We
also conducted sensitivity analyses by omitting one study at a time to present relative inuence of each study on
pooled ORs. Statistical calculations and gures were produced with soware STATA version 12.0 (StataCorp LP,
College Station, TX, USA).
Results
Characteristics of the study. e meta-analysis included 69 studies (26 case-control studies, 14 cohort
studies, 19 nested case-control studies, 5 case-cohort studies, 5 randomized controlled trials) reporting 114 inde-
pendent estimates (as shown in table1) from Asia (4 studies from China, 2 from Japan, and 1 from Malaysia, Iran,
and India, respectively), Europe (8 from Netherlands, 5 studies from Sweden, 5 from Finland, 3 from Poland, 2
from Belgium, 1 from Northern Ireland, Britain, Germany and France, respectively, and 3 studies from European
countries) and America (27 studies from the United States, 2 from Canada and 1 from Austria). ere were more
than 364742 participants with 26138 cancer events. 5 studies used all types of cancer as outcome, 14 studies used
breast cancer as outcome, 13 studies used lung cancer as outcome, 5 studies used esophageal cancer as outcome,
6 studies used gastric cancer as outcome, 10 studies used colorectal cancer as outcome, 9 studies used bladder
cancer as outcome, 25 studies used prostate cancer as outcome, 4 studies used skin cancer as outcome, 1 study
regarded urinary tract cancer, pancreas cancer, leukemia/lymphoma, uterine and ovarian cancer as outcome
respectively. 11 studies23–33 mentioned above reported more than one cancer as an outcome, and several studies
reported more than one estimate (as shown in table1). 56 studies assessed biochemical selenium status: 37 used
plasma/serum specimens and 19 used toenail specimens as exposure. 11 studies investigated selenium supple-
ment or intake as exposure, using interviews or validated food frequency questionnaires. One study34 used breast
tissue selenium as exposure, and the last one35 reported selenium intake, plasma selenium and toenail selenium
as exposure respectively.
Selenium exposure and all cancer. e relation between selenium exposure and all cancer risk, repre-
sented 114 independent estimates from 69 studies (as shown in Table1). Meta-regression was done to detect the
possible inuencing factors, and we found that exposure mode (plasma/serum selenium, toenail selenium or sele-
nium supplement), area (Asia, Europe and America) and design (case-control, cohort or RCT) were not inuenc-
ing factors (exposure mode: P = 0.388; area: P = 0.523; design: P = 0.715). erefore, we took the 114 estimates
into meta-analysis. e result of the pooled analysis showed that high selenium exposure had a protective ecacy
on cancer at the highest compared with the lowest category (pooled OR = 0.78; 95%CI: 0.73–0.83), with obvious
heterogeneity (Q = 423.52; P = 0.000; I2 % = 73.3) and publication bias (Begger’s test zc = 2.55, P = 0.011; Egger’s
test t = 2.61, P = 0.010). Sensitivity analysis showed that the result was robust (as shown in Supplementary
Table S1). e heterogeneity was due to a large amount of included estimates and dierent types of cancer.
Study Countr y Design Subject Case age Gender Follow-up
Measurements of
selenium
Type of
cancer OR(95%CI) Quality sore
Clark LC(1996) USA RCT P:659, e: 653 P:190e:218 mean 63 M and F 6.4 Y Selenium supple-
ment
squamous
cell carcino-
ma basal cell
carcinoma
1.14(0.93,1.39) low risk of
bias
P:350e:377 1.10(0.95,1.28)
Other cancer
Knekt P(1990) USA cohort 15–99 N/A 26 Men N/A Serum selenium Urinary tract
cancer 0.34(0.06,2.06) 8
Knekt P(1990) USA cohort 15–99 N/A 22 Wom e n N/A Serum selenium Pancreas
cancer 0.86(0.21,3.52) 8
Clark LC(1996) USA RCT P:659, e: 653 P:5, e: 8 mean 63 M and F 6.4 Y Selenium supple-
ment
leukemia/
lymphomas 1.50(0.49,4.60) low risk of
bias
Garland M(1995) USA nested-
case-control 182 91 30–55 women 41 M Toenail selenium Uterine
cancer 1.38(0.62,3.08) 8
Garland M(1995) USA nested
case-control 182 91 30–55 women 41 M Toenail selenium Ovarian
cancer 1.22(0.44,3.38) 8
Table 1. Characteristics of studies included in meta-analysis of studies on selenium and cancer.
Abbreviation: M and F: Male and Female; p: placebo; e: exposure; RCT: randomized controlled trials; N/A: not
available; EAC: esophageal adenocarcinoma; ESCC: esophageal squamous cell carcinoma; GCC: gastric cardia
cancer; GNC: gastric noncardia cancer; M: months; Y: years.
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e pooled result from 58 independent estimates showed that high serum/plasma selenium had a eect on
cancer prevention at the highest compared with the lowest category (pooled OR = 0.75, 95%CI: 0.69–0.82, Fig.2),
with obvious heterogeneity (Q = 268.57; P = 0.000; I2 % = 78.8) and publication bias (Begger’s test zc = 2.54,
P = 0.025; Egger’s test t = 2.43, P = 0.018). But the funnel plot was symmetry (supplementary Fig. S1). e
heterogeneity could be due to a large amount of included estimates and publication bias. 17 groups of data were
incorporated into dose-response analysis. e pooled OR was 0.95 (95%CI: 0.94–0.98) with 10 ug/L increase of
plasma/serum selenium. Otherwise, we found obvious downward trends in the plots between plasma/serum
selenium and total cancer risk in nonlinear dose-response analysis (P = 0.67 for non-linearity, Fig.3).
ere were 32 independent estimates describing the relation between toenail selenium and cancer risk. e
result showed that high toenail selenium decreased cancer risk (pooled OR = 0.74, 95%CI: 0.62–0.87, as shown
in Fig.4), with obvious heterogeneity (Q = 70.95, P = 0.000; I2 % = 56.3). ere was no publication bias (Begger’s
test zc = 0.05; P = 0.961; Eggers test t = 0.52, P = 0.605), and the funnel plot did not show asymmetry (Fig. S2). 15
groups of data were incorporated into dose-response analysis. e pooled OR was 0.94 (95%CI: 0.92–0.97) with
per 0.1 ug/g increase of toenail selenium. An downward trends was found in the plots of nonlinear dose-response
analysis between toenail selenium and cancer risk (P = 0.500 for non-linearity, Fig.5).
ere were 23 independent estimates describing the relation between selenium supplement and cancer
risk. e result showed that selenium supplement was not associated with cancer risk (pooled OR = 0.91;
95%CI: 0.80–1.03, Fig.6), with obvious heterogeneity (Q = 49.35, P = 0.001; I2 % = 55.4). ere was no pub-
lication bias (Begger’s test zc = 1.98; P = 0.05; Egger’s test t = 0.06, P = 0.21), and the funnel plot did not show
Figure 2. Forest plot of meta-analysis on serum/plasma selenium and cancer risk.
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asymmetry (Fig. S3). However, we just extracted two relevant data for selenium supplement and all cancer risk,
the linear or nonlinear dose-response analysis was not conducted.
Selenium exposure and breast cancer. 18 estimates from 14 studies were incorporated in the pooled
analysis. We found that exposure mode, area and design were not inuencing factor (exposure mode: P = 0.417;
Figure 3. Summary nonlinear dose-response curves: plasma/serum selenium and cancer risk.
Figure 4. Forest plot of meta-analysis on toenail selenium and cancer risk.
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area: P = 0.705; design: P = 0.095) aer Meta-regression. e pooled result showed that high selenium exposure
decreased risk of breast cancer (pooled OR = 0.88; 95%CI: 0.84–0.93, Fig.7), with no heterogeneity (Q = 20.83,
P = 0.234; I2 % = 18.4) and publication bias (Begger’s test zc = 1.74; P = 0.081; Egger’s test t = 1.21, P = 0.245).
Sensitivity analysis showed the result was robust (as shown in Supplemental Table S1). We lacked sucient data
to conduct the linear or nonlinear dose-response analysis.
Selenium exposure and lung cancer. 13 estimates from 13 studies were incorporated into the pooled
analysis. We found that exposure mode, area and design were not inuencing factor(exposure mode: P = 0.706;
area: P = 0.581; design: P = 0.705). erefore, we took the 13 estimates into meta-analysis. e result showed
that high selenium exposure presented a protective eect on lung cancer (pooled OR = 0.60, 95%CI: 0.41–0.88,
Fig.8), with moderate heterogeneity (Q = 52.34, P = 0.000; I2 % = 77.1), but without publication bias (Begger’s
test zc = 1.16; P = 0.246; Egger’s test t = 0.79, P = 0.448). Sensitivity analysis showed the result was robust
(Supplemental Table S1). 5 groups of data were incorporated into dose-response analysis between plasma/serum
selenium and lung cancer risk. e result of linear dose-response analysis presented that plasma/serum selenium
Figure 5. Summary nonlinear dose-response curves: toenail selenium and cancer risk.
Figure 6. Forest plot of meta-analysis on selenium supplement and cancer risk.
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was not associated with cancer risk per 10 ug/L increases of plasma/serum selenium (pooled OR, 0.92; 95%CI:
0.83–1.01, P = 0.0001). Otherwise, we did not nd a threshold eect in the plot between plasma/serum selenium
and lung cancer risk in nonlinear dose-response analysis (P = 0.182 for non-linearity; Fig. S4).
Selenium exposure and esophageal cancer. 7 estimates from 5 studies were incorporated into the
pooled analysis. e pooled OR was 0.88 (95%CI: 0.84–0.93, Fig.9) with no heterogeneity (Q = 9.60, P = 0.142;
I2 % = 37.5) and publication bias (Begger’s test zc = 1.80; P = 0.072; Egger’s test t = 4.57, P = 0.006). Sensitivity
Figure 7. Forest plot of meta-analysis on selenium and breast cancer.
Figure 8. Forest plot of meta-analysis on selenium and lung cancer.
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analysis showed that the result was robust (Supplemental Table S1). We lacked sucient data to conduct the linear
or nonlinear dose-response analysis.
Selenium exposure and gastric cancer. 10 estimates from 6 studies were incorporated into the pooled
analysis. We found that exposure mode, area and design were not inuencing factor (exposure mode: P = 0.288;
area: P = 0.077; design: P = 0.769). erefore, we took the 10 estimates into meta-analysis. e pooled OR was
0.86 (95%CI: 0.77–0.96, as shown in Fig.10) with moderate heterogeneity (Q = 22.63, P = 0.007; I2 % = 60.2).
ere was no publication bias (Begger’s test zc = 0.54; P = 0.592; Egger’s test t = 1.29, P = 0.235). Sensitivity
analysis showed that the result was robust (as shown in Supplemental Table S1). We lacked sucient data to con-
duct the linear or nonlinear dose-response analysis.
Selenium exposure and colorectal cancer. 13 estimates from 10 studies were incorporated into the
pooled analysis. We found that exposure mode, area and design were not inuencing factor (exposure mode:
P = 0.671; area: P = 0.871; design: P = 0.963). erefore, we took the 13 estimates into meta-analysis. e result
Figure 9. Forest plot of meta-analysis on selenium and esophageal cancer.
Figure 10. Forest plot of meta-analysis on selenium and gastric cancer.
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showed that high selenium exposure was not associated with colorectal cancer (pooled OR = 0.89, 95%CI:
0.67–1.17, Fig.11), with moderate heterogeneity (Q = 26.71, P = 0.009; I2 % = 55.1), but without publication bias
(Begger’s test zc = 0.06; P = 0.951; Egger’s test t = 0.49, P = 0.634). Sensitivity analysis showed that the result was
robust (Supplemental Table S1).
Selenium exposure and bladder cancer. 10 estimates from 9 studies were incorporated in the pooled
analysis. We found that exposure mode, area and design were not inuencing factor (exposure mode: P = 0.05;
area: P = 0.708; design: P = 0.601). erefore, we took the 10 estimates into meta-analysis. e result showed that
high selenium exposure was not associated with bladder cancer (pooled OR = 0.76, 95%CI: 0.58–1.01, as shown
in Fig.12) with moderate heterogeneity (Q = 25.06, P = 0.003; I2 % = 64.1), but without publication bias (Begger’s
test zc = 0.72; P = 0.474; Egger’s test t = 0.90, P = 0.395). 3 groups of data were incorporated into dose-response
Figure 11. Forest plot of meta-analysis on selenium and colorectal cancer.
Figure 12. Forest plot of meta-analysis on selenium and bladder cancer.
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analysis between toenail selenium and bladder cancer risk. e consequence of linear dose-response analysis pre-
sented that toenail selenium was not associated with bladder cancer risk per 0.1 ug/g increase of toenail selenium
(pooled OR = 0.95, 95%CI: 0.90–1.01). Otherwise, we did not nd a threshold eect in the plot between toenail
selenium and bladder cancer risk in nonlinear dose-response analysis (P = 0.413 for non-linearity; Fig. S5)
Selenium exposure and prostate cancer. 26 estimates from 25 studies described the association
between selenium and risk of prostate cancer. We found that exposure mode, area and design were not inu-
encing factor (exposure mode: P = 0.682; area: P = 0.362; design: P = 0.478). erefore, we took the 26 estimates
into meta-analysis. e result showed that high selenium exposure decreased risk of prostate cancer (pooled
OR = 0.72, 95%CI: 0.61–0.86, Fig.13), with moderate heterogeneity (Q = 81.6, P = 0.000; I2 % = 69.4). ere
was no publication bias (Begger’s test zc = 1.92; P = 0.055; Egger’s test t = 1.90, P = 0.070). Sensitivity analysis
showed that the result was robust (Supplemental Table S1).
7 groups of data were incorporated into dose-response analysis between plasma/serum selenium and pros-
tate cancer and 5 groups of data were included between toenail selenium and prostate cancer. e result of lin-
ear dose-response analysis presented that plasma/serum selenium was associated with prostate cancer risk per
10 ug/L increases (pooled OR = 0.97, 95%CI: 0.95–0.99; Q = 19.5, P = 0.003). e result presented that toenail
selenium was associated with prostate cancer risk per 0.1 ug/g increases (pooled OR = 0.94, 95%CI: 0.89–0.99;
Q = 20.27, P = 0.000). We did not nd threshold eects in the plots between plasma/serum and toenail selenium
and prostate cancer risk in nonlinear dose-response analyses (P = 0.739, P = 0.886 for non-linearity, respectively;
Fig. S6,S7).
Selenium exposure and risk of skin cancer. 6 estimates from 4 studies were incorporated into the
pooled analysis. We found that exposure mode and area were not inuencing factor (exposure mode: P = 0.395;
area: P = 0.454). erefore, we took the 6 estimates into meta-analysis. e result of the pooled analysis showed
that high selenium exposure was not associated with skin cancer (pooled OR = 1.09, 95%CI: 0.98–1.21, Fig.14),
with no heterogeneity (Q = 3.65, P = 0.601; I2 % = 0.0) and publication bias (Begger’s test zc = 0.00; P = 1.000;
Egger’s test t = 0.42, P = 0.697). Sensitivity analysis showed that the result was robust (Supplemental Table S1).
Other subgroup analysis. e further stratied analysis were conducted by gender and study design. e
results indicated that the protective eect of high selenium exposure had no gender dierence (as shown in
Table2). When stratied by design, we found the results from observational studies presented the protective eect
of selenium on cancer while the results from RCTs indicated null eect (as shown in Table2).
Figure 13. Forest plot of meta-analysis on selenium and prostate cancer.
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Discussion
Debating on Se-Cancer association is persistent. Selenium has been hypothesized to be a cancer preventive
agent, a cancer therapeutic agent, or be a carcinogen36. Several37–41 studies presented results that blood sele-
nium was associated with cancer. According to breast cancer, results from Harris H R et al.42, Rejali et al.43, and
Hardell, L44 et al. studies presented a protective eect of selenium, while other observational studies23,24,34,35,45–51
showed null associations between selenium and breast cancer. For lung cancer, ndings from Jaworska K et al.52,
Gromadzinska, J et al.53, Hartman, T. J et al.54, Knekt, P. et al.55, van den Brandt, P. A et al.56 and Knekt, P et al.24
studies showed that high selenium exposure decreased lung cancer risk, but other 6 observational stud-
ies24–26,33,57,58 did not present similar results. Two randomized controlled trials27,28 found that selenium supple-
ment was not associated with lung cancer (HR:1.12; 95%CI: 0.73–1.72; 0.56; 95%CI: 0.31–1.01, respectively).
Several studies23–26,28–32,59–63 described the relation between digest system cancer, but the results were also incon-
sistent. Stevens, J et al.29 study presented that toenail selenium was associated with esophageal squamous cell
carcinoma, but not with gastric cardia cancer. Wei WQ et al.30 study in China showed that serum selenium was
associated with mortality of esophageal squamous cell carcinoma and gastric cardia cancer. Several studies32,60
presented null relation between serum selenium and colon cancer, rectal cancer. However, Clark LC et al.28
randomized controlled trial showed selenium supplement decreased risk of colorectal cancer in people with skin
carcinoma. According to bladder cancer, dierent studies64–71 showed dierent results. Hotaling JM et al.64 study
presented that long-term use of supplemental selenium could not decrease bladder cancer risk aer 6 years’
follow-up. Lotan Y et al.71 randomized controlled trial presented a similar result. Michaud, D. S et al.67 study
showed a gender-specic relation between toenail selenium and bladder cancer that high toenail selenium had a
protective eect on female bladder cancer. According to prostate cancer, the US Selenium and Vitamin E Cancer
Prevention Trial showed that a long term oral supplement of selenomethionie(200ug/d) did not prevent pros-
tate cancer27. And numerous observational studies23,24,72–91 also presented inconsistent results. Hurst, R et al.92
meta-analysis which included twelve studies showed that prostate cancer risk reduced with the increase of
plasma/serum and toenail selenium. e Nutritional Prevention of Cancer Trial (NPCT)28 investigated the eect
of selenium supplement on the development of skin cancer, and found no protective ecacy, Reid, M. E et al.93
study which was a sub-study of NPCT showed a similar result.
e results of meta-analysis suggest an inverse relation between selenium exposure and the total cancer risk
(including breast cancer, lung cancer, esophageal cancer, gastric cancer, colorectal cancer, bladder cancer, pros-
tate cancer, skin cancer, not site-specic cancer and other cancer). What is more, the results of dose-response
analysis show a downward trend between plasma/serum selenium, toenail selenium and total cancer risk. e
biomarker of selenium (serum/plasma and toenail selenium) was associated with cancer risk and could be easily
measured and monitored to evaluate people health status. However, our results nd that selenium supplement is
not associated with cancer risk. Selenium supplement contains either inorganic or organic species or a mixture
of both. e SELECT trial uses L-selenomethionie as an oral supplement, while the NPCT trial uses selenium
yeast tablets. e dierent types of selenium supplement may present dierent eects on human health. On
the other hand, rst-pass elimination and bioavailability of dierent participants should be considered. Burk
et al.94, study presents the results that the full expression of selenoprotein P requires more Se intake than that
required by the full expression of GPxs, indicating that the Se intakes of the current studies are probably inade-
quate for optimizing the protective eects. We also cannot exclude the possibility that it is what associated with
higher biochemical selenium level presents the shielding eect other than selenium exposure itself. We know
that RCTs should research the association between selenium supplement and cancer risk, while observational
Figure 14. Forest plot of meta-analysis on selenium and skin cancer.
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studies usually research the relation between the biomarker of selenium and cancer risk. ese reasons could be
used to explain the inconsonant consequences of our stratied analysis by study design. And Vinceti, M11 et al.
meta-analysis also nd the inconsistent results between RCTs and observational studies. Future mechanism stud-
ies should pay more attention to the procedure from selenium supplement to biochemical selenium status to
gure out the reasons for inconsonant eects of selenium supplement and biochemical selenium for preventing
cancer. And future epidemiological studies and intervention trials should try to research selenium supplement,
plasma/serum selenium and toenail selenium at the same time to reduce the potential bias.
We also nd that selenium has diverse eects on specic types of cancer. According to breast cancer, we
nd an inverse relation when taking all relevant estimates into account. Nonetheless, we lack sucient data to
conduct dose-response analyses. According to lung cancer, we nd that high selenium exposure presents a pro-
tective ecacy. ough a downward trend is seen in the nonlinear dose-response analysis, there is no statistical
signicance between plasma/serum selenium and lung cancer risk in linear dose-response analysis. e associ-
ation between lung cancer and selenium exposure needs more discussion. According to esophageal cancer and
gastric cancer, we nd an obvious inverse relation. e quantity of estimates included in meta-analyses is not
as many as other types of cancer, and we lack sucient data to conduct dose-response analyses. According to
colorectal cancer, we nd no association between selenium exposure and cancer risk. Nevertheless, Ou Y et al.95
meta-analysis which included seven studies showed a protective eect of selenium on colorectal adenomas
(OR = 0.67; 95%CI: 0.55–81). Selenium exposure probably plays a protective role in colorectal benign tumor
rather than cancer, and the results need more researches. According to bladder cancer, we nd no statistical
signicance between selenium exposure and bladder cancer. However, Amaral A F et al.96 meta-analysis which
included seven epidemiologic studies presents that plasma/serum selenium and toenail selenium have protective
eects on bladder cancer risk. According to prostate cancer, we nd a protective eect of high selenium expo-
sure for prostate cancer. e results of linear dose-response analyses between plasma/serum selenium, toenail
selenium and prostate cancer support the result, and downward trends are shown in nonlinear dose-response
analyses. However, two randomized controlled trials (the NPCT trial28 and the SELECT trial27) focusing on sele-
nium supplement present the consequence that selenium supplement is not associated with prostate cancer risk.
According to skin cancer, we nd selenium is not associated with skin cancer risk.
ere are numerous hypotheses about the potential anticarcinogenic mechanisms of selenium. e major pos-
itive eect may be contributed by the antioxidant function of GPxs and selenoprotein P94. Selenium is associated
with the regulation of protein folding via the function of the endoplasmic reticulum to inuence the process of
necrosis and apoptosis of malignant cells97,98. Selenium also has the eect on DNA stability98. However, dierent
malignant cells have their special biological characteristics and microenvironment for progress and invasion.
ey probably have disparate abilities of utilizing selenium. Hence, selenium probably has no eect on some types
of cancer. e exact mechanism has yet to be investigated. On the other hand, the adverse eects of selenium
supplement: mainly diabetes27,99, glaucoma28, and dermatologic alterations27 could not be ignored. So we should
try to clarify what level of selenium supplement is needed for adequate nutrition and at what level dose is “unsafe.
Our meta-analysis has several limitations clearly. Measurement errors in the assessment of selenium exposure
may bias the eect estimates. Even among those studies regarding the same biochemical selenium as exposure,
dierent measurement methods, dierent facilities and dierent stas are all easy to produce measurement errors,
and it is hard to make corrections. As showed in our inclusion criteria, we select case-control studies, cohort stud-
ies and RCTs into our meta-analysis. Selenium exposure may be linked to other behaviors like age, income, race,
smoking status, alcohol consumption, body mass index, physical activity. ese controlled confounding factors
dier among sixty-nine studies and may inuence the association between selenium exposure and cancer risk.
Because of the insucient number of relevant estimates, we have limited power to conduct subgroup analysis of
pathological types of dierent cancer, and other controlled confounding factors.
Our study also has a few strength. We bring in a large number of studies and have largely avoided some main
inuencing factors by meta-regression analyses. And the robust outcomes of sensitivity analysis suggest that there
is no distinct date making particularly contribution to the results. We detect the association between selenium
exposure and dierent types of cancer to nd a comprehensive understanding from global eects to local eects.
We also conduct linear dose-response analyses which are stricter than high-versus-low analysis and the results of
nonlinear dose-response analyses show dose-response trends in plots which are visual and accessible.
Conclusions
High selenium exposure could decrease cancer risk, especially high plasma/serum selenium and toenail selenium.
High selenium exposure may have dissimilar eects on specic types of cancer. Future epidemiological studies
Subgroup Type of subgroup No of estimates OR(95%CI)
Homogeneity test
PI2(%)Q
Design
cohort 40 0.75(0.68,0.82) 209.01 0.000 81.8
Case-control 61 0.77(0.69,0.86) 162.63 0.000 63.7
RCT 13 0.89(0.74,1.08) 31.32 0.002 61.7
Gender
Men 39 0.74(0.64,0.86) 111.94 0.000 66.1
Wom e n 31 0.90(0.86,0.95) 42.01 0.071 28.6
Both combined 44 0.73(0.66,0.80) 260.02 0.000 83.5
Table 2. e stratied analysis by gender and study design.
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and intervention trials should try to research selenium supplement, plasma/serum selenium and toenail selenium
at the same time to reduce the potential bias. e exact mechanism needs to be further investigated.
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Acknowledgements
is research was supported by the So Science Key Project of the Science and Technology Department of
Zhejiang Province (2015C25027), the Medical Health Scientic Research Fund Project of Zhejiang Province
(2015KYA070), and Zhejiang University Undergraduate Zetetic Experiment Project of Public Health (2013).
Author Contributions
X.C. and C.W. conducted the search work and all the data were extracted independently by X.C., C.W. and N.S.
X.C. and C.W. wrote the main manuscript text and prepared the tables. N.S.,W.Y., W.F., S.W. and P.W. prepared
gures. X.L. reviewed and corrected the manuscript. F.W. reviewed the manuscript.
Additional Information
Supplementary information accompanies this paper at http://www.nature.com/srep
Competing nancial interests: e authors declare no competing nancial interests.
How to cite this article: Cai, X. et al. Selenium Exposure and Cancer Risk: an Updated Meta-analysis and Meta-
regression. Sci. Rep. 6, 19213; doi: 10.1038/srep19213 (2016).
is work is licensed under a Creative Commons Attribution 4.0 International License. e images
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unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license,
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... Consistent with the previous studies, low levels of Zn indicate an increased risk for ESCC in a linear dose-response relationship. Interestingly, BKMR analysis showed Se, another element that is associated with a decreased risk for ESCC [28,29], has a synergistic anticancer effect with higher doses of Zn. As a metalloid, Se is an essential trace element in the human body, regulating selenoprotein synthesis, which is involved in antioxidant defense and prevents oxidative stress damage [30,31]. ...
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We investigated the associations between multiple serum trace element levels and risk for esophageal squamous cell carcinoma (ESCC). A total of 185 ESCC patients and 191 healthy individuals were recruited in our study. The concentration of 13 trace elements (Al, V, Cr, Mn, Co, Ni, Cu, Zn, As, Se, Sr, Cd and Pb) in serum was determined with inductively coupled plasma mass spectrometry (ICP-MS). Logistic regression and the Probit extension of Bayesian Kernel Machine Regression (BKMR) models was established to explore the associations and the cumulative and mixed effects of multiple trace elements on ESCC. Three elements (Zn, Se and Sr) displayed a negative trend with risk for ESCC, and a significant overall effect of the mixture of Al, V, Mn, Ni, Zn, Se and Sr on ESCC was found, with the effects of V, Ni and Sr being nonlinear. Bivariate exposure-response interactions among these trace elements indicated a synergistic effect between Zn and Se, and an impactful difference of V combined with Ni, Sr or Zn. Our results indicate that Ni, V, Al, Mn, Zn, Se and Sr are associated with ESCC risk, providing additional evidence of the complex effects of trace elements disorder during the etiology of EC development.
... High serum selenium levels have been suggested to prevent some cancers [46]. Similarly, 676 magnesium has been associated with decreased cancer risk [47] with its deficiency inhibiting 677 primary tumor growth but promoting metastasis [48]. ...
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High-dose ascorbate (vitamin C) has shown promising anticancer activity. Two redox mechanisms have been proposed: hydrogen peroxide generation by ascorbate itself or glutathione depletion by dehydroascorbate (formed by ascorbate oxidation). Here we show that the metabolic effects and cytotoxicity of high-dose ascorbate in vitro result from hydrogen peroxide independently of dehydroascorbate. These effects were suppressed by selenium through antioxidant selenoenzymes including glutathione peroxidase 1 (GPX1) but not the classic ferroptosis-inhibiting selenoenzyme GPX4. Selenium-mediated protection from ascorbate was powered by NADPH from the pentose phosphate pathway. In vivo, dietary selenium deficiency resulted in significant enhancement of ascorbate activity against glioblastoma xenografts. These data establish selenoproteins as key mediators of cancer redox homeostasis. Cancer sensitivity to free radical-inducing therapies, including ascorbate, may depend on selenium, providing a dietary approach for improving their anticancer efficacy. Significance Selenium restriction augments ascorbate efficacy and extends lifespan in a mouse xenograft model of glioblastoma, suggesting that targeting selenium-mediated antioxidant defenses merits clinical evaluation in combination with ascorbate and other pro-oxidant therapies.
... For instance, selenium is a cofactor of glutathione transferase and other selenoproteins [59]. It has notable antioxidant activity [60] and may be beneficial in chronic conditions such as cancer [61], heart disease [62], and cognitive disorders [63]. And copper, zinc, and manganese are cofactors of superoxide dismutase [64]. ...
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The consumption of diets rich in antioxidants may minimize the chances of developing debilitating diseases such as cardiovascular, diabetic, inflammatory, neoplastic, and cognitive disorders. The Fabaceae or pea family is the third most species-rich plant family on Earth and includes more than 19,000 species in over 700 genera. Many species of Fabaceae are ingredients of staple diets and medicinal substances. This may be attributable to the presumably high content of antioxidants in these plants, particularly phenolic compounds. The Republic of Suriname (South America) harbors over 400 species of Fabaceae in more than 100 genera and has a rich ethnopharmacological tradition that also involves a number of Fabaceae species. In this chapter, we evaluated the literature to determine whether the traditional use of eight of the medicinally most commonly employed Surinamese species of Fabaceae may be associated with their phenolic content and antioxidant activity. Our results suggest that this may hold true for Caesalpinia pulcherrima, Cajanus cajan, Clitoria ternatea, Desmodium adscendens, Lablab purpureus, and Tamarindus indica but not for Copaifera guyanensis and Dipteryx odorata, the bioactivities of which mainly seem to be determined by terpenoids and coumarins, respectively, without an apparent involvement of antioxidant effects.
... In addition to its role in immune function, Se also has a neuroprotective function through the role of selenoprotein P in delivery of Se to the brain, with risk of Alzheimer's and dementia being linked to Se status [2]. High Se exposure has also been found to reduce the risk of certain cancers including breast, lung, oesophageal, gastric, and prostate cancers [13]. ...
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Background: Selenium (Se) is a trace element found in many foodstuffs and critical for antioxidant and immune functions. Widespread Se deficiency has been noted in populations of some sub-Saharan African countries including Ethiopia and Malawi. As a first step towards developing a fuller understanding of problems with the availability of Se in the diet in Lusaka province, Zambia, we measured plasma Se in adults and children in this geographic area. Methods: Total plasma Se was measured using inductively coupled plasma optical emission spectrometry (ICP-OES) in several groups of adults recruited to various pre-existing studies, including those of high and low socioeconomic status (SES) and pregnant women, and children with a range of nutritional states (healthy, stunted or wasted). Results: A total of 660 plasma samples from 391 adults and 269 children were included. Adults had a median plasma Se concentration of 0.27 μmol/l (IQR 0.14-0.43). Concentrations consistent with deficiency (<0.63 μmol/l) were found in 83% of adults. Low SES was associated with low plasma Se among adults, [OR 0.1; 95% CI 0.1-0.3, p < 0.0001]. Among the children, 24% had plasma Se less than 0.41 μmol/l. There was a statistically significant positive correlation between plasma Se and age among children, Spearman's rho 0.47, p < 0.0001. Conclusions: These data suggest that Se deficiency is widespread in Lusaka province and could in part be related to socio-economic status. Supplementation or agronomic biofortification may therefore be needed.
... Hence, Bi-based nanocomponents such as Bi 2 S 3 nanorods, Bi 2 S 3 nanodots, and Bi 2 Se 3 nanostructures with various morphologies have been recemented as contrast agents (CT) photothermal/radiotherapy sensitizing agents [7]. Remarkably, Bi 2 Se 3 nanostructures possibly release vivacious selenium ions for reducing the fatality and occurrence of the prostate, liver, and lung cancers compared with Bi 2 S 3 [10] and also stated that two-dimensional materials have remarkable attention in X-ray irradiation and related metabolization to inhibit the growth of tumor [11]. Bi is one of the lessreactive heavy metals in the biological environment with minimal toxicity, and this is more appropriate for in vivo applications than other metals like silver [12]. ...
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Cancer is a lethal disease ravaging mankind claiming millions of lives. Most frequent methods of management include surgery, radiotherapy, chemotherapy, or a combination of all the above-mentioned methods. However, there is no specific medication available to cure this condition completely and several compounds and drugs are constantly explored for their therapeutic effects. Recently, photothermal therapy, photodynamic therapy, radiotherapy, targeted drug delivery, and hyperthermia have shown to be of great interest in cancer treatment. In this direction, bismuth oxide (Bi2O3) nanoparticles can be a promising option in cancer treatment and diagnosis as well. Bi is a well-known radioactive isotope; this emits high-energy gamma (γ) rays to the affected cells. This technology can pair with existing chemotherapy to enhance the therapeutic efficacy.
... The level of high Se exposure may have different effects on specific types of carcinomas. It alleviates the risk of lung carcinoma, breast carcinoma, prostate carcinoma, gastric carcinoma, and esophageal carcinoma (Cai et al. 2016). Selenium level in the serum of EC patients was significantly lower than the healthy controls (Goyal et al. 2006;Yang et al. 2021). ...
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Esophageal cancer is a very deadly disease ranking 8th most common cancer in terms of incidence and the 6th highest in terms of mortality both in the USA and around the world. A growing body of evidence indicated that changes in the concentrations of essential and toxic elements may affect/increase esophagus carcinoma risk. The aim of this study was to measure serum levels of essential and toxic (Fe, Na, Ca, K, Zn, Mg, Co, Se, Cu, Ni, Mn, Sr, Pb, Li, Sb, Cr, Ag, Cd, As, and Hg) elements in patients with esophagus carcinoma and controls. Atomic absorption spectroscopy was used to determine serum concentrations of essential and toxic elements by using nitric acid/perchloric acid–based wet digestion method. Mean levels of Cu, Ni, Cr, Cd, Pb, As, and Ag were exhibited to be significantly higher and mean Se, Co, Zn, Ca, Fe, Hg, Li, and Mg were noted lower in the serum of cancer patients than controls. The correlation coefficients among the elements in the cancerous patients revealed significantly dissimilar communal relationships than the controls. Furthermore, multivariate methods demonstrated considerably different apportionment between the elements in the cancerous patients and the controls. Significant inequalities in the elemental concentrations were also observed for esophagus cancer types (adenocarcinoma and squamous cell carcinoma) and stages (I, II, III, and IV) between the patients. Majority of the elements exposed perceptible disparities in their levels based on smoking habits, dietary habits, habitat, and gender of the esophagus cancer patients and controls. Multivariate analysis of the essential and toxic elemental data explained significantly divergent apportionment in the serum of esophagus cancer patients when compared to controls.
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Selenium, reported as an important medium for maintaining the body’s homeostasis, acts to have multiple bioeffects including anti-inflammatory, anti-oxidant and anti-apoptosis effects. However, its role in heart failure still remains unclear. In this study, we explored the effects of selenium on heart failure and its possible mechanism. The heart failure models were induced by aortic banding and isoproterenol. H&E, TUNEL and PSR staining were performed to detect the degree of cardiomyocyte hypertrophy, apoptosis rates and heart fibrosis, respectively. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to detect different mRNA levels, and western blot was applied to assess the expressions of relative proteins. Immunofluorescence staining was used to evaluate α-SMA density. We first found that treatment of selenium alleviated heart fibrosis and the development of heart failure but not cardiomyocyte cross sectional areas. Besides, selenium improved heart levels of superoxide dismutase2 (SOD2), glutathione peroxidase (Gpx) and glutathione (GSH) and the activity of SOD, accompanied by decreased apoptosis rate. In addition, our in vitro study has shown that selenium reduced mRNA levels of collagen Ⅰ and collagen III, expressions of a-SMA, p-AKT/AKT and p-GSK-3β/ GSK-3β, apoptosis rates and reactive oxygen species (ROS) levels in H9C2 cardio-myoblasts treated with TGF-β1. Moreover, the level of Sirt1 was found to be up-regulated by selenium which effects were weakened after the administration of small interfering RNA (siRNA)-Sirt1 or EX527 (inhibitor of Sirt1). Our current results have demonstrated that the protective effects of selenium on heart hypertrophy is through the regulation of Sirt1 and AKT/GSK-3β pathway.
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Background: Vitamin C is an essential micronutrient and powerful antioxidant. Observational studies have shown an inverse relationship between vitamin C intake and major cardiovascular events and cardiovascular disease (CVD) risk factors. Results from clinical trials are less consistent. Objectives: To determine the effectiveness of vitamin C supplementation as a single supplement for the primary prevention of CVD. Search methods: We searched the following electronic databases on 11 May 2016: the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library; MEDLINE (Ovid); Embase Classic and Embase (Ovid); Web of Science Core Collection (Thomson Reuters); Database of Abstracts of Reviews of Effects (DARE); Health Technology Assessment Database and Health Economics Evaluations Database in the Cochrane Library. We searched trial registers on 13 April 2016 and reference lists of reviews for further studies. We applied no language restrictions. Selection criteria: Randomised controlled trials of vitamin C supplementation as a single nutrient supplement lasting at least three months and involving healthy adults or adults at moderate and high risk of CVD were included. The comparison group was no intervention or placebo. The outcomes of interest were CVD clinical events and CVD risk factors. Data collection and analysis: Two review authors independently selected trials for inclusion, abstracted the data and assessed the risk of bias. Main results: We included eight trials with 15,445 participants randomised. The largest trial with 14,641 participants provided data on our primary outcomes. Seven trials reported on CVD risk factors. Three of the eight trials were regarded at high risk of bias for either reporting or attrition bias, most of the 'Risk of bias' domains for the remaining trials were judged as unclear, with the exception of the largest trial where most domains were judged to be at low risk of bias.The composite endpoint, major CVD events was not different between the vitamin C and placebo group (hazard ratio (HR) 0.99, 95% confidence interval (CI) 0.89 to 1.10; 1 study; 14,641 participants; low-quality evidence) in the Physicians Health Study II over eight years of follow-up. Similar results were obtained for all-cause mortality HR 1.07, 95% CI 0.97 to 1.18; 1 study; 14,641 participants; very low-quality evidence, total myocardial infarction (MI) (fatal and non-fatal) HR 1.04 (95% CI 0.87 to 1.24); 1 study; 14,641 participants; low-quality evidence, total stroke (fatal and non-fatal) HR 0.89 (95% CI 0.74 to 1.07); 1 study; 14,641 participants; low-quality evidence, CVD mortality HR 1.02 (95% 0.85 to 1.22); 1 study; 14,641 participants; very low-quality evidence, self-reported coronary artery bypass grafting (CABG)/percutaneous transluminal coronary angioplasty (PTCA) HR 0.96 (95% CI 0.86 to 1.07); 1 study; 14,641 participants; low-quality evidence, self-reported angina HR 0.93 (95% CI 0.84 to 1.03); 1 study; 14,641 participants; low-quality evidence.The evidence for the majority of primary outcomes was downgraded (low quality) because of indirectness and imprecision. For all-cause mortality and CVD mortality, the evidence was very low because more factors affected the directness of the evidence and because of inconsistency.Four studies did not state sources of funding, two studies declared non-commercial funding and two studies declared both commercial and non-commercial funding. Authors' conclusions: Currently, there is no evidence to suggest that vitamin C supplementation reduces the risk of CVD in healthy participants and those at increased risk of CVD, but current evidence is limited to one trial of middle-aged and older male physicians from the USA. There is limited low- and very low-quality evidence currently on the effect of vitamin C supplementation and risk of CVD risk factors.
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BACKGROUND: Selenium is a trace element essential to humans. Higher selenium exposure and selenium supplements have been suggested to protect against several types of cancers. OBJECTIVE: Two research questions were addressed in this review: What is the evidence for: 1. an aetiological relationship between selenium exposure and cancer risk in women and men?; 2. the efficacy of selenium supplementation for cancer prevention in women and men? SEARCH STRATEGY: We searched electronic databases and bibliographies of reviews and included publications. SELECTION CRITERIA: We included prospective observational studies to answer research question (a) and randomised controlled trials (RCTs) to answer research question (b). DATA COLLECTION AND ANALYSIS: We conducted random effects meta-analyses of epidemiological data when five or more studies were retrieved for a specific outcome. We made a narrative summary of data from RCTs. MAIN RESULTS: We included 49 prospective observational studies and six RCTs. In epidemiologic data, we found a reduced cancer incidence (summary odds ratio, OR, 0.69; 95% confidence interval, CI, 0.53 to 0.91) and mortality (OR 0.55, 95% CI 0.36 to 0.83) with higher selenium exposure. Cancer risk was more pronouncedly reduced in men (incidence: OR 0.66, 95% CI 0.42 to 1.05) than in women (incidence: OR 0.90, 95% CI 0.45 to 1.77). These findings have potential limitations due to study design, quality and heterogeneity of the data, which complicated the interpretation of the summary statistics. The RCTs found no protective efficacy of selenium yeast supplementation against non-melanoma skin cancer or L-selenomethionine supplementation against prostate cancer. Study results for the prevention of liver cancer with selenium supplements were inconsistent and studies had an unclear risk of bias. The results of the Nutritional Prevention of Cancer Trial (NPCT) and SELECT raised concerns about possible harmful effects of selenium supplements. AUTHORS' CONCLUSIONS: No reliable conclusions can be drawn regarding a causal relationship between low selenium exposure and an increased risk of cancer. Despite evidence for an inverse association between selenium exposure and the risk of some types of cancer, these results should be interpreted with care due to the potential limiting factors of heterogeneity and influences of unknown biases, confounding and effect modification. The effect of selenium supplementation from RCTs yielded inconsistent results. To date, there is no convincing evidence that selenium supplements can prevent cancer in men, women or children.
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Background: This review is the third update of the Cochrane review "Selenium for preventing cancer". Selenium is a naturally occurring element with both nutritional and toxicological properties. Higher selenium exposure and selenium supplements have been suggested to protect against several types of cancer. Objectives: To gather and present evidence needed to address two research questions:1. What is the aetiological relationship between selenium exposure and cancer risk in humans?2. Describe the efficacy of selenium supplementation for cancer prevention in humans. Search methods: We updated electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2), MEDLINE (Ovid, 2013 to January 2017, week 4), and Embase (2013 to 2017, week 6), as well as searches of clinical trial registries. Selection criteria: We included randomised controlled trials (RCTs) and longitudinal observational studies that enrolled adult participants. Data collection and analysis: We performed random-effects (RE) meta-analyses when two or more RCTs were available for a specific outcome. We conducted RE meta-analyses when five or more observational studies were available for a specific outcome. We assessed risk of bias in RCTs and in observational studies using Cochrane's risk assessment tool and the Newcastle-Ottawa Scale, respectively. We considered in the primary analysis data pooled from RCTs with low risk of bias. We assessed the certainty of evidence by using the GRADE approach. Main results: We included 83 studies in this updated review: two additional RCTs (10 in total) and a few additional trial reports for previously included studies. RCTs involved 27,232 participants allocated to either selenium supplements or placebo. For analyses of RCTs with low risk of bias, the summary risk ratio (RR) for any cancer incidence was 1.01 (95% confidence interval (CI) 0.93 to 1.10; 3 studies, 19,475 participants; high-certainty evidence). The RR for estimated cancer mortality was 1.02 (95% CI 0.80 to 1.30; 1 study, 17,444 participants). For the most frequently investigated site-specific cancers, investigators provided little evidence of any effect of selenium supplementation. Two RCTs with 19,009 participants indicated that colorectal cancer was unaffected by selenium administration (RR 0.99, 95% CI 0.69 to 1.43), as were non-melanoma skin cancer (RR 1.16, 95% CI 0.30 to 4.42; 2 studies, 2027 participants), lung cancer (RR 1.16, 95% CI 0.89 to 1.50; 2 studies, 19,009 participants), breast cancer (RR 2.04, 95% CI 0.44 to 9.55; 1 study, 802 participants), bladder cancer (RR 1.07, 95% CI 0.76 to 1.52; 2 studies, 19,009 participants), and prostate cancer (RR 1.01, 95% CI 0.90 to 1.14; 4 studies, 18,942 participants). Certainty of the evidence was high for all of these cancer sites, except for breast cancer, which was of moderate certainty owing to imprecision, and non-melanoma skin cancer, which we judged as moderate certainty owing to high heterogeneity. RCTs with low risk of bias suggested increased melanoma risk.Results for most outcomes were similar when we included all RCTs in the meta-analysis, regardless of risk of bias. Selenium supplementation did not reduce overall cancer incidence (RR 0.99, 95% CI 0.86 to 1.14; 5 studies, 21,860 participants) nor mortality (RR 0.81, 95% CI 0.49 to 1.32; 2 studies, 18,698 participants). Summary RRs for site-specific cancers showed limited changes compared with estimates from high-quality studies alone, except for liver cancer, for which results were reversed.In the largest trial, the Selenium and Vitamin E Cancer Trial, selenium supplementation increased risks of alopecia and dermatitis, and for participants with highest background selenium status, supplementation also increased risk of high-grade prostate cancer. RCTs showed a slightly increased risk of type 2 diabetes associated with supplementation. A hypothesis generated by the Nutritional Prevention of Cancer Trial - that individuals with low blood selenium levels could reduce their risk of cancer (particularly prostate cancer) by increasing selenium intake - has not been confirmed. As RCT participants have been overwhelmingly male (88%), we could not assess the potential influence of sex or gender.We included 15 additional observational cohort studies (70 in total; over 2,360,000 participants). We found that lower cancer incidence (summary odds ratio (OR) 0.72, 95% CI 0.55 to 0.93; 7 studies, 76,239 participants) and lower cancer mortality (OR 0.76, 95% CI 0.59 to 0.97; 7 studies, 183,863 participants) were associated with the highest category of selenium exposure compared with the lowest. Cancer incidence was lower in men (OR 0.72, 95% CI 0.46 to 1.14, 4 studies, 29,365 men) than in women (OR 0.90, 95% CI 0.45 to 1.77, 2 studies, 18,244 women). Data show a decrease in risk of site-specific cancers for stomach, colorectal, lung, breast, bladder, and prostate cancers. However, these studies have major weaknesses due to study design, exposure misclassification, and potential unmeasured confounding due to lifestyle or nutritional factors covarying with selenium exposure beyond those taken into account in multi-variable analyses. In addition, no evidence of a dose-response relation between selenium status and cancer risk emerged. Certainty of evidence was very low for each outcome. Some studies suggested that genetic factors might modify the relation between selenium and cancer risk - an issue that merits further investigation. Authors' conclusions: Well-designed and well-conducted RCTs have shown no beneficial effect of selenium supplements in reducing cancer risk (high certainty of evidence). Some RCTs have raised concerns by reporting a higher incidence of high-grade prostate cancer and type 2 diabetes in participants with selenium supplementation. No clear evidence of an influence of baseline participant selenium status on outcomes has emerged in these studies.Observational longitudinal studies have shown an inverse association between selenium exposure and risk of some cancer types, but null and direct relations have also been reported, and no systematic pattern suggesting dose-response relations has emerged. These studies suffer from limitations inherent to the observational design, including exposure misclassification and unmeasured confounding.Overall, there is no evidence to suggest that increasing selenium intake through diet or supplementation prevents cancer in humans. However, more research is needed to assess whether selenium may modify the risk of cancer in individuals with a specific genetic background or nutritional status, and to investigate possible differential effects of various forms of selenium.
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Background: From March 1986 through May 1991, we conducted a randomized nutritional intervention trial, the General Population Trial, in Linxian, China, a region with epidemic rates of squamous esophageal and adenomatous gastric cardia cancers. We found that participants who received selenium, β-carotene, and vitamin E had significantly lower cancer mortality rates than those who did not. In the current study, we examined the relationship between selenium levels measured in pretrial (1985) sera from participants and the subsequent risk of developing squamous esophageal, gastric cardia, and gastric non-cardia cancers during the trial. Methods: This study was designed and analyzed in accord with a stratified case-cohort sampling scheme, with the six strata defined by sex and three age categories. We measured serum selenium levels in 590 case subjects with esophageal cancer, 402 with gastric cardia cancers, and 87 with gastric non-cardia cancers as well as in 1062 control subjects. Relative risks (RRs), absolute risks, and population attributable risk for cancers were estimated on the basis of the Cox proportional hazards models. All statistical tests are two-sided. Results: We found highly significant inverse associations of serum selenium levels with the incidence of esophageal (P for trend <10 -4 ) and gastric cardia (P for trend <10 -6 ) cancers. The RR and 95% confidence interval (CI) for comparison of highest to lowest quartile of serum selenium was 0.56 (95% CI = 0.44-0.71) for esophageal cancer and 0.47 (95% CI = 0.33-0.65) for gastric cardia cancer. The population proportion of these cancers that is attributable to low selenium levels was 26.4% (95% CI = 14.45-38.36). We found no evidence for a gradient of serum selenium associated with incidence of gastric non-cardia cancer (P for trend =.96), with an RR of 1.07 (95% CI = 0.55-2.08) for the highest to lowest quartile of serum selenium. Conclusions: Our study supports findings from previous prospective studies and randomized trials that variations in selenium levels affect the incidence of certain cancers. In the United States, where intervention trials of selenium are in the planning stages, consideration should be given to including populations at high risk for squamous esophageal and gastric cardia cancers.