nu ien s
A icle
Associa ion be ween Polyphenol In ake and Gas ic
Cance Risk by Ana omic and His ologic
Sub ypes: MCC-Spain
Ma ía Rubín-Ga cía1, Facundo Vi elli-S o elli 1,* , An onio JoséMolina 1,
Raúl Zamo a-Ros 2, Nu ia A agonés3,4, E a Ada naz 4,5, Gemma Cas año-Vinyals 4,6,7,8 ,
Mi eia Obón-San acana 9,10 , Inés Gómez-Acebo 4,11 , Ana Molina-Ba celó12,
Guille mo Fe nández-Ta dón4,13, JoséJ Jiménez-Moleón4,14 , Juan Alguacil 4,15,
Ma ía Dolo es Chi laque 4,16, Es e anía Toledo 5,17,18 , Bea iz Pé ez-Gómez 4,19,20 ,
Ma ina Pollán4,19, Manolis Koge inas 4,6,7,8 and Vicen e Ma ín1,4
1G oup o In es iga ion in In e ac ions Gene-En i onmen and Heal h (GIIGAS); Ins i u e o
Biomedicine (IBIOMED), Uni e si y o León, 24071 León, Spain; [email p o ec ed] (M.R.-G.);
[email p o ec ed] (A.J.M.); [email p o ec ed] (V.M.)
2Uni o Nu i ion and Cance , Cance Epidemiology Resea ch P og amme, Ca alan Ins i u e o
Oncology (ICO), Bell i ge Biomedical Resea ch Ins i u e (IDIBELL), L’Hospi ale del Llob ega ,
08908 Ba celona, Spain; aulzamo a [email p o ec ed]
3Depa men o Heal h o Mad id, Epidemiology Sec ion, Public Heal h Di ision, 28035 Mad id, Spain;
[email p o ec ed]
4Conso ium o Biomedical Resea ch in Epidemiology & Public Heal h (CIBER en Epidemiología y Salud
Pública-CIBERESP), 28029 Mad id, Spain; [email p o ec ed] (E.A.);
[email p o ec ed] (G.C.-V.); [email p o ec ed] (I.G.-A.);
[email p o ec ed] (G.F.-T.); jjmoleon@ug .es (J.J.J.-M.); [email p o ec ed] (J.A.);
[email p o ec ed] (M.D.C.); bpe [email p o ec ed] (B.P.-G.); [email p o ec ed] (M.P.);
[email p o ec ed] (M.K.)
5Ins i u e o Heal h Resea ch (IdiSNA), 31008 Pamplona, Spain; e oledo@una .es
6Ba celona Ins i u e o Global Heal h (ISGlobal), 08036 Ba celona, Spain
7Hospi al del Ma Medical Resea ch Ins i u e (IMIM), 08003 Ba celona, Spain
8Depa men o Public Heal h, Uni e si a Pompeu Fab a (UPF), Campus del Ma , 08002 Ba celona, Spain
9ONCOBELL P og am, Bell i ge Biomedical Resea ch Ins i u e (IDIBELL), L’Hospi ale De Llob ega ,
08908 Ba celona, Spain; [email p o ec ed]
10
Oncology Da a Analy ics P og am (ODAP), Ca alan Ins i u e o Oncology (ICO), L’Hospi ale Del Llob ega ,
08908 Ba celona, Spain
11 Facul ad de Medicina, Uni e sidad de Can ab ia; IDIVAL, 39011 San ande , Spain
12 Cance and Public Heal h A ea, FISABIO-Public Heal h, 46020 Valencia, Spain; [email p o ec ed]
13 Heal h Resea ch Ins i u e o he P incipali y o As u ias (ISPA), Oncology Ins i u e, Uni e si y o O iedo,
33003 O iedo, As u ias
14
Ins i u o de In es igaci
ó
n Biosani a ia de G anada (ibs.GRANADA), Hospi ales Uni e si a ios de G anada;
Uni e sidad de G anada, 18071 G anada, Spain
15 Cen o de In es igación en Recu sos Na u ales, Salud y Medio Ambien e (RENSMA), Uni e sidad de
Huel a, Campus Uni e si a io de El Ca men, 21071 Huel a, Spain
16 Depa men o Epidemiology, Regional Heal h Council, IMIB-A ixaca, Mu cia Uni e si y,
Campus de Ciencias de la Salud, 30120 El Palma , Mu cia, Spain
17 Cen o de In es igación Biomédica en Red Fisiopa ología de la Obesidad y la Nu ición (CIBEROBN),
Ins i u e o Heal h Ca los III, 28029 Mad id, Spain
18 Depa men o P e en i e Medicine and Public Heal h, Uni e si y o Na a a, 31008 Pamplona, Spain
19 Cance and En i onmen al Epidemiology Uni , Depa men o Epidemiology and Ch onic Diseases,
Na ional Cen e o Epidemiology, Ca los III Ins i u e o Heal h, 28029 Mad id, Spain
20 Cance Epidemiology Resea ch G oup, Oncology and Hema ology A ea, IIS Pue a de Hie o, IDIPHIM,
28222 Mad id, Spain
*Co espondence: [email p o ec ed]; Tel.: +34-625-070-838
Nu ien s 2020,12, 3281; doi:10.3390/nu12113281 www.mdpi.com/jou nal/nu ien s
Nu ien s 2020,12, 3281 2 o 16
Recei ed: 17 Sep embe 2020; Accep ed: 21 Oc obe 2020; Published: 26 Oc obe 2020


Abs ac :
Se e al an icance p ope ies ha e been la gely a ibu ed o phenolics in
in i o
and
in i o s udies, bu epidemiologic e idence is s ill sca ce. Fu he mo e, some classes ha e no been
s udied in ela ion o gas ic cance (GC). The aim o his s udy was o assess he ela ionship be ween
he in ake o phenolic acids, s ilbenes, and o he phenolics and he isk o de eloping GC and i s
ana omical and his ological sub ypes. We used da a om a mul i-case-con ol s udy (MCC-Spain)
ob ained om di e en egions o Spain. We included 2700 con ols and 329 GC cases. Odds
a ios (ORs) we e calcula ed using mixed e ec s logis ic eg ession conside ing qua iles o phenolic
in ake. Ou esul s showed an in e se associa ion be ween s ilbene and lignan in ake and GC isk
(OR
Q4 s. Q1
=0.47; 95% CI: 0.32–0.69 and OR
Q4 s. Q1
=0.53; 95% CI: 0.36–0.77, espec i ely). We
ound no o e all associa ion be ween o al phenolic acid and o he polyphenol class in ake and GC
isk. Howe e , hyd oxybenzaldehydes (OR
Q4 s. Q1
=0.41; 95% CI: 0.28–0.61), hyd oxycouma ins
(OR
Q4 s. Q1
=0.49; 95% CI: 0.34–0.71), and y osols (OR
Q4 s. Q1
=0.56; 95% CI: 0.39–0.80) we e
in e sely associa ed wi h GC isk. No di e ences we e ound in he analysis by ana omical o
his ological sub ypes. In conclusion, a die high in s ilbenes, lignans, hyd oxybenzaldehydes,
hyd oxycouma ins, and y osols was associa ed wi h a lowe GC isk. Fu he p ospec i e s udies
a e needed o con i m ou esul s.
Keywo ds:
die ; epidemiology; gas ic cance ; polyphenols; phenolic acids; s ilbenes; lignans;
ana omic; his ologic; MCC-Spain
1. In oduc ion
Gas ic cance (GC) is he hi d leading cause o cance - ela ed dea h in he wo ld [
1
], and i s
5-yea su i al a e diagnosis is below 30% in many coun ies [
2
]. GC incidence a es a y ac oss
geog aphical a eas, p obably due o isk ac o s such as die a y pa e ns, li es yle habi s, gene ics,
and exposu e o ca cinogens [3].
Be ween 10% and 20% o GC pa ien s ha e a amily his o y—al hough only 1–3% o hem show a
clea Mendelian inhe i ance pa e n—and 80% o 90% a e conside ed spo adic [
4
]. Thus, en i onmen al
ac o s seem highly ele an o gas ic ca cinogenesis and, he e o e, a la ge p opo ion o GC cases
a e po en ially p e en able.
Mo e han 20% o dea hs due o GC a e a ibu ed o obesi y/o e weigh , 5% o physical inac i i y,
5% o excessi e alcohol consump ion, and 5% o a poo die [
5
], which a e all ela ed o li es yles.
Acco dingly, ui consump ion has been iden i ied as a p o ec i e ac o agains GC and his may
pa ly be due o he ui ’s con en o polyphenols (PLPs) [6].
PLPs a e seconda y me aboli es o plan s, which can be ound in ui , ege ables, ce eals, and hei
de i ed be e ages (such as co ee, ea, wine, and juices). These compounds ha e been shown o exe
p e en i e p ope ies agains a wide ange o ch onic condi ions, including diabe es, ca dio ascula
p oblems, neu odegene a i e diseases, and cance [7,8].
The an icance p ope ies o PLPs ha e been la gely a ibu ed o hei g ea an i-in lamma o y
and an ioxidan po en ial, as well as hei abili y o modula e signaling pa hways and molecula a ge s.
These mechanisms ha e been associa ed wi h cance p ocesses such as cell su i al, di e en ia ion,
p oli e a ion, mig a ion, ho monal ac i i ies, angiogenesis, immune esponses, o de oxi ying
enzymes [9].
Mos o his knowledge has been ob ained om
in i o
s udies, which ha e mainly ocused on
he la onoid amily [
10
]. O he PLP amilies, such as phenolic acids, s ilbenes, lignans, and o he
phenolics, ha e been less s udied; howe e , epidemiological e idence is s ill limi ed [11].
Nu ien s 2020,12, 3281 3 o 16
Since isk ac o s o GC a e di e en depending on i s ana omical and his ological sub ype [
12
,
13
],
we hypo hesize ha he di e en classes o PLPs can be associa ed wi h di e en GC ypes. The aim o
his s udy was o assess whe he he in ake o phenolic acids, s ilbenes, lignans, and o he PLPs was
associa ed wi h he isk o de eloping GC, also acco ding o i s ana omical and his ological sub ypes.
2. Ma e ials and Me hods
2.1. S udy Popula ion
The mul i-case-con ol (MCC)-Spain s udy is a mul icen e , popula ion-based case-con ol s udy
ha was ca ied ou in 12 Spanish p o inces o examine po en ial associa ions be ween en i onmen al
and gene ic ac o s and he isk o i e common cance s. De ailed in o ma ion on he s udy design
can be ound elsewhe e [
14
]. Cases and con ols we e ec ui ed om 2008 o 2013 in 16 hospi als.
The inclusion c i e ia o cases o his ologically con i med gas ic umo s we e ha ing li ed o a leas
six mon hs in he a ea o he hospi al and being be ween 20 and 85 yea s old. Con ols we e equency
ma ched o he o e all dis ibu ion o cance cases by age, sex, and egion (p o ince).
Fo he speci ic case o GC, MCC-Spain ec ui ed 459 cases o GC and 3440 con ols. In he
p esen s udy, 329 cases and 2700 con ols we e included a e excluding pa icipan s wi h missing
da a (Figu e 1).
Nu ien s 2020, 12, x FOR PEER REVIEW 3 o 17
PLPs was associa ed wi h he isk o de eloping GC, also acco ding o i s ana omical and his ological
sub ypes.
2. Ma e ials and Me hods
2.1. S udy Popula ion
The mul i-case-con ol (MCC)-Spain s udy is a mul icen e , popula ion-based case-con ol s udy
ha was ca ied ou in 12 Spanish p o inces o examine po en ial associa ions be ween
en i onmen al and gene ic ac o s and he isk o i e common cance s. De ailed in o ma ion on he
s udy design can be ound elsewhe e [14]. Cases and con ols we e ec ui ed om 2008 o 2013 in 16
hospi als. The inclusion c i e ia o cases o his ologically con i med gas ic umo s we e ha ing li ed
o a leas six mon hs in he a ea o he hospi al and being be ween 20 and 85 yea s old. Con ols
we e equency ma ched o he o e all dis ibu ion o cance cases by age, sex, and egion (p o ince).
Fo he speci ic case o GC, MCC-Spain ec ui ed 459 cases o GC and 3440 con ols. In he
p esen s udy, 329 cases and 2700 con ols we e included a e excluding pa icipan s wi h missing
da a (Figu e 1).
All pa icipan s signed he in o med consen a e ha ing been p e iously in o med abou he
s udy. The s udy was designed acco ding o he Decla a ion o Helsinki and he Spanish Da a
P o ec ion Ac 1999, and he e hics commi ees o he pa icipa ing ins i u ions app o ed he MCC-
Spain s udy p o ocol [15].
Figu e 1. Flowcha o he pa icipan s’ selec ion in he mul i-case-con ol (MCC)-Spain s udy.
2.2. Classi ica ion o Tumo s
The pa hology in o ma ion and he es o eco ds ob ained ega ding he his ology and
ana omy o he GC we e e iewed by quali ied pe sonnel. Collec ed clinical in o ma ion o each
gas ic umo case included ana omical sub ype (ca dia and non-ca dia), ex ension, and his ological
sub ype (in es inal and di use).
2.3. Va iables and Da a Collec ion
Cases and con ols we e in e iewed by ained pe sonnel a baseline. In o ma ion on
sociodemog aphic ac o s, heal h beha io s (as physical ac i i y o smoking), medical condi ions and
medical ea men s, and amily his o y o cance was collec ed. In addi ion, cases and con ols
epo ed die a y habi s, including cu en and pas alcohol consump ion ( om 30 o 40 yea s old),
mainly wi h a sel -adminis e ed ques ionnai e.
2.3.1. Assessmen o Nu ien In ake
Figu e 1. Flowcha o he pa icipan s’ selec ion in he mul i-case-con ol (MCC)-Spain s udy.
All pa icipan s signed he in o med consen a e ha ing been p e iously in o med abou he
s udy. The s udy was designed acco ding o he Decla a ion o Helsinki and he Spanish Da a P o ec ion
Ac 1999, and he e hics commi ees o he pa icipa ing ins i u ions app o ed he MCC-Spain s udy
p o ocol [15].
2.2. Classi ica ion o Tumo s
The pa hology in o ma ion and he es o eco ds ob ained ega ding he his ology and ana omy
o he GC we e e iewed by quali ied pe sonnel. Collec ed clinical in o ma ion o each gas ic
umo case included ana omical sub ype (ca dia and non-ca dia), ex ension, and his ological sub ype
(in es inal and di use).
2.3. Va iables and Da a Collec ion
Cases and con ols we e in e iewed by ained pe sonnel a baseline. In o ma ion on
sociodemog aphic ac o s, heal h beha io s (as physical ac i i y o smoking), medical condi ions and
medical ea men s, and amily his o y o cance was collec ed. In addi ion, cases and con ols epo ed
Nu ien s 2020,12, 3281 4 o 16
die a y habi s, including cu en and pas alcohol consump ion ( om 30 o 40 yea s old), mainly wi h a
sel -adminis e ed ques ionnai e.
2.3.1. Assessmen o Nu ien In ake
A alida ed ood- equency ques ionnai e (FFQ) [
16
] was collec ed a ec ui men . The MCC-Spain
die a y ques ionnai e includes ques ions abou he p e ious yea ’s equency o consump ion o oods
g ouped unde en ood ca ego ies: (1) Mea (p oduc s such as lamb, poul y, bee , po k, eggs, ish and
sea ood, and p ecooked mea -de i ed ood), (2) legumes and ege ables, (3) nu s and ui s, (4) dai y
p oduc s, (5) ce eals (including b ead and pas a), (6) seasonings and sauces, (7) oils and a s, (8) swee s
and snacks, (9) i amin and mine al supplemen s, (10) alcoholic and o he be e ages.
The daily consump ion o each ood was es ima ed based on e e ence ables o ood se ings.
As in o he s udies, i a gi en ood was a ecipe (e.g., ege able pu ee o gazpacho) he lis o ing edien s
was calcula ed [17].
2.3.2. Analysis o PLP In ake
The PLP classes conside ed in he p esen s udy we e phenolic acids (including hyd oxybenzoic
acids, hyd oxycinnamic acids, and hyd oxyphenylace ic acids) s ilbenes, lignans, and o he
phenolics (including alkylme hoxyphenols, me hoxyphenols, hyd oxycouma ins, y osols, and o he
mino phenolics).
Fo he analysis o PLP in ake, a subse o 58 oods was conside ed, including legumes and
ege ables, ui s, ce eals, swee s and snacks, and alcoholic be e ages and o he s. To es ima e PLP
in ake, ins ead o conside ing he amoun o all indi idual PLP chemical species (glycosides, es e s,
e c.) epo ed o di e en oods, we used aglycone equi alen s. Die a y in ake o he aglycone o ms
o PLP was es ima ed om he Phenol-Explo e da abase [
18
]. The a ionale o his decision was o
s anda dize da a om di e en analy ical me hods o acili a e compa isons be ween s udies [19].
PLP in ake was calcula ed in millig ams pe day, based on he ood consump ion da a om he
FFQ and he aglycone PLP con en o each ood e e ed in he Phenol-Explo e da abase. Es ima ion
o he PLP con en s in ol ed ob aining he aglycone equi alen s o each PLP subg oup and oods
included in he Phenol-Explo e da abase. No e en ion ac o s we e applied in he calcula ion o he
amoun o PLP in ake.
2.4. S a is ical Analysis
Desc ip i e s a is ics we e used o display cha ac e is ics o cases and con ols and by he umo ’s
speci ic loca ion and his ology. Compa isons be ween cases and con ols and be ween ana omical and
his ological sub ypes we e ca ied ou using he Pea son chi squa e es (
χ2
) o ca ego ical a iables.
Depending on he no mali y o he con inuous a iables, ANOVA o K uskal-Wallis es s we e used
o quali a i e ai s. Signi icance o all s a is ical es s was se a p<0.05.
PLP in ake alues we e adjus ed o ene gy in ake [
20
] o es ima e isocalo ic in ake o PLPs,
sepa a ely o men and women.
PLP in ake was ca ego ized in o qua iles acco ding o he sample dis ibu ion among con ols
s a i ied by sex, and he lowes consump ion ca ego y was always used as e e ence.
As addi ional analysis, PLP in ake was ans o med o log2, since he da a we e igh -skewed [
21
].
This ans o ma ion had he same no malizing e ec as he ene gy-adjus ed by esidual me hod.
I s in e p e a ion is simple , gi en ha he odds a ios (ORs) indica e he odds o GC when he in ake
is doubled (Supplemen a y Table S1).
Mixed-e ec s mul i a ia e logis ic eg ession models we e pe o med o assess he associa ion
be ween PLP in ake and cance isk, including s udy a ea as a andom e ec e m. Values a e shown
as OR and 95% con idence in e al (CI). O he a iables included in he mul i a iable model we e age;
sex; socioeconomic s a us (low, medium, and high); i s -deg ee amily his o y o GC; physical ac i i y
(as me abolic equi alen ask (MET)-h/week); body mass index (BMI); smoking s a us; consump ion o
Nu ien s 2020,12, 3281 5 o 16
alcohol, ege ables, ed mea , and sal ; and o al ene gy in ake. Mixed-e ec s logis ic eg essions we e
pe o med wi h S a a s a is ical so wa e elease 13 [
22
]. Py hon e sion 3.14 [
23
] was used o he
ex ac ion o Phenol-Explo e web da a on polyphenol con en in oods, and R e sion 3.6 [
24
] was
used o he calcula ion o he PLP in ake by indi iduals.
3. Resul s
This s udy includes 329 GC cases and 2700 con ols whose cha ac e is ics a e desc ibed in Table 1.
Cases we e mos ly male (72.6%) and had a highe pe cen age o amily his o y o GC han ha in
con ols (16.1 s. 6.3). In addi ion, hey p esen ed a la ge pe cen age o high alcohol d inke s and
consumed on a e age mo e ed mea (84.4 s. 64.0 g/d) and mo e sodium (3529.3 s. 3008.6 mg/g).
The a e age consump ion o he PLP subclasses o he en i e sample is shown in Table 2, as well as
main ood sou ces o he di e en PLP subclasses.
Associa ions be ween he in ake o phenolic classes and subclasses and he odds o de eloping
GC a e shown in Figu e 2. S ilbenes we e associa ed wi h a educ ion in he odds o o al GC by 53%
(95% CI 0.32–0.69), lignans educed he isk by 47% (95% CI 0.36–0.77), and hyd oxybenzaldehydes by
59% (95% CI 0.28–0.61). The hyd oxycouma in subclass was associa ed wi h a 51% (95% CI 0.34–0.71)
educ ion in o al GC isk, and y osols we e associa ed wi h 44% lowe odds o GC (95% CI 0.39–0.80).
Rega ding he consump ion o o he PLP subclass, he isk o o al GC inc eased by 49% (95% CI
1.06–2.10). Hyd oxybenzoic acids and hyd oxyphenylace ic acids showed p o ec i e endencies and
hyd oxycinnamic acids, me hoxyphenols, and o he PLPs (subclass) ended o inc ease he isk agains
GC al hough none o hese associa ions we e s a is ically signi ican .
Nu ien s 2020, 12, x FOR PEER REVIEW 8 o 17
Associa ions be ween he in ake o phenolic classes and subclasses and he odds o de eloping
GC a e shown in Figu e 2. S ilbenes we e associa ed wi h a educ ion in he odds o o al GC by 53%
(95% CI 0.32–0.69), lignans educed he isk by 47% (95% CI 0.36–0.77), and hyd oxybenzaldehydes
by 59% (95% CI 0.28–0.61). The hyd oxycouma in subclass was associa ed wi h a 51% (95% CI 0.34–
0.71) educ ion in o al GC isk, and y osols we e associa ed wi h 44% lowe odds o GC (95% CI
0.39–0.80). Rega ding he consump ion o o he PLP subclass, he isk o o al GC inc eased by 49%
(95% CI 1.06–2.10). Hyd oxybenzoic acids and hyd oxyphenylace ic acids showed p o ec i e
endencies and hyd oxycinnamic acids, me hoxyphenols, and o he PLPs (subclass) ended o
inc ease he isk agains GC al hough none o hese associa ions we e s a is ically signi ican .
When he associa ion be ween he in ake o PLP and GC was analyzed acco ding o he
ana omical si e (Figu e 3), esul s we e simila o he esul s o GC isk. Hyd oxyphenylace ic acids
showed a 50% dec ease (95% CI 0.26–0.96) in he isk o he ca dia sub ype, s ilbenes o 56% (95% CI
0.28–0.70), and o he PLP subclasses o 50% (95% CI 1.01–2.23) o non-ca dia GC. Lignans we e
associa ed wi h a educ ion in he odds o bo h sub ypes, a 55% isk educ ion (95% CI 0.22–0.93) in
ca dia GC and 45% educ ion (95% CI 0.35–0.84) in non-ca dia GC. Hyd oxybenzaldehydes educed
he isk by 59% in ca dia and non-ca dia GC and hyd oxycouma in by 61% (95% CI 0.20–0.77) and
55% (95% CI 0.36–0.84), espec i ely. Finally, y osols we e associa ed wi h a 61% (95% CI 0.20–0.77)
educ ion in ca dia GC isk and 55% educ ion (95% CI 0.36–0.84) in non-ca dia GC isk.
Acco ding o his ological sub ypes (Figu e 4), we ound some di e ences be ween PLP g oups.
Fo he in es inal sub ype, hyd oxycinnamic acids, alkylphenols, and o he PLP classes, doubled he
odds o GC isk; while me hoxyphenols we e associa ed wi h an inc ease o 78% in he odds o GC.
Lignans we e associa ed wi h a educ ion o di use GC bu we e no associa ed wi h in es inal
sub ype. Hyd oxybenzoic acids showed a non-signi ican endency o educe he odds o in es inal
GC bu no o he di use ype. S ilbenes, hyd oxybenzaldehydes, and y osols showed in e se
associa ions agains bo h ypes. Table 2 summa izes he esul s p esen ed in Figu es 2–4.
Figu e 2. Adjus ed odds a ios (ORs) and 95% con idence in e als (CIs) o gas ic cance (GC) o qua ile 4 (Q4)
s. qua ile 1 (Q1) o polyphenol in ake in he MCC-Spain s udy. Es ima ed using uncondi ional logis ic eg ession
Figu e 2.
Adjus ed odds a ios (ORs) and 95% con idence in e als (CIs) o gas ic cance (GC) o
qua ile 4 (Q4) s. qua ile 1 (Q1) o polyphenol in ake in he MCC-Spain s udy. Es ima ed using
uncondi ional logis ic eg ession models adjus ed o age; sex; socioeconomic s a us; smoking s a us;
i s -deg ee amily his o y o GC; physical ac i i y; body mass index; alcohol consump ion; and
ege ables, ed mea , sal , and o al ene gy in ake including he s udy a ea as a andom e ec e m.
* O he polyphenols (subclass): Es ima ed ORs and hei co esponding 95% con idence in e als o
o he polyphenols subclasses (including a bu in, ca echol, coumes ol, phenol, phlo in, and py ogallol).

Nu ien s 2020,12, 3281 6 o 16
Table 1. Cha ac e is ics o con ols cases o gas ic cance , also by ana omical and his ological ype.
Va iables Con ols Cases
To al By Ana omical Sub ypes By His ological Sub ypes
(n=2700) (n=329) p-Value 1Ca dia
(n=84)
Non-Ca dia
(n=238) p-Value 2In es inal
(n=122)
Di use
(n=75) p-Value 3
Age (yea ) mean (SE) 63.5 (0.2) 65.4 (0.7) 0.001 63.4 (1.3) 66.1 (0.8) 0.036 69.5 (1.0) 61.8 (1.6) 0.000
Sex (men, %) 1522 (56.4) 239 (72.6) 0.000 77 (91.7) 156 (65.6) 0.000 87 (70.7) 45 (60.0) 0.120
Socioeconomic s a us
High (%) 448 (16.6) 27 (8.2)
0.000
9 (10.7) 18 (7.6)
0.679
8 (6.6) 8 (10.7)
0.372
Medium (%) 1361 (50.4) 146 (44.4) 38 (45.2) 103 (43.3) 49 (40.2) 34 (45.3)
Low (%) 891 (33.0) 156 (47.4) 37 (44.1) 117(49.1) 65 (53.3) 33 (44.0)
Smoking s a us (%) yes 1531 (56.7) 201 (61.1) 0.138 65 (77.4) 130 (54.6) 0.000 60 (49.2) 45 (60.0) 0.229
no 1169 (43.3) 128 (38.9) 19 (22.6) 108 (45.4) 62 (50.8) 30 (40.0)
GC amily his o y (%) yes 170 (6.3) 53 (16.1) 0.000 11 (13.0) 40 (16.8) 0.423 27 (22.1) 13 (17.3) 0.432
no 2530 (93.7) 276 (83.9) 73 (87.0) 198 (83.2) 95 (77.9) 62 (82.7)
Physical ac i i y
(MET-h/week)
<8 1374 (50.9) 201 (61.1) 0.000 50 (59.5) 147 (61.8) 0.717 66 (54.1) 48 (64.0) 0.187
≥8 1326 (49.1) 128 (38.9) 34 (40.5) 91 (38.2) 56 (45.9) 27 (36.0)
Body mass index (kg/m2)
≤25 1026 (38.0) 103 (31.3)
0.057
21 (25.0) 80 (33.6)
0.135
41 (33.6) 32 (42.7)
0.415
>25–30 1129 (41.8) 150 (45.6) 37 (44.0) 110 (46.2) 59 (48.4) 31 (41.3)
≥30 545 (20.2) 76 (23.1) 26 (31.0) 48 (20.2) 22 (18.0) 12 (16.0)
Alcohol consump ion
(g/day)
0 418 (15.5) 47 (14.3)
0.000
8 (9.5) 39 (16.4)
0.002
22 (18.0) 13 (17.3)
0.592
<12 1179 (43.7) 103 (31.3) 16 (19.0) 84 (35.3) 40 (32.8) 27 (36.0)
12–47 787 (29.1) 101 (30.7) 34 (40.5) 66 (27.7) 30 (24.6) 22 (29.4)
>47 316 (11.7) 78 (23.7) 26 (31.0) 49 (20.6) 30 (24.6) 13 (17.3)
Vege ables o al in ake (g/d), mean (SE) 191.3 (2.4) 180.8 (7.0) 0.112 184.8 (18.3) 177.9 (7.0) 0.821 189.3 (170.1) 185.6 (13.9) 0.626
Red mea in ake (g/d), mean (SE) 64.0 (0.8) 84.4 (2.9) 0.000 97.50 (6.5) 80.10 (3.3) 0.006 84.6 (4.6) 73.1 (5.2) 0.143
Sodium in ake (mg/d), mean (SE) 3008.6 (24.0) 3529.3 (86.3) 0.000 3758.6 (200.7) 3443.9 (94.9) 0.175 3403.2 (144.6) 3821.4 (187.7) 0.044
To al phenolic acid in ake (mg/d), mean (SE) 166.5 (2.0) 170.7 (5.4) 0.233 191.0 (12.2) 161.1 (5.8) 0.023 178.4 (10.3) 164.5 (10.6) 0.667
To al s ilbene in ake (mg/d), mean (SE) 1.9 (0.1) 1.67 (0.2) 0.022 2.4 (0.4) 1.4 (0.2) 0.061 1.6 (0.3) 1.3 (0.3) 0.719
To al lignan in ake (mg/d), mean (SD) 2.7 (1.7) 2.5 (1.4) 0.085 2.5 (1.3) 2.5 (1.4) 0.712 2.7 (1.5) 2.4 (1.3) 0.260
To al o he polyphenol in ake (mg/d), mean (SE) 16.4 (0.3) 16.3 (0.9) 0.844 16.1 (1.1) 15.3 (1.3) 0.395 15.3 (1.3) 18.8 (2.6) 0.305
1
Di e ences in ca ego ical and con inuous a iables be ween cases and con ols using he Pea son chi squa e es (
χ2
) and ANOVA o K uskal–Wallis es s, espec i ely.
2
Di e ences in
ca ego ical and con inuous a iables be ween ca dia and non-ca dia g oups using he Pea son chi squa e es (
χ2
) and ANOVA o K uskal-Wallis es s, espec i ely.
3
Di e ences in
ca ego ical and con inuous a iables be ween in es inal and di use g oups using he Pea son chi squa e es (
χ2
) and ANOVA o K uskal-Wallis es s, espec i ely. MET, me abolic
equi alen ask.
Nu ien s 2020,12, 3281 7 o 16
Table 2.
Associa ions o polyphenols (PLPs) wi h gas ic cance (GC), a e age PLP consump ion (mg/day) and pe cen age o PLP daily in ake in all subjec s o he
s udy so ed by he h ee mos consumed oods.
PLP Classes To al Ana omical His ological PLP In ake
mg/day ±SD
Foods wi h Highes Con ibu ion in All Cases and Con ols
Ca dia Non-ca dia In es inal Di use Fi s (%) Second (%) Thi d (%)
Phenolic
acids
Hyd oxybenzoic acids ↓ ↓ ↓ ↓ ↑ 15.73 ±11.72 Swiss cha d (24.4) Wine (Red) (22.3) Nu s (14.2)
Hyd oxycinnamic acids ↑ ↑ ↑ ↑ *↓150.51 ±99.41 Co ee (45) Co ee (deca eina ed) (25) Apple (5.3)
Hyd oxyphenylace ic acids ↓ ↓ *↓ ↓ ↑ 0.71 ±1.13 Oli es (83.5) Wine (Red) (11.12) Bee (Ale/Regula ) (3.8)
Phenolic acids (class) ↑ ↑ ↑ ↑ *↓
S ilbenes S ilbenes ↓*↓ ↓ *↓ ↓ 1.86 ±3.06 Wine (Red) (92.2) Wine (Rosé) (3.8) G ape (2)
Lignans Lignans ↓*↓*↓*↓ ↓ * 2.71 ±1.70 B assica ole acea (22.4) G een bean (17.4) O ange ange ine (11.9)
O he
polyphenols
Alkylme hoxyphenols ↑ ↑ ↑ ↑ ↑ 0.74 ±0.92 Co ee (70.4) Co ee (deca eina ed (22.3) Bee (Ale/Regula ) (7.3)
Alkylphenols ↑ ↓ ↑ ↑ *↓0.09 ±0.09 Co ee (98) Bee (1.8) Cocoa powde (0.2)
Hyd oxybenzaldehydes ↓*↓*↓*↓*↓* 0.38 ±0.63 Wine (Red) (92.7) Wine (Rosé) (2.8) Bee (Ale/Regula ) (18)
Hyd oxycouma ins ↓*↓*↓*↓ ↓ 0.07 ±0.14 Bee (Ale/Regula ) (55.2) Wine (Rosé) (44) She y (0.7)
Me hoxyphenol ↑ ↑ ↑ ↑ *↓0.10 ±0.13 Co ee (100)
Ty osols ↓*↓*↓*↓*↓14.06 ±16.18 Oli es (58.2) Oli e oil (26.4) Wine (Red) (12.8)
O he polyphenols (subclass) a↑*↑ ↑ *↑*↓0.89 ±0.90 Co ee (36.9) O ange juice (23.2) O he juice (13.7)
O he polyphenols (class) ↑ ↑ ↑ ↑*↓
O he polyphenols (subclass)
a
This subclass con ains he in ake o a bu in, ca echol, coumes ol, phenol, phlo in, and py ogallol.
↑
inc eased isk;
↓
dec eased isk; * s a is ically signi ican .
Nu ien s 2020,12, 3281 8 o 16
When he associa ion be ween he in ake o PLP and GC was analyzed acco ding o he ana omical
si e (Figu e 3), esul s we e simila o he esul s o GC isk. Hyd oxyphenylace ic acids showed a
50% dec ease (95% CI 0.26–0.96) in he isk o he ca dia sub ype, s ilbenes o 56% (95% CI 0.28–0.70),
and o he PLP subclasses o 50% (95% CI 1.01–2.23) o non-ca dia GC. Lignans we e associa ed wi h a
educ ion in he odds o bo h sub ypes, a 55% isk educ ion (95% CI 0.22–0.93) in ca dia GC and 45%
educ ion (95% CI 0.35–0.84) in non-ca dia GC. Hyd oxybenzaldehydes educed he isk by 59% in
ca dia and non-ca dia GC and hyd oxycouma in by 61% (95% CI 0.20–0.77) and 55% (95% CI 0.36–0.84),
espec i ely. Finally, y osols we e associa ed wi h a 61% (95% CI 0.20–0.77) educ ion in ca dia GC
isk and 55% educ ion (95% CI 0.36–0.84) in non-ca dia GC isk.
Nu ien s 2020, 12, x FOR PEER REVIEW 9 o 17
models adjus ed o age; sex; socioeconomic s a us; smoking s a us; i s -deg ee amily his o y o GC; physical
ac i i y; body mass index; alcohol consump ion; and ege ables, ed mea , sal , and o al ene gy in ake including
he s udy a ea as a andom e ec e m. * O he polyphenols (subclass): Es ima ed ORs and hei co esponding
95% con idence in e als o o he polyphenols subclasses (including a bu in, ca echol, coumes ol, phenol,
phlo in, and py ogallol).
Figu e 3. Adjus ed odds a ios (ORs) and 95% con idence in e als (CIs) o gas ic cance (GC) by ana omical
loca ion o qua ile 4 (Q4) s. qua ile 1 (Q1) o polyphenol in ake in he MCC-Spain s udy. Es ima ed using
uncondi ional logis ic eg ession models adjus ed o age; sex; socioeconomic s a us; smoking s a us; i s -deg ee
amily his o y o GC; physical ac i i y; body mass index; alcohol consump ion; and ege ables, ed mea , sal , and
o al ene gy in ake including he s udy a ea as a andom e ec e m. * O he polyphenols (subclass): Es ima ed
ORs and hei co esponding 95% con idence in e als o o he polyphenols subclasses (including a bu in,
ca echol, coumes ol, phenol, phlo in, and py ogallol).
Figu e 3.
Adjus ed odds a ios (ORs) and 95% con idence in e als (CIs) o gas ic cance (GC) by
ana omical loca ion o qua ile 4 (Q4) s. qua ile 1 (Q1) o polyphenol in ake in he MCC-Spain
s udy. Es ima ed using uncondi ional logis ic eg ession models adjus ed o age; sex; socioeconomic
s a us; smoking s a us; i s -deg ee amily his o y o GC; physical ac i i y; body mass index; alcohol
consump ion; and ege ables, ed mea , sal , and o al ene gy in ake including he s udy a ea as a
andom e ec e m. * O he polyphenols (subclass): Es ima ed ORs and hei co esponding 95%
con idence in e als o o he polyphenols subclasses (including a bu in, ca echol, coumes ol, phenol,
phlo in, and py ogallol).
Acco ding o his ological sub ypes (Figu e 4), we ound some di e ences be ween PLP g oups.
Fo he in es inal sub ype, hyd oxycinnamic acids, alkylphenols, and o he PLP classes, doubled he
odds o GC isk; while me hoxyphenols we e associa ed wi h an inc ease o 78% in he odds o GC.
Lignans we e associa ed wi h a educ ion o di use GC bu we e no associa ed wi h in es inal sub ype.
Hyd oxybenzoic acids showed a non-signi ican endency o educe he odds o in es inal GC bu
no o he di use ype. S ilbenes, hyd oxybenzaldehydes, and y osols showed in e se associa ions
agains bo h ypes. Table 2summa izes he esul s p esen ed in Figu es 2–4.
Nu ien s 2020,12, 3281 9 o 16
Nu ien s 2020, 12, x FOR PEER REVIEW 10 o 17
Figu e 4. Adjus ed odds a ios (ORs) and 95% con idence in e als (CIs) o gas ic cance (GC) by his ological
sub ype o qua ile 4 (Q4) s. qua ile 1 (Q1) o polyphenol in ake in he MCC-Spain s udy. Es ima ed using
uncondi ional logis ic eg ession models adjus ed o o age; sex; socioeconomic s a us; smoking s a us; i s -
deg ee amily his o y o GC; physical ac i i y; body mass index; alcohol consump ion; and ege ables, ed mea ,
sal , and o al ene gy in ake including he s udy a ea as a andom e ec e m. * O he polyphenols (subclass):
Es ima ed ORs and hei co esponding 95% con idence in e als o o he polyphenols subclasses (including
a bu in, ca echol, coumes ol, phenol, phlo in, and py ogallol).
4. Discussion
In he cu en case-con ol s udy, ou esul s sugges an in e se associa ion be ween s ilbene and
lignan in ake and GC isk. We ound no o e all associa ion be ween o al phenolic acid and o he
polyphenol classes’ in ake and his ype o cance . Howe e , he in ake o hyd oxybenzaldehydes,
hyd oxycouma ins, and y osols was in e sely associa ed wi h GC.
By ana omical subsi e, no subs an ial di e ences we e ound compa ed o o al GC isk. By
his ological sub ype, he in ake o lignans was in e sely associa ed wi h di use GC and ha o
hyd oxybenzaldehydes, y osols, and s ilbenes wi h bo h di use and in es inal GC. We ound a di ec
associa ion be ween hyd oxycinnamic acids, phenolic acids, alkylphenols, me hoxyphenol, and o he
polyphenol subclass in ake and in es inal GC isk.
The e a e ha dly any epidemiological s udies in which he associa ion be ween hese classes o
PLPs and GC has been assessed [25–27]. Ne e heless, ou esul s a e plausible gi en he esul s om
in i o and in i o s udies. Di e en mechanisms by which PLPs could play a ole in he p e en ion
o ea men o GC ha e been desc ibed in hese s udies.
Rega ding he s ilbene amily, bo h es e a ol and p e os ilbene ha e shown p o ec i e e ec s
agains GC. Res e a ol has demons a ed he abili y o inhibi he g ow h o human GC cells by
induc ion o apop osis, inc easing he cell load in he G0/G1 phase, and dec easing he p opo ion o
cells in he S and G2/M phases [28]. Res e a ol has also been sugges ed o show an imic obial ac i i y
Figu e 4.
Adjus ed odds a ios (ORs) and 95% con idence in e als (CIs) o gas ic cance (GC) by
his ological sub ype o qua ile 4 (Q4) s. qua ile 1 (Q1) o polyphenol in ake in he MCC-Spain s udy.
Es ima ed using uncondi ional logis ic eg ession models adjus ed o o age; sex; socioeconomic
s a us; smoking s a us; i s -deg ee amily his o y o GC; physical ac i i y; body mass index; alcohol
consump ion; and ege ables, ed mea , sal , and o al ene gy in ake including he s udy a ea as a
andom e ec e m. * O he polyphenols (subclass): Es ima ed ORs and hei co esponding 95%
con idence in e als o o he polyphenols subclasses (including a bu in, ca echol, coumes ol, phenol,
phlo in, and py ogallol).
4. Discussion
In he cu en case-con ol s udy, ou esul s sugges an in e se associa ion be ween s ilbene and
lignan in ake and GC isk. We ound no o e all associa ion be ween o al phenolic acid and o he
polyphenol classes’ in ake and his ype o cance . Howe e , he in ake o hyd oxybenzaldehydes,
hyd oxycouma ins, and y osols was in e sely associa ed wi h GC.
By ana omical subsi e, no subs an ial di e ences we e ound compa ed o o al GC isk.
By his ological sub ype, he in ake o lignans was in e sely associa ed wi h di use GC and ha
o hyd oxybenzaldehydes, y osols, and s ilbenes wi h bo h di use and in es inal GC. We ound a
di ec associa ion be ween hyd oxycinnamic acids, phenolic acids, alkylphenols, me hoxyphenol,
and o he polyphenol subclass in ake and in es inal GC isk.
The e a e ha dly any epidemiological s udies in which he associa ion be ween hese classes o
PLPs and GC has been assessed [
25
–
27
]. Ne e heless, ou esul s a e plausible gi en he esul s om
in i o
and
in i o
s udies. Di e en mechanisms by which PLPs could play a ole in he p e en ion
o ea men o GC ha e been desc ibed in hese s udies.
Nu ien s 2020,12, 3281 16 o 16
66.
Liu, R.H. Po en ial syne gy o phy ochemicals in cance p e en ion: Mechanism o ac ion. J. Nu .
2004
,
134, 3479S–3485S. [C ossRe ]
67.
de Kok, T.M.; an B eda, S.G.; Manson, M.M. Mechanisms o combined ac ion o di e en chemop e en i e
die a y compounds: A e iew. Eu J. Nu . 2008,47, 51–59. [C ossRe ]
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