Selected Micro Nutrient Intake and the Risk of Gastric Cancer

8/14/2019 Selected Micro Nutrient Intake and the Risk of Gastric Cancer

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V o l. 3 , 393 -398 , ju ly /A ugus t 1994 C anc er E pide mio lo gy , B io mark ers & P re ven tio n 39 3

S e le c te d M ic ro n u trie n t In ta ke a n d th e R isk o f G a s tric C a n ce r1

C arlo La Vecch ia ,2 M on ica Fe rra ron i, B a rb a ra D A vanzo ,A driano D eca rli, and S ilv ia F rancesch iIs titu to d i B iom etria e S ta tis tica M ed ica , U niv e rs it# {224 } d i M ilano , Is titu toN az ion a le T u m ori, V ia V e nez ian 1 , 201 33 M ilano , Ita ly IC . L . V .,M . F ., A . D I; Is titu to d i R ice rche F arm ac o log ic he M ario N egri,V ia E ritrea 62 , 20 157 M ilan o , Ita ly IC . L . V . , B . D . A .]; and C en tro d iR ife rim en to O nc o log ic o , V ia Pe dem on tana O cc iden ta le , 330 81 Av iano(P N ), Ita ly IS . F .]

Abs trac tTh e re la tio nsh ip b e tw een in take o f se lededm ic ronu trien ts and gas tric can ce r risk w as in ves tiga tedus in g da ta from a case -con tro l s tud y conduded in Ita lyb e t w e e n 1 9 85 and 1 9 92 on 723 cases o f h is to lo g ica llycon firm ed , in c iden t gas tric can ce r , and 2024 con tro lshosp ita liz ed fo r acu te , n onneop las tic , nond ig es tive tradd iseases . R e la tive risks o f subsequen t qu in tiles o f in takew ere com puted a fte r a llow ance fo r sex , ag e , and o th e rm ajo r id en tif ied po ten tia l con found ing fado rs , inc lu d in gan estim ate o f to ta l ca lo rie in take . N o trend in r iskem erg ed fo r in take o f re tin o l, v itam in D and v itam in E ,w hereas a p ro ted ive pa tte rn w as obse rved fo rconsum p tio n o f b eta -caro tene , asco rb ic ac id , fo la te , andn itra te s , w ith risk e s tim a te s fo r th e h igh e s t in tak eq u in tile s o f 0 .2 7 , 0 .4 0 , 0 .5 8 , a n d 0 .4 3 , re sp e d ive ly .S ign ifican t d ired trends in risk w ere found fo rm e th ion in e , c a lc iu m , an d n itrite s . W h e n th e e ffe d o fva rio us m ic ronu trien ts w as taken in to accoun t, ares id ua l p ro ted ive e ffed w as o bse rve d fo r b e ta -ca ro te n eand ascorb ic ac id , and a d ired assoc ia tion w ithm e th ion ine rem a in ed , w hereas th e pro ted ive e ffed o ffo la tes and n itra tes and th e d ired assoc ia tio ns o f n itr itesw ere no longe r ev iden t. T he risk es tim a tes fo r th e upperq u in tile s o f b e ta -ca ro te n e , a s co rb ic a c id , a n d m eth io n in econsum p tio n w ere resped ive ly 0 .38 , 0 .53 , and 2 .40 , anda ll th e trends in risk w ere s ign ifican t and cons is ten tac ro ss s trata o f sex and age . W he the r th is re fled s aspec ific e ffed o f these m ic ronu trien ts , ra th er th anp rob lem s o f co llin ea rity o r o th e r lim ita tio ns o f the d a ta ,is op en fo r d iscuss io n . N one the less , these da ta in d ica tetha t se led ed m ic ronu trien ts m ay have an im pad in thep ro ce ss o f g as tric c arc in og en es is .In t rodud ionD ie ta ry h ab its a re im po rtan t d e te rm ina n ts o f ga s tric ca n ce r ,a nd im p rove m e n ts in d ie t ha ve b ee n a sso c ia ted w ith a

R ec e ived 1 2 /22 /93 ; rev ise d 3 /9 /94 ; a ccep ted 3 /10 /94 .1 T h is w o rk w as co nd ucted w ith in the fra m ew ork o f th e C N R (Ita l ian N a -tiona l R e search C ounc il) App lied P ro jec ts C lin ica l Ap p lica tions o f O nco -log ic a l R es earch (C on trac ts N o . 93 .0 2360 .P F 39 and N o . 93 .0 21 52 .PF 39 ),and w ith the con trib u tions o f the Ita lian A ssoc ia tion fo r C an ce r R esearch , theIta lian Leagu e ag a inst T um o urs , M ilan , and A nge la M arc heg iano Bo rg o -mainerio.2 T o w hom requests fo r rep rin ts s hou ld be addres sed .

g e ne ra l d e c line o f ga s tric ca nc e r an d re la te d m or ta lity (1 ).T h e p rec ise co m p on e n ts o f d ie t w h ich m a y h a ve so m eim pa c t on g as tric ca rc ino g en es is a re , h ow e ver , s ti ll la rg e lyu nd e fine d . M o s t s tu d ie s b as ed on fo o d ite m s fo un d pro te c -tive e ffe c ts o f fre sh fru its an d ve g e ta b les , w h ile p re se rve dm ea t a n d s e lec te d s ta rch y fo o ds -o ften ind ica to rs o f a les sa fflu en t d ie t-w ere as soc ia ted w ith inc rea se d ris k (2 -1 0 ).

S c an ty ep id e m io log ica l d a ta a re , h ow e ver , av a ila b leo n th e ro le o f n u trien ts , a n d m ic ron u trien ts , on g a s tricc an ce r risk . T he re a re in d ica tio ns tha t se le c te d m ic ro nu tri-e n ts w ith an tio x id a n t e ffec t, suc h as a sco rb ic a c id , be ta -c a ro ten e , a nd c t-toco p he ro l, a re p ro te c tive a ga in s t g a s tricc a rc in og en e s is (2 , 1 1 -1 6 ), w h ile n itr ites , w h ich m a y c au sein tra ga s tric sy n th es is o f N -n itro so c om po un d s , ha ve be ena sso c ia te d w ith in c re a sed r isk , b u t th e ir im p ac t o n a po p-u la tio n le ve l re m a in s op e n fo r d isc uss io n (1 4 -2 0 ). F u rthe r-m ore , th e re is a g en era l p a uc ity o f sy s tem atic e ffo rts toco n s id e r s im u lta n eo us ly th e ro le o f va riou s m ic ro nu trie n tso n g a s tric ca rc ino g en es is , in o rde r to u n de rs ta nd a nd qu a n-tify th e sep a ra te e ffe c t o f e ac h fac to r a fte r a llo w a nc e fo ro the rs .

T o p rov id e fu r th e r in fo rm a tion o n th is issu e , w e ha veco n s id e red th e ro le o f se le c ted m ic ro nu trie n ts o n th e r isk o fs to m a ch c an ce r, u s in g d a ta from a ca se -con tro l s tu d y co n -d u c ted in N orth e rn Ita ly , an a re a w ith re la tive ly h ig h g a s tricca n ce r ra te s a m o ng d e ve lop e d cou n trie s o n a w o rld w id esc a le (21 ), pre v iou s ly c on s id e red w ith re fe ren ce to in take o fva riou s foo d s (4 ). T h a t an a lys is sh ow e d an a sso c ia tio n w ithfre qu e n t con su m p tio n o f s ta rch y foo d s typ ica l o f th e tra d i-t io n a l d ie t a nd p ro tec tion s from fre sh fru its a nd veg e ta b le s .T h e qu e s tio n a rise s , th e re fo re , o f w h e th e r the re is an in flu -e nc e o f s pe c ific m ic ro nu trie n ts on g as tric c a rc in og en e s is .

Sub jed s and M ethodsD a ta w e re de riv ed fro m a n on go in g c ase -co n tro l s tud yco n du c ted in the m a jo r te ac h ing a nd g en e ra l h os p ita ls inth e G rea te r M ila n a rea s in ce 1 98 5 . T h e pre se n t an a lys es a reb ase d o n d a ta co llec te d u n til D ece m b er 1 992 . T h e ge ne ra ld es ig n o f th e s tud y ha s b e en p re v io us ly d es c rib e d (4 ).B rie fly , tra ine d in te rv iew ers ide n tif ie d a n d q ue s tio ne d ca seso f g as tr ic ca nc e r an d co n tro ls a dm itted to ho sp ita l in th ea rea u nd er su rve illan ce fo r no n ne op las tic , n on d ig es tivetra c t d ise as es , no t re la ted to lo ng -te rm m o d ifica tio ns o f d ie t.

T h e s tan da rd qu e s tio nn a ire inc lud e d q ue s tio ns a bo u tso c io d em og ra ph ic a n d an th ro po m e tric cha ra c te ris tic s , ap ro b le m -o rie n te d m e d ica l h is to ry , fa m ily h is to ry o f g as trica nd co lo re c ta l ca n ce rs , an d in fo rm a tion a bo u t th e fre -q ue nc y o f co nsu m p tio n o f 29 in d ica to r foo ds . T h es e ite m sinc lu de d m a jo r sou rce s o f b e ta -ca ro te ne , re tino l; v itam in sC , D , a nd E ; fo la te ; m e th io n in e a n d ca lc iu m ; a n d n itr itesan d n itra te s . F ro m the se ite m s , th e n u trien t in ta ke w a sco m p u te d b y m u ltip ly ing the fre qu e ncy o f in tak e o f ea chun it o f fo od by the n u trien t c on ten t o f a s tan d ard a ve rag epo rtio n . M ic ron u tr ie n t v a lue s w ere d e r ive d fro m Ita lia n ta -b les o f fo od co m p os itio n (2 2 ), in teg ra ted by o the r so u rces ,


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C an ce r E pid em io log y, B iom arke rs & P rev en tio n 39 5

Tab le 3 R e la tive ris k es tim a tes (and 95% con fidenc e in te rv a ls) o f s to m ach canc e r in re la tion to se lec ted m icronu trien t in take . M lan , Ita ly , 19 85 -1992Q u in tile o f in ta ke MH b M L R Q u in tile o f in take M H M LR B e ta -ca ro tene F o la te

2# {176 } 0 .78 (0 .6 1 -1 .01 ) 0 .80 (0 .61 -1 .0 4 ) 2# {176 } 0 .89 (0 .6 9 -1 .16 ) 0 .82 (0 .62 -1 .08 )3# {176 } 0 .60 (0 .46 -0 .77 ) 0 .59 (0 .45 -0 .78 ) 3# {176 } 0 .79 (0 .6 0 -1 .04 ) 0 .71 (0 .53 -0 .96 )4 # {176 } 0 .61 (0 .47 -0 .79 ) 0 .54 (0 .41 -0 .72 ) 4# {176 } 0 .81 (0 .6 2 -1 .07 ) 0 .59 (0 .43 -0 .80 )5# {176 }h ighest) 0 .33 (0 .24 -0 .45 ) 0 .27 (0 .19 -0 .38 ) 5# {176 }h ighes t) 0 .84 (0 .6 4 -1 .1 1 ) 0 .58 (0 .42 -0 .80 )P (trend ) < 0 .001 < 0 .0 01 P (trend ) N S < 0 .001

R e tino l M e th ion ine2# {176 } 1 .36 (1 .03 -1 .80 ) 1 .24 (0 .93 -1 .67 ) 2# {176 } 1 .35 (1 .00 -1 .82 ) 1 . 31 ( 0. 95 -1 .8 1)3# {176 } 1 .07 (0 .80 -1 .43 ) 0 .99 (0 .74 -1 .34 ) 3# {17 6 } 1 .36 (1 .01 -1 .84 ) 1 .27 (0 .91 -1 .76 )4# {176 } 1 .38 (1 .05 -1 .82 ) 1 .21 (0 .91 -1 .62 ) 4# {176 } 1 .58 (1 .1 8 -2 .13 ) 1 .52 (1 .08 -2 .14 )5# {176 }h ighest) 1 .1 7 (0 .88 -i .55 ) 0 .94 (0 .70 -1 .27 ) 5# {176 }h ighes t) 2 .4 6 (1 .85 -3 .28 ) 2 .07 (1 .4 5 -2 .94 )P (trend ) N S d NS P (trend ) < 0 .001 < 0 .001

A sco rb ic A cid Ca lc ium2#{176 } 0 .61 (0 .48 -0 .79 ) 0 .61 (0 .47 -0 .79 ) 2# {176 } 1 .23 (0 .92 -1 .65 ) 1 .15 (0 .85 -1 .51 )3# {176 } 0 .54 (0 .42 -0 .70 ) 0 .52 (0 .40 -0 .68 ) 3# {17 6 } 1 .38 (1 .03 -1 .86 ) 1 .26 (0 .92 -1 .71 )4# {176 } 0 .42 (0 .32 -0 .56 ) 0 .41 (0 .31 -0 .55 ) 4# {176 } 1 .33 (1 .00 -1 .78 ) 1 .24 (0 .91 -1 .68 )5# {176 }h ighest) 0 .44 (0 .33 -0 .58 ) 0 .40 (0 .30 -0 .55 ) 5# {176 }h ighest) 1 .71 (1 .29 -2 .26 ) 1 .41 (1 .03 -1 .92 )P (trend ) < 0 .00 1 < 0 .0 01 P ( t rend ) < 0 .001 < 0 .05

V itam in D Nitr ites2# {176 } 1 .18 (0 .89 -1 .57 ) 1 .19 (0 .88 -1 .60 ) 2# {176 } 1 .10 (0 .83 -1 .48 ) 0 .98 (0 .72 -1 .33 )3# {176 } 1 .48 (1 .1 2 -1 .95 ) 1 .45 (1 .08 -1 .93 ) 3# {17 6 } 1 .1 3 (0 .84 -1 .52 ) 0 .99 (0 .72 -1 .36 )4# {176 } 1 .29 (0 .97 -1 .71 ) 1 .29 (0 .96 -1 .74 ) 4# {176 } 1 .44 (1 .08 -1 .92 ) 1 .15 (0 .84 -1 .59 )5# {176 }h igh est) 1 .32 (0 .99 -1 .76 ) 1 .35 (1 .00 -1 .83 ) 5# {17 6 }h ighes t) 1 .90 (1 .43 -2 .52 ) 1 .35 (0 .96 -1 .88 )P (trend ) < 0 .0 5 < 0 .05 P (trend ) < 0 .001 < 0 .05

V itam in E Ni t ra tes2# {176 } 0 .96 (0 .74 -1 .26 ) 0 .91 (0 .68 -1 .21 ) 2# {17 6 } 0 .6 9 (0 .53 -0 .88 ) 0 .64 (0 .49 -0 .83 )3# {176 } 0 .91 (0 .69 -1 .21 ) 0 .75 (0 .54 -1 .03 ) 3# {17 6 } 0 .5 5 (0 .42 -0 .72 ) 0 .50 (0 .38 -0 .67 )4# {176 } 1 .05 (0 .80 -1 .39 ) 0 .83 (0 .60 -1 .16 ) 4# {176 } 0 .5 9 (0 .45 -0 .77 ) 0 .52 (0 .39 -0 .70 )5# {176 }h igh est) 1 .26 (0 .96 -1 .66 ) 0 .88 (0 .62 -1 .24 ) 5# {17 6 }h ighest) 0 .5 4 (0 .41 -0 .71 ) 0 .43 (0 .32 -0 .59 )P (trend ) N S N S P ( t rend ) < 0 .001 < 0 .00 1

a R efe renc e ca teg o ry is the low e st qu in tile o f in take .b M ante l-H a ensze l est im a tes ad justed fo r age in dec ades and sex.C E stim a tes fro m m u ltip le log is tic reg ress ion equa tion s inc lu d ing te rm s fo r age , s ex, educa tio n , fam ily h is to ry o f gastric canc e r, body m as s index, and to ta l ene rgyin take .d N S, n ot s ig nific an t.

te nd ed to d iffe r w ith re sp ec t to ye a rs o f ed u ca tion , w ithco n tro ls b e ing s ign ific an tly m ore e d uc a te d th a n ca se s .

T a b le 2 sh o w s th e d is tr ib u tion o f ca ses a n d co n tro lsa cco rd in g to q u in tile o f in take o f 1 0 se le c te d m ic ro nu trie n tso r su bs ta nc es . A p pa re n t d iffe ren ce s in th e d is tr ib u tionemerged for beta-carotene, ascorbic acid, folate, methio-n ine , c a lc iu m , a nd n itra te s , w ith a lo w er fre q ue nc y o f ca se sin the h igh es t q u in tile s o f in ta ke , a s w e ll a s fo r ca lc ium a ndm e th ion in e , w ith a lo w e r fre qu en cy o f ca se s in the lo w e s tqumnt i les .

T he co rres po n d ing O R s a re sh ow n in T a b le 3 . N o tre n din risk e m e rg ed fo r in take o f re tino l (O R , 0 .9 4 ; 95 % C I,0 .7 0 -1 .2 7 , fo r the h ig he s t co n sum ption qu in tile ), v ita m in D(O R , 1 .3 5 ; 95 % C I, 1 .00 -1 .83 ) a nd v ita m in E (O R , 0 .88 ;95 % C I, 0 .62 -i .24 ), w h erea s a p ro te c tive p a tte rn w a s ob -se rve d fo r c on su m p tion o f b e ta -ca ro te ne , as co rb ic a c id ,fo la te , an d n itra tes , w ith re la tive risk es tim a tes o f 0 .27 ( 95%C I, 0 .19 -0 .3 8 ), 0 .40 (95 % C l, 0 .30 -0 .55 ), 0 .58 (95% C I,0 .4 2 -0 .8 0 ), a nd 0 .4 3 (9 5 % C I, 0 .32 -0 .5 9 ), re sp ec tive ly .S ig n ifica n tly in c re ase d risks acc o rd in g to le ve l o f co ns um p-tio n o f m e th ion in e (O R , 2 .0 7 ; 95 % C I, 1 .45 -2 .9 4 , fo r th eh ig h es t in ta ke qu in tile ), ca lc ium (O R , 1 .41 ; 9 5% C l, 1 .03 -1 .9 2 ) , a nd n itr ites (O R , 1 .3 5 ; 9 5 % C I, 0 .9 6 -i .8 8 ) w e refound .

A ll the tre n ds fo r th e se v a riab le s w e re s ig n ifica n t a fte rco n tro ll in g fo r ed uc a tio n , fam ily h is to ry o f g as tric ca nce r,b od y m as s ind ex , an d to ta l ca lo rie in ta ke , be s ide s se x a nda ge , in m u ltiva ria te a na ly s is . H ow e ver , a llow an ce fo r ca l-o n es a nd o th e r p o te n tia l co n fo un d in g fac to rs in m u ltiva r i-a te an a lys is te nd e d to red u ce th e ass oc ia tion w ith n itr ite sand to increase the protection for folate.

T h e corre la tion m atrix fo r v a riou s m ic ro nu trie n ts s ig -n if ica n tly as so c ia ted to g as tric ca nce r ris k is g iv en in T a b le4 . A ll th e co r re la tion co e ffic ie n ts w ere po s itive , bu t on lyth ree o f th ese (i .e., be tw e e n n itra te s , b e ta -ca ro te n e , a ndas co rb ic ac id , a n d b e tw ee n n itr ite s a nd m e th ion in e ) w ereab o ve 0 .5 .

In T a b le 5 re la tive risk e s tim ate s tak in g s im ulta n eo us lyin to a cco un t th e e ffe c t o f va rio u s m ic ro nu trie n ts a re p re -se n te d . A res idu a l p ro tec tive e ffe c t w as o b se rved fo r be ta -ca ro te ne an d as co rb ic ac id , a n d th e inc rea se d risk o f g as tricca n ce r ass oc ia te d w ith m e th io n in e re m a in ed , re su ltin g inris k e s tim a tes o f 0 .3 8 , 0 .5 3 , a nd 2 .40 , re sp ec tive ly , w h e rea sthe p ro tec tive e ffec t o f fo la te an d n itra te s , a nd th e d ire c tas soc ia tion w ith n itr ites w e re no lon g er ev id en t a fte r th es ed ie ta ry va r ia b les w e re a d de d to the lo g is tic m o de ls .

R e la tive risk es tim a tes fo r g a s tric c an ce r a cco rd in g toleve ls o f con su m p tio n o f th e th ree n u trie n ts e m e rg ed as th e


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3 96 M icro nu trie n t In ta ke a nd G as tric C anc er

Tab le 4 C orre la tion coe f fic ien ts be tw e en se lected m ic ro nu tr ien ts . M ilan , Ita ly , 19 8 1 992f3 -c a ro tene A sco rb ic ac id F o la te M eth ion ine N itr ites N itra tes

f3 -ca ro teneAsco rb icac idFo la teMeth ion ineNitr i tesNi t ra tes

1 .000 .470 .230 .330 .240 .52

1 .000 .380 .190 .090 .62

1 .000 .470 .140 .41

1 .000 .710 .36

1 .000 .24 1 .00

Tab le 5 M ultiv a ria te re la tive risk estim a te s (9 5% c on fidenc e in te rva ls) o fs to m ach cance r in re la tion to se le cted m ic ronu trien t in take . M ilan , Ita ly ,

1 985 -1 992 Q u in ti le o f i n tak e M LR b p ( t rend )Beta-carotene

2#{176 } 0 .92 (0 .70 -1 .22 )3# {176 } 0 .73 (0 .55 -0 .99 )4# {17 6 } 0 .71 (0 .52 -0 .98 )5# {176 }h igh est) 0 .38 (0 .26 -0 .56 ) < 0 .001

As co rb ic ac id2# {176 } 0 .63 (0 .49 -0 .84 )3# {176 } 0 .56 (0 .41 -0 .78 )4# {176 } 0 .47 (0 .32 -0 .68 )5# {176 }h igh est) 0 .53 (0 .35 -0 .81 ) < 0 .00 1

Fo la te2# {176 } 1 .24 (0 .90 -1 .71 )3# {176 } 1 .32 (0 .91 -1 .92 )4# {176 } 1 .22 (0 .80 -1 .87 )5# {176 }h igh est) 1 .33 (0 .82 -2 .18 ) NS C

Meth ion ine2# {176 } 1 .40 (1 .01 -1 .96 )3 1 .32 (0 .94 -1 .86 )4# {176 } 1 .6 5 (1 .15 -2 .36 )5# {176 }h igh est) 2 .40 (1 .6 4 -3 .51 ) < 0 .001

Nitr i tes2# {176 } 0 .96 (0 .69 -1 .32 )3# {17 6 } 0 .97 (0 .70 -1 .35 )4# {176 } 1 .02 (0 .73 -1 .43 )5# {176 }h igh est) 1 .12 (0 .78 -1 .59 ) N S

Ni tra tes2# {176 } 0 .71 (0 .53 -0 .96 )3 # {176 } 0 .66 (0 .47 -0 .92 )4# {176 } 0 .78 (0 .54 -1 .12 )5# {176 }h ighes t) 0 .64 (0 .43 -0 .97 ) N S

a R efe renc e ca tego ry is the low es t qu in tile .b E stim a tes fo r m u ltip le log is tic reg res s ion equa tion s inc lu d ing te rm s fo r age ,se x , e du ca tion , fa m ily h is to ry o f ga s tr ic ca nce r, body m ass index , to ta len e rg y in take , p lus a ll the above v a riab les.C N S, n ot s ig nific an t.

m o st im p or ta n t d e te rm ina n ts o f ga s tric c an ce r risk (i .e.,b e ta -ca ro te ne , asc o rb ic ac id , a nd m eth io n in e ) w ere c om -p u te d a c ro ss s tra ta o f se x a nd a g e (T a b le 6 ). T he tre nd s inrisk w ere s ig n ifica n t a n d co n s is te n t a c ro ss va rio u s s tra tac on s id e red , in the ab se nc e o f an y re le va n t in te ra c tio n w itht he se c ov ar ia te s.

Discuss ionT h is s tu dy co n firm s th a t be ta -ca ro te ne a n d as co rb ic a c idh av e a p ro te c tive e ffec t a ga in s t ga s tric ca rc ino g en es is .T h e re w a s a lso so m e p ro te c tio n b y fo la te a nd n itra tes , b u tth is w a s n o lo ng er e v ide n t a fte r s im u lta ne o us in c lus ion o f

the se fac to rs in a s in g le m od e l w ith b e ta -ca ro te n e an da sco rb ic a c id . A s ig n ifica n t d ire c t ass oc ia tion e m e rg ed fo rm e th io n ine a nd n itr ite co nsu m p tio n , w h ere a s a -toc o -p h e ro l, v ita m in D , an d ca lc iu m s ho w e d n o c lea r p a tte rn o fa sso c ia tion w ith g as tric c an ce r risk .

A n ea rlie r s tud y on a n Ita lia n p op u la tion fo u nd a p ro -te c tiv e e ffe c t from b e ta -ca ro te ne , v itam in C a nd E , b u t n oa sso c ia tion w ith re tino l a n d c a lc iu m ; n itr ite s w e re d ire c tlya n d n itra tes s ligh tly in ve rse ly a sso c ia ted w ith th e r isk o fg a s tric c an ce r (1 5 ). In m o s t p rev io us s tud ie s , th e re w a s ,h ow e ver , little sys te m a tic e ffo rt to m u tua lly a llow fo r th ep os s ib le e ffe c ts o f va rio us m ic ro n u trien ts . In a s tu dy fro mC a na da (1 3 ), v itam in C an d n itra tes sho w ed so m e pro te c -tive e ffec t, an d v ita m in E sh ow ed n o ass oc ia tion . In a s tu dyfro m G e rm a ny (1 1 ), th e o n ly s ign ific an t a sso c ia tio n w ithg a s tric c an ce r, a fte r a d jus tm en t fo r o th e r n u trien ts , w as anin ve rse o n e w ith v itam in C . N o ne the le ss , o the r s tu d iesfo un d a s ig n ifica n tly de c re as ed risk re la ted to in ta ke o fv itam in A or be ta -c a ro ten e (5 , 1 4 , 1 5). In a S p an is h s tu dy(2 6 ), the s tro ng es t p ro tec tion w a s ob se rve d fo r v ita m in Ca nd v ita m in A fro m fru its an d ve g e ta b les . It ap p ea rs , th e re -fo re , tha t be ta -c a ro ten e a nd as co rb ic a c id a re am on g th em o s t co ns is te n t p ro te c tive fac to rs a g a ins t g as tric ca rc ino -g en e s is . T h is m igh t b e re la ted to a n an tio x id a n t e ffec t o fth es e v ita m ins , a lth o ug h the p ro te c tio n is le ss co nv in c in gfo r o the r po w erfu l an tio x id an ts , in c lu d in g a -toco p he ro l. Itis a lso po ss ib le , h o w e ve r, th a t asc o rb ic ac id ha s a sp ec ifica n tiox ida n t an d a n tin itro sa tin g e ffe c t in th e aq u eo us (bu tn o t lip id ) p ha se o f g as tric ju ic e (27 , 2 8 ).

Folate has been shown protective against colorectalca rc ino g en es is (2 9 ) , b u t da ta a re s ca n ty o n s tom ac h ca nce rrisk . In th is p op u la tio n , fo la te w a s m a in ly d e rive d fromve g e ta b les . T he la ck o f a sso c ia tio n in th e m u ltiva ria te a na l-ys is m ay th us s im p ly re flec t a s tro ng co llin ea rity b e tw ee nfo la te a nd th e se n u tr ie n ts , an d he nc e a co rre la te o f p ro tec -tio n o f b e ta -ca ro te n e an d as co rb ic ac id , o r o th e r co ns titu -e n ts o f ve g e ta b les a nd fru it, as s ug ge s te d b y th e a b sen ce o fre s id u a l as soc ia tion s in th e m od e l in c lu d in g th es e nu trie n ts .

T h ese re su lts co n firm a n inc rea se d risk o f g a s tric ca n -ce r w ith n itr ite in tak e , p re v iou s ly fou n d in e p id em io lo g ica la nd exp e rim e n ta l s tud ie s (1 8 ), b u t an inv e rs e as so c ia tio nw ith n itra te s . A lth ou g h ca rc ino g en ic N -n itros o co m p ou n dsca n be fo rm ed from n itr ite s a nd n itra te s in th e g as tr ic lu m e n ,th e res u lts fro m prev iou s s tu d ies a re no t c on s is te n t. S till, ing en e ra l, th ey d o n o t su gg e s t an y s tron g an d g e ne ra l a sso -c ia tion b e tw ee n d ie ta ry in ta ke o f n itr ites an d n itra te s a ndg as tr ic c an ce r r isk o n a p o pu la tio n lev e l (1 4 -15 , 17 -2 0 ,3 0 ). In th is s tu dy , th e po s itive as so c ia tio n o f n itr ites (de riv ede sse n tia lly fro m ca nn ed m ea t, b rea d , an d s om e veg e ta b le s )w ith ga s tric ca nc e r is e xp la in ab le th rou g h a re a l c on trib u -tio n o f e xog e no us n itr ite s to th e p ro du c tion o f N -n itrosoco m p o un ds o r b y co n fo u nd in g b y o th e r d ie ta ry fa c to rs . Th ea sso c ia tio n b e ca m e, in fa c t, w e ake r a nd w as n o t s ign ifican t


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C an cer E pide mio lo gy , B iom arke rs & P re ve ntion 39 7

Tab le 6 R e la t ive risk est im a tes (95% con fidence in te rv a ls ) o f s toMm ach canc e r in re la tion to se

i la n, Ita ly , 1 98 5-1 99 2lec te d m icronu trien t in take in s epara te stra ta o f sex and age .

Q ui nt il e o f i nt ak eS ex A ge

Males F em a les < 60 yr 60 yrBe ta -ca ro tene

2#{176 } 1 .09 (0 .78 -1 .52 ) 0 .47 (0 .29 -0 .75 ) 0 .72 (0 .49 -1 .06 ) 0 .89 (0 .61 -1 .30 )3 #{1 76 } 0 .6 5 (0 .4 5 -0 .9 2 ) 0 .5 1 (0 .33 -0 .7 9 ) 0 .60 (0 .41 -0 .88 ) 0 .59 (0 .40 -0 .88 )4 #{1 76 } 0 .48 (0 .3 3 -0 .69 ) 0 .58 (0 .37 -0 .92 ) 0 .58 (0 .40 -0 .85 ) 0 .49 (0 .32 -0 .75 )5# {176 }h ighest) 0 .36 (0 .2 3 -0 .57 ) 0 .17 (0 .10 -0 .29 ) 0 .22 (0 .13 -0 .35 ) 0 .32 (0 .20 -0 .52 )P (trend ) < 0 .001 < 0 .001 < 0 .001 < 0 .001

A sco rb ic ac id2#{176} 0 .89 (0 .6 4 -1 .24 ) 0 .33 (0 .21 -0 .50 ) 0 .53 (0 .36 -0 .78 ) 0 .69 (0 .49 -0 .99 )3# {176 } 0 .83 (0 .5 9 -1 .18 ) 0 .24 (0 .15 -0 .38 ) 0 .42 (0 .29 -0 .63 ) 0 .6 5 ( 0. 44 -0 .9 6)4# {176 } 0 .48 (0 .3 3 -0 .72 ) 0 .28 (0 .17 -0 .45 ) 0 .29 (0 .19 -0 .44 ) 0 .59 (0 .38 -0 .91 )5# {176 }h ighest) 0 .12 (0 .41 -0 .90 ) 0 .18 (0 .11 -0 .31 ) 0 .28 (0 .18 -0 .42 ) 0 .61 (0 .38 -0 .96 )P (trend ) < 0 .001 < 0 .001 < 0 .001 < 0 .01

Meth ion ine2# {176 } 1 .1 8 (0 ,76 -1 .83 ) 1 .53 (0 .95 -2 .45 ) 1 .29 ( 0 .81 - 2 .08 ) 1 .33 (0 .86 -2 .07 )3# {176 } 1 .50 (0 .95 -2 .35 ) 1 .13 (0 .69 -1 .84 ) 1 .1 9 (0 .71 -1 .97 ) 1 .3 6 (0 .87 -2 .11 )4 # {1 76 } 1 .90 (1 .21 -2 .99 ) 1 .14 (0 .66 -1 .95 ) 1 .6 9 (1 .03 -2 .77 ) 1 .3 7 (0 .85 -2 .21 )5# {176 }h ighest) 2 .41 (1 .52 -3 .8 3 ) 1 .70 ( 0 .96 -2 .99 ) 2 .27 (1 .37 -3 .75 ) 1 .86 (1 .1 2 -3 .09 )P (trend ) < 0 .001 < 0 .001 < 0 .001 < 0 .05

a R e fe ren ce ca teg o ry is the lo w e st q u in tile o f in tak e . E st im ates fo r m ult ip le log is tic re g re ss ion e qua tio ns in c lu d in g te rm s fo r a ge , s ex (w h en re qu ired ), fam ily h is to ryo f g as tr ic ca nc er, bo dy m ass index , and to ta l ene rgy in tak e .

a fte r ad ju s tm e n t fo r d ie ta ry v a riab le s . B eca u se n itra te s a red e r ive d m a in ly fro m ve g e ta b les (inc lu d ing ca bb ag e s a ndo th e r c ruc ife ra e , g ree n sa lad , to m a toe s , p ep p ers , b e s id e sb rea d , be e r, a n d ca nn e d m e a t), th e ir p ro te c tio n is like ly tore fle c t th e p ro te c tio n co nv ey ed b y b e ta -ca ro te ne an d v ita -m m C a n d o th e r p o te n tia l p ro te c tive fa c to rs o f a d ie t ric h infru it a n d ve ge tab le s (4 , 3 1 , 3 2 ).

S o m e in d ire c t as so c ia tio ns o r lack o f a sso c ia tio ns d e -se rve co n s id e ra tio n , a ls o . T h e se inc lu de th e inc rea se d ris kw ith in c re as in g m e th ion in e co n sum ption , w h ich is d e r ive dm a in ly fro m le g um es a nd p o ta toe s , an d m a y th e re fo re re p -res en t a n as pe c ific ind ica to r o f a less a fflu e n t d ie t in th isp op u la tion , an d fo r m e a t, inc lud in g h am , vea l, ch ic ken ,liv e r, b aco n , can n ed m e a t, a nd s au sa ge s , an d m ay th u sind ica te s om e ro le o f m e a t, o r so m e o f its c om po ne n ts , ong as tric ca rc in og e ne s is (1 , 4) . Th e lac k o f p ro tec tio n b ya -toco p he ro l, if n o t d u e to ch an ce or b ia s , m a y b e d u e toth e le ve ls o f in ta ke w h ic h ca n e xe rt som e pro te c tive e ffe c t,w he re as the re is little ev ide n ce th a t re tin o l, v itam in D , a ndca lc iu m a re p ro tec tive a ga in s t g a s tric ca rc in og e ne s is .

The size of this data set allowed sufficient statisticalpo w er to o b ta in re a son a b ly p rec ise risk e s tim a te s an d s ig -n if ica n t tren ds in ris k fo r se ve ra l m ic ro nu trie n ts . R e lia b ilityo fth e e s tim a te d m ic ron u tr ie n t in ta ke sh ou ld be sa tis fac to ry .W ith re fe ren ce to rep ro du c ib ility , a com pa n io n s tu dy (3 3 )g ave fo r nu trie n ts a m e d ian co rre la tio n c oe ffic ie n ts o f 0 .67 ,w ith m os t v a lue s fa llin g b e tw e en 0 .6 0 an d 0 .7 0 . A s fo rva lid ity , th e co m p a riso n w ith a va ila b le a ve rag e re co m -mended daily intake for the Italian population (34) is reas-su rin g w ith re fe ren ce to th e co m p le ten es s a n d re lia b ility o fou r in fo rm a tio n , a lth ou g h o u r e s tim a te s w e re ba se d on th eco nsu m p tio n o f a re s tric te d nu m b er o f ite m s .

C a se s an d co n tro ls cam e from com pa ra b le ca tc hm e n ta reas (i .e., o ve r 8 0 % com e fo r th e sa m e re g ion ); an d th ealmost complete participation rate, the similar interviewse tting fo r c ase s a nd con tro ls , an d th e a llow a nce fo r m a jo rp o te n tia l c on fou nd in g fac to rs , in c lu d ing a n es tim a te o f to ta len e rgy in take (3 5 ) , a re rea ssu ring a g a ins t se le c tio n , in fo r-m a tion , a n d con fou n d ing b ia s .

In co nc lu s io n , th is la rg e ca se -co n tro l s tud y p rov id ess up po rt fo r a p ro tec tive e ffec t o f va riou s m ic ron u trien ts o ng a s tric ca n ce r risk , w h ic h p e rs is te d a fte r a llo w an ce fo r 5 ev -e ra l po ten tia l con fou n d ing fac to rs , inc lud in g to ta l ca lo riein tak e . T h e re w as a ls o so m e ind ic a tio n tha t n itr ite s a rea sso c ia ted to th e risk , bu t o n ly be ta -c a ro ten e a n d a sco rb ica c id re m a in e d s ig n ific an tly p ro te c tive a fte r s im u lta ne o usa llow an ce fo r va r io us m ic ro nu trie n ts . W h e th e r th is re fle c tsa m o re sp e c ific o r s tro ng e r e ffe c t o f the se m ic ro nu trie n tsra th e r th an lim ita tion s in da ta co llec tion fo llow ing co l-line a rity be tw e e n va rio us fac to rs re m a in s to b e c la rif ied infu rth er rese arch .

Acknow le dgmen tsT he au th o rs tha nk J udy B ag go tt, Iv an a G a rim o ld i, a nd th e G . A . P fe if fe rM em o ria l L ib ra ry s ta ff fo r ed ito ria l ass is tance .

Refe rences1 . H o w s on , C . P ., H iy am a, 1 ., an d W y nd er, E . L . T he d ec lin e in gastricca nce r: ep idem io logy o f an unp lanned trium ph . E p idem io l. R ev., 8: 1-27 ,1986.2 . C orrea , P ., C ue llo , C ., F a ja rdo , L . F ., H a ensze l, W ., B o la nos, 0 . , and deR a m irez, B . D ie t and gastric cance r: nu trition su rvey in a h igh -ris k a re a .J , N a tI. C anc e r Inst., 70 :67 3 -6 78 , 1983 .3 . C orrea , P ., F on tham , E ., P ick le , L . W ., C hen , V ., L in , Y ., an d H aens ze l, W .D ie ta ry de te rm inan ts o f gastric can ce r in S ou th Lou is iana inhab itan ts . J . N a tI.C an ce r In st., 75 : 64 5-6 54 , 1 985 .4 , La V ecc h ia , C ., N egri, E ., D ec a rli, A ., D A vanz o , B ., and F rancesc h i, S . Aca se -co n tro l s tu dy o f d ie t an d ga str ic ca nce r in N orthe rn Ita ly . n t. J . C ance r,40 :484 -489 , 1987 .5 . Y ou , W -C ., B lo t, W . J., C hang , Y -S ., E rshow , A . G ., Y ang , Z-T ., A n Q .,H enders on , B ., xu , G -W ., F ra um en i, J . F . , J r., an d W a ng , T -G . D ie t a nd h ighrisk o f s to m ach cance r in S handong , C h ina . C ance r R es ., 48 : 3518-3523 ,1988 .6 . C orrea , P . A hum an m o de l o f gastric c a rc inogen esis . C ance r R es., 48 :3554-3560, 1988.7. Bu ia tti, E ., Pa lli, D ., D eca rli, A ., A m adori, D ., A ve llin i, C ., B ianch i, S .,B is e rn i, R ., C ip rian i, F ., C o cco , P ., G iacosa , A ., M arub in i, E ., P un ton i, R .,V ind ign i, C ., F raum en i, J . F ., Jr., a nd B lo t, W . j. A cas e -con tro l s tudy o fgastric canc e r and d ie t in Ita ly . m t. J . C a n ce r , 44 : 611-616 , 1989 .


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39 8 M ic ro nu trie n t In tak e and Gastric C an ce r

8 . N egri, E ., La V ecch ia , C ., F rances ch i, S ., D A vanz o , B ., and P ara zz in i, F .Vege tab le and fru it cons um ption and c ance r risk . In t . J . C ance r, 48 : 350-354 , 1991 .9 . G onz a lez, C . A ., Sanz , J . M ., M arcos , G ., P ita , S ., B ru lle t, E ., S a ig i, E .,B ad ia , A ., and R ibo li, E . D ie ta ry facto rs and stom a ch cance r in S pa in : am u lti-cen tre c ase -con tro l s tu dy. In t. J . C ance r, 49 : 513-519 , 1991 .10 . R am o n , J. M ., S e rra , L ., C e rdo , C ., and O rom i, J . D ie ta ry facto rs an dgastric cance r ris k . A case -co n tro l s tudy in S pa in . C a nce r, 71 : 1 7 31 -1 735 ,1993.1 1 . B oe in g , H ., F ren tze l-Bey m e, R ., B e rge r, M ., B e rnd t, V ., G ore s, W .,K orn e r , M ., Lo hm e ie r, R ., M e na rch e r, A ., M a nn l, H . F . K ., M e inh a rd t, M .,M ulle r, R ., O ste rm e ie r, H ., P au l, F ., Sc hw em m le , K ., W agner, K . H ., andW ahren dorf, J . C ase -co n tro l s tudy on s tom ach ca nce r in G erm any . m t. J.Canc er , 47 : 8 58 -86 4 , 19 91 .1 2 . H ansson , L -E ., N yr# {233 }n , ., B e rgstrom , R ., W o lk , A ., L ind g ren , A ., Ba ron ,J . , and Adam i, H -O . D ie t and risk o f gas tric ca nce r: a p opu la tion -b asedc ase -c on tro l s tu dy in S w ed en . In t. ). Canc er , 55 : 181-189 , 1993 .1 3. R isch , H . A ., J am , M ., C ho i, N . W ., F od or, J . G ., P fe iffe r, C . J ., H ow e ,G . R ., H arrison , L . W ., C ra ib , K . J . P ., and M il le r, A . B . D ie ta ry fa cto rs andthe inc ide nce o f canc e r o f the sto m ach . A m . J. E p idem io l., 122 : 947-959 ,1985 .1 4 . S teh r, P . A ., G lon inge r, M . F., K u lle r, L . H ., M arsh , G . M ., R ad fo rd , E . P .,and W e inbe rg , G . B . D ie ta ry v itam in A de fic ienc ies and s tom ach c ance r.A m . J . E pid em io l., 121 : 65-70 , 198 5 .1 5 . B u ia tti, E ., P a lli, D . , D ec a rli, A ., A m adori, D . , A ve llin i, C ., B ianch i, S .,Bo naguri, C ., C ip rian i, F ., C occo , P ., G iac osa , A ., M arub in i, E ., M inacc i, C .,Pu n ton i, R ., R usso , A ., V ind ign i, C ., F raum en i, J . F ., Jr., and B lo t, W . J. Ac ase -c on tro l s tu dy o f ga s tric c anc e r an d d ie t in Ita ly : II. A s soc ia t ion w ithnu tr ien ts . m t. J. C ance r, 45 :89 6 -901 , 1 990 .1 6 . G raha m , S ., H aughe y, B ., M arsha ll, J ., B rasu re , J ., Z ie le zny, M .,F re udenhe im , J., W es t, D ., N o lan , J ., and W ilk inson , G . D ie t in th e ep ide -m io lo gy o f gas tric c ance r. N u tr. C ance r, 13 : 19 -34 , 199 0 .1 7. F orm an , D ., A l-D abbagh , S ., K n igh t , T . , and D o ll, R . N itra te expo su rean d th e ca rc inog en ic p ro ce ss . A nn . N . Y . A cad . S c i., 534 : 5 97-60 3 , 19 88 .1 8. F o rm an , D ., A l-D a bbagh , S ., and D o ll, R . N itra tes, n itr ites and gastriccanc e r in G re a t B rita in . N a tu re (Lond .), 313 :62 0 -6 25 , 1985 .19 . Z a tons k i, W ., O hsh im a , H ., P rz ew oz n iak, K ., D ro s ik , K ., M ie rzw inska ,J ,, K ry g ie r, M ., C hm ie la rcz yk, W ., and B artsc h , H . U rina ry ex cre tion o fN -n itrosam ino ac ids and n itra te by inhab itan ts o f h ig h - and low -risk a reas fo rs tom ach c ance r in P o la nd . In t. J . C anc e r, 44 : 823-827 , 1 989 .20 . Kn igh t, 1 . M ., F o rm an , D ., P irastu , R ., C om ba , P ., lanna rill i, R ., C occo ,P . L ., A ngo tz i, G ., N inu , E ., and Sch ie rano , S . N itra te an d n itr ite ex posu re inIta lian popu la tio ns w ith d iffe ren t g astric c ance r ra tes. m t. J . E p id e m io l ., 19 :510-515 , 1990 .

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Selected Micro Nutrient Intake and the Risk of Gastric Cancer

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