Characterization of a population with an increased risk of gastric cancer: first degree relatives of early-onset gastric carcinoma patients

R ICARDO J ORGE M ARCOS P INTO C C H HA AR RA AC CT TE ER RI IZ ZA AT TI IO ON N O OF F A A P P O OP PU UL LA AT TI IO ON N W W I IT TH H A AN N I I N NC CR RE EA AS SE ED D R R I IS SK K O OF F G G A AS ST TR RI IC C C C A AN NC CE ER R : : F F I IR RS ST T D D E EG GR RE EE E R R E EL LA AT TI IV VE ES S O OF F E E A AR RL LY Y - -O O N NS SE ET T G G A AS ST TR RI IC C C C A AR RC CI IN NO OM MA A P P A AT TI IE EN NT TS S Tese de Candida u a ao g au de Dou o em Ciências Médicas subme ida ao Ins i u o de Ciências Biomédicas Abel Salaza da Uni e sidade do Po o O ien ado - P o . Dou o Jo ge A eias Ca ego ia - P o esso Ca ed á ico Con idado A iliação - Ins i u o de Ciências Biomédicas Abel Salaza da Uni e sidade do Po o Co-o ien ado - P o . Dou o Má io Dinis Ribei o Ca ego ia - P o esso Associado Con idado A iliação - Faculdade de Medicina da Uni e sidade do Po o Co-o ien ado - P o . Dou o a Fá ima Ca nei o Ca ego ia - P o esso a Ca ed á ica A iliação - Faculdade de Medicina da Uni e sidade do Po o 2 3 T To o m my y p pa a e en n s s a an nd d s si is s e e T To o m my y w wi i e e a an nd d d da au ug gh h e e - - h he e s so ou u c ce e o o m my y i in ns sp pi i a a i io on n- - T Th ha an nk k y yo ou u! ! 4 T T A AB BL LE E O OF F C C O ON NT TE EN NT TS S 6 7 A AC CK KN NO OW WL LE ED DG GE EM ME EN NT TS S 9 F FI IN NA AN NC CI IA AL L S SU UP PP PO OR RT T 1 3 O OU UT TL LI IN NE E O OF F T TH HE E T TH HE ES SI IS S A AN ND D L LI IS ST T O OF F P PU UB BL LI IC CA AT TI IO ON NS S 1 7 S SU UM MM MA AR RY Y 2 5 R RE ES SU UM MO O 31 I I C CH HA AP PT TE ER R I I 3 7 I I N NT TR RO OD DU UC CT TI IO ON N A A. . G G E EN NE ER RA AL L I I N NT TR RO OD DU UC CT TI IO ON N 3 7 1 Epidemiology o Gas ic Cance 39 2 In es inal e sus Di use: Two Pa hways o Gas ic Cance 4 1 3 Risk Fac o s o Gas ic Cance 4 5 4 P emalignan Condi ions and Lesions o he S omach 5 3 5 Family His o y and Gas ic Cance isk 6 0 6 Ea ly-Onse Gas ic Cance 6 2 B. R ATIONALE AND A IMS 6 5 I I I I CHAPTER II 7 3 S ELECTION OF P ARTICIPANTS A. S ELECTION OF C ASES 7 5 B. S ELECTION OF CONTROLS 79 F IRST D EGREE R ELATIVES AND F AMILIAL A GGREGATION OF G ASTRIC C ANCER : W HO TO C HOOSE FOR C ONTROL IN C ASE -C ONTROL STUDIES ? I I I I I I C CH HA AP PT TE ER R I II II I 89 P REMALIGNANT C ONDITIONS AND L ESIONS AND C LASSIFICATION S YSTEMS IN F IRST D EGREE R ELATIVES OF E ARLY -O NSET G ASTRIC C ARCINOMA P ATIENTS F IRST - DEGREE RELATIVES OF PATIENTS WITH EARLY - ONSET GASTRIC CARCINOMA SHOW 8 EVEN AT YOUNG AGES A HIGH PREVALENCE OF ADVANCED OLGA/OLGIM STAGES AND DYSPLASIA I I V V C CH HA AP PT TE ER R I IV V 10 1 H H O OS ST T A AN ND D H H E EL LI IC CO OB BA AC CT TE ER R P PY YL LO OR RI I G GE EN NO OT TY YP PE ES S IN F IRST D EGREE R ELATIVES OF E ARLY - O NSET G ASTRIC C ARCINOMA P ATIENTS F IRST D EGREE R ELATIVES OF E ARLY -O NSET G ASTRIC C ANCER P ATIENTS SHOW A HIGH RISK FOR GASTRIC CANCER : PHENOTYPE AND GENOTYPE PROFILE V V C CH HA AP PT TE ER R V V 1 29 D D I IS SC CU US SS SI IO ON N A AN ND D C C O ON NC CL LU UD DI IN NG G R R E EM MA AR RK KS S V V I I C CH HA AP PT TE ER R V VI I 1 39 F F U UT TU UR RE E S S T TU UD DI IE ES S A AP PP PE EN ND DI IX X A A P PP PE EN ND DI IX X 1 1 14 3 G UIDELINES FOR THE M ANAGEMENT OF P RECANCEROUS C ONDITIONS AND L ESIONS IN THE S TOMACH (MAPS) : GUIDELINE FROM THE E UROPEAN S OCIETY OF G ASTROINTESTINAL E NDOSCOPY (ESGE) , GUIDELINE FROM THE E UROPEAN S OCIETY OF G ASTROINTESTINAL E NDOSCOPY (ESGE) , (ESP) , AND THE S OCIEDADE P ORTUGUESA DE E NDOSCOPIA D IGESTIVA (SPED) A A P PP PE EN ND DI IX X 2 2 16 5 A M ULTICENTER V ALIDATION OF AN E NDOSCOPIC C LASSIFICATION WITH N ARROW B AND I MAGING FOR G ASTRIC P RECANCEROUS AND C ANCEROUS L ESIONS R RE EF FE ER RE EN NC CE ES S 1 79 L LI IS ST T O OF F A AB BB BR RE EV VI IA AT TI IO ON NS S 20 1 A A C CK KN NO OW WL LE ED DG GE EM ME EN NT TS S F F I IN NA AN NC CI IA AL L S SU UP PP PO OR RT T 16 O O U UT TL LI IN NE E O OF F T TH HE E T TH HE ES SI IS S A AN ND D L LI IS ST T O OF F P PU UB BL LI IC CA AT TI IO ON NS S O O U UT TL LI IN NE E O OF F T TH HE E T TH HE ES SI IS S A AN ND D L LI IS ST T O OF F P PU UB BL LI IC CA AT TI IO ON NS S 18 O O U UT TL LI IN NE E O OF F T TH HE E T TH HE ES SI IS S A AN ND D L LI IS ST T O OF F P PU UB BL LI IC CA AT TI IO ON NS S 19 The p esen hesis is s uc u ed in he ollowing way: Fi s , a Summa y consis ing in a b ie desc ip ion o he hesis will be p esen ed. In Chap e I, In oduc ion, a gene al in oduc ion gi ing he backg ound o he hesis is p esen ed. The ele ance o gas ic cance in he Wo ld and in Po ugal is highligh ed. Also, he wo pa hways o gas ic cance de elopmen (in es inal s di use) as well he knowledge abou amilial agg ega ion and ea ly-onse gas ic cance will be add essed. Risk ac o s including Helicobac e pylo i in ec ion and hos gene ic a ia ions as well p emalignan lesions o he s omach will be e iewed. In Ra ionale and Aims, he a ionale o his hesis will be desc ibed. In Chap e II, Selec ion o Pa ien s and Con ols, a desc ip ion o selec ion o pa ien s is desc ibed. Addi ionally an o iginal pape add essing me hodology issues ega ding he alidi y o he ype o selec ed con ols is included. I was he basis o he case- con ol design o he s udy and a suppo o discuss expec ed bias. In Chap e III, P emalignan Condi ions and Lesions and Classi ica ion Sys ems in Fi s Deg ee Rela i es o Ea ly-Onse Gas ic Ca cinoma Pa ien s, an o iginal pape was included desc ibing he high p e alence o p emalignan lesions in cases is desc ibed. Addi ionally, we g aded and compa ed he s ages o he p emalignan lesions using OLGA s aging sys em, he newly desc ibed OLGIM sys em and also wi h an o iginal classi ica ion sys em which excludes incisu a angula is biopsy. O O U UT TL LI IN NE E O OF F T TH HE E T TH HE ES SI IS S A AN ND D L LI IS ST T O OF F P PU UB BL LI IC CA AT TI IO ON NS S 20 Chap e IV, Hos and Helicobac e pylo i geno ypes in Fi s Deg ee Rela i es o Ea ly- Onse Gas ic Ca cinoma Pa ien s, , consis s in an o iginal pape which ep esen s he “in dep h” s udy and sea ch o he explana ion o he high isk pheno ype p e iously shown. He e we desc ibe he case-speci ic hos gene ic a ia ions ( ega ding in lamma o y hos esponse) including he adi ional desc ibed polymo phisms (1β- 511 and IL-1RN) and a new one which can be popula ion speci ic (IFNGR1). We analyzed also H. pylo i known speci ic i ulence ac o s (CagA, VacA s and VacA m). In Chap e V, Discussion and Concluding Rema ks, an o e all discussion o all he a icles will be p o ided and a gene al conclusion will be p esen ed. In Chap e VI, Fu u e S udies, as new answe s came wi h he p esen wo k new ques ions eme ged and po en ial lines o in es iga ion a e s essed. The Appendix consis s in wo o iginal publica ions in which he au ho ac i ely pa icipa ed and a e ela ed o he con en o he hesis. The i s one conce ns in he i s in e na ional guidelines on ollow-up o p emalignan condi ions and lesions o he s omach. The con en o his disse a ion is closely ela ed o he e idence ha cons i u ed he basis o g ading e idence in he a o emen ioned guidelines, namely amilial agg ega ion o gas ic cance , hos and H.pylo i gene ic a ia ions and p emalignan condi ions and lesions sampling and g ading (Appendix 1). The second publica ion is based on endoscopic classi ica ion o di e en pa e ns o gas ic mucosa and i s co espondence o his ology. I opens he way o u he esea ch on i s alida ion and co ela ion o he classical his ological-based s aging sys ems (Appendix 2). O O U UT TL LI IN NE E O OF F T TH HE E T TH HE ES SI IS S A AN ND D L LI IS ST T O OF F P PU UB BL LI IC CA AT TI IO ON NS S 21 The p esen disse a ion includes se e al pee - e iewed publica ions p esen ed below. Full lis o publica ions: 1. Chap e II F IRST D EGREE R ELATIVES AND F AMILIAL A GGREGATION OF G ASTRIC C ANCER : W HO TO C HOOSE FOR C ONTROL IN C ASE -C ONTROL STUDIES ? Rica do Ma cos-Pin o, Má io Dinis-Ribei o, Fá ima Ca nei o, José Ca los Machado, Céu Figuei edo, Celso A. Reis, José Fe ei a, Jo ge A eias. Familial Cance . 2012 Ma ;11 (1):137-43 2. Chap e III F IRST - DEGREE RELATIVES OF PATIENTS WITH EARLY - ONSET GASTRIC CARCINOMA SHOW EVEN AT YOUNG AGES A HIGH PREVALENCE OF ADVANCED OLGA/OLGIM STAGES AND DYSPLASIA Rica do Ma cos-Pin o, Má io Dinis-Ribei o, Fá ima Ca nei o, Xiaogang Wen, Ca los Lopes, Céu Figuei edo, José Ca los Machado, Rui Fe ei a, Celso A. Reis, José Fe ei a, Isabel Ped o o, Jo ge A eias. Alimen a y Pha macology and The apeu ics. 2012 Jun; 35(12):1451-9 O al communica ion a he Fi s Diges i e Week (Es o il, Po ugal, 2011). O O U UT TL LI IN NE E O OF F T TH HE E T TH HE ES SI IS S A AN ND D L LI IS ST T O OF F P PU UB BL LI IC CA AT TI IO ON NS S 22 3. Chap e IV F IRST D EGREE R ELATIVES OF E ARLY -O NSET G ASTRIC C ANCER P ATIENTS SHOW A HIGH RISK FOR GASTRIC CANCER : PHENOTYPE AND GENOTYPE PROFILE Rica do Ma cos-Pin o, Má io Dinis-Ribei o, Fá ima Ca nei o, Xiaogang Wen, Ca los Lopes, Céu Figuei edo, José Ca los Machado, Rui Fe ei a, Celso A. Reis, José Fe ei a, Isabel Ped o o, Jo ge A eias. Unde Re iew O al communica ion a he XXX Cong esso Nacional de Gas en e ologia e Endoscopia Diges i a (Vilamou a, Po ugal, 2010). O al communica ion a he Fi s Diges i e Week (Es o il, Po ugal, 2011). Pos e p esen a ion a Diges i e Disease Week/113 h Annual Mee ing o he Ame ican-Gas oen e ological-Associa ion (USA, 2012). 4. Appendix 1 G UIDELINES FOR THE M ANAGEMENT OF P RECANCEROUS C ONDITIONS AND L ESIONS IN THE S TOMACH (MAPS): GUIDELINE FROM THE E UROPEAN S OCIETY OF G ASTROINTESTINAL E NDOSCOPY (ESGE), GUIDELINE FROM THE E UROPEAN S OCIETY OF G ASTROINTESTINAL E NDOSCOPY (ESGE), (ESP), AND THE S OCIEDADE P ORTUGUESA DE E NDOSCOPIA D IGESTIVA (SPED) Dinis-Ribei o M, A eia M, de V ies A, Ma cos-Pin o R, Mon ei o-Soa es M, O’Conno A, Pe ei a C, Pimen el-Nunes P, Co eia R, Ensa i A, Dumonceau JM, Machado JC, Macedo G, Mal e heine P, Ma ysiak-Budnik T, Meg aud F, Miki K, O’Mo ain C, Peek RM, Ponchon T, Ris imaki A, Rembacken B, Ca nei o F, Kuipe s EJ. Endoscopy. 2012. Jan;44(1):74-94. O O U UT TL LI IN NE E O OF F T TH HE E T TH HE ES SI IS S A AN ND D L LI IS ST T O OF F P PU UB BL LI IC CA AT TI IO ON NS S 23 O al communica ions a he MAPS mee ing (Po o, Po ugal, 2012) Session II - Which ca e should be aken on biopsies (numbe and si es) o a co ec diagnosis and s aging? Session III - Should o he sou ces o da a be added o s aging? 5. Appendix 2 A M ULTICENTER V ALIDATION OF AN E NDOSCOPIC C LASSIFICATION WITH N ARROW -B AND I MAGING FOR G ASTRIC P RECANCEROUS AND C ANCEROUS L ESIONS . Ped o Pimen el-Nunes, Má io Dinis-Ribei o, João B uno Soa es, Rica do Ma cos-Pin o, C is ina San os, Ca la Rolanda, Rui Ped o Bas os, Miguel A eia, Jacques Be gman, P a eek Sha ma, Takuji Go oda, Rui Hen ique, Luís Mo ei a. Endoscopy. 2012 Ma ;44(3):236-46 O O U UT TL LI IN NE E O OF F T TH HE E T TH HE ES SI IS S A AN ND D L LI IS ST T O OF F P PU UB BL LI IC CA AT TI IO ON NS S 24 S S U UM MM MA AR RY Y R R E ES SU UM MO O 32 R R E ES SU UM MO O 33 INTRODUÇÃO O canc o gás ico é a qua a neoplasia mais equen e no Mundo. Em Po ugal o canc o gás ico si ua-se na quin a posição em incidência e mo alidade pa a ambos os sexos e espe a-se que a sua p e alência aumen e nos p óximos anos. O ipo in es inal é mais equen e em doen es com idade a ançada e ep esen a o culmina de uma “casca a” de e en os com início na gas i e a ó ica mul i ocal após exposição a ac o es de isco ambien ais, al como a in ecção po Helicobac e pylo i. No malmen e es as al e ações são acompanhadas po me aplasia in es inal dando o igem ao canc o o qual é p ecedido po displasia. Es e p ocesso len o, conhecido como a “casca a de Co ea” é dependen e de in lamação c ónica con inuada. Ao con á io do canc o de ipo in es inal, o ipo di uso desen ol e-se em con ex o de in lamação c ónica sem passa pelas e apas in e médias. A in ecção po H. pylo i é um ac o de isco c ucial pa a o desen ol imen o de canc o com a p og essão pa a neoplasia oco endo apenas numa pequena pa e dos indi íduos in ec ados, p o a elmen e naqueles com suscep ibilidade gené ica em associação com es i pes i ulen as da bac é ia. Vá ios es udos demons a am que o isco de canc o gás ico es á aumen ado nos indi íduos com condições p émalignas gás icas ex ensas (de ec adas no an o e co po simul aneamen e) o que é de e minado po amos as colhidas po biopsias com a aliação his ológica de aco do com o Sis ema de classi icação de Sydney. O sis ema de classi icação OLGA (Ope a i e Link o Gas i is Assessmen ) ecen emen e p opos o em como objec i o a anslação dos dados ana omopa ológicos das condições p émalignas ( opog a ia e ex ensão da a o ia) pa a um sis ema de g aduação que ag upa os doen es po isco de desen ol imen o de canc o gás ico. Tendo em con a que a ex ensão e a se e idade da a o ia são os pa âme os em a aliação e que a conco dância in e obse ado pa a a o ia é baixa oi p opos o um no o sis ema de R R E ES SU UM MO O 34 classi icação baseado na a aliação da me aplasia in es inal, com um melho ní el de conco dância (OLGIM). A ag egação amilia de canc o gás ico pode se secundá ia a suscep ibilidade gené ica mas ac o es não he edi á ios pode ão ambém es a implicados ais como a in ecção po H. pylo i, exposição a abaco ou ao mesmo ipo de die a. É econhecido que ce ca de 10% dos canc os gás icos êm ag egação amilia , suge indo uma o ma de p edisposição amilia . O signi icado des a ag egação e da his ó ia amilia não es á cla amen e elucidado. O canc o gás ico p ecoce (CGP) é de inido pelo desen ol imen o de canc o an es dos 45 anos de idade; ap oximadamen e 10% dos canc os pe encem a es e subg upo. Ac edi a-se que os ac o es gené icos e ão mais ele ância nes a subpopulação do que nos doen es com canc o em idade a ançada, mas os ac o es ambien ais al como a in ecção a H. pylo i pode ão ambém se impo an es no desen ol imen o da doença em doen es jo ens. O mo i o da oco ência da doença nes es doen es jo ens pe manece la gamen e inexplicado podendo co esponde a uma in e acção en e um genó ipo com p edisposição e ac o es desencadean es ambien ais. Não há es udos em amilia es de doen es com CGP. OBJECTIVOS Ca ac e iza os amilia es de p imei o g au (FPG) de doen es com canc o gás ico p ecoce (CGP) em elação a pa âme os his ológicos da mucosa gás ica, suscep ibilidade gené ica e i ulência das es i pes de H. pylo i. Es uda o sis ema de classi icação OLGA na es a i icação segundo o isco de canc o assim como o sis ema OLGIM e os dois sis emas modi icados (excluindo a biopsia da incisu a angula is). R R E ES SU UM MO O 35 MÉTODOS P ocedeu-se a um es udo caso-con olo com FPG de doen es com CGP (casos; n=103) e con olos empa elhados pa a o sexo e idade (n=101; idade média 43 anos; 41% sexo masculino; englobando cônjuges (n=25), izinhos (n=25) e doen es dispép icos (n=51)). Foi e ec uada endoscopia diges i a al a com biopsias segundo o p o ocolo de Sydney- Hous on e es adiamen o segundo os sis emas OLGA, OLGIM e os mesmos modi icados com exclusão da biopsia da incisu a. P ocedeu-se à cul u a e geno ipagem das es i pes de H. pylo i (cagA e egiões m e s acA) assim como à geno ipagem do hospedei o ela i amen e aos genes IL1B -511, IL1RN e IFNGR1-56. RESULTADOS Se en a po cen o dos FPG de CGP ap esen a am a o ia (Es adios OLGA I-IV) com 19% deles com es ádio a ançado (Es adios OLGA III-IV) (p<0.001) com 7 displasias nos casos e nenhuma nos con olos (p=0.007). A aplicação dos sis emas OLGIM e OLGA e OLGIM modi icados le ou ao in aes adiamen o de es adios em compa ação com a classi icação OLGA (27%, 15% e 30%, espec i amen e). Em odos os sis emas de classi icação, 86% das displasias ag upa am-se nos g upos de al o isco. A in ecção po H. pylo i oi diagnos icada em 82% dos casos e 62% dos con olos (p=0.004), com as es i pes acA s1/m1 + signi ica i amen e associadas à p esença de a o ia na mucosa gás ica. Adicionalmen e oi demons ado que a homozigo ia pa a IL1B–511*T con e ia um maio isco pa a es adios OLGA a ançados e displasia. Um aumen o de p e alência global do polimo ismo IFNGR1-56*T/*T oi obse ado nos casos (37% nos casos s 24% nos con olos; p=0.03), sem elação com es adios de a o ia ou p esença de displasia. Todas as di e enças obse adas se man i e am quando a compa ação oi e ec uada com os di e en es ipos de con olos: cônjuges, izinhos ou dispép icos. R R E ES SU UM MO O 36 CONCLUSÕES FPG de doen es com CGP êm uma ele ada p e alência de es adios OLGA de isco e displasia os quais pa ecem es a associados a es i pes de isco de H. pylo i e genó ipos p ó-in lama ó ios do hospedei o. FPG de doen es com CGP pode ão se al o de o ien ação di e enciada com e adicação de H. pylo i e a aliação endoscópica e his ológica da mucosa gás ica e igilância. C CH HA AP PT TE ER R I I A. G ENERAL I NTRODUCTION I IA A. . G ENERAL I NTRODUCTION 38 I IA A. . G ENERAL I NTRODUCTION 39 I IA A. .1 1. . E Ep pi id de em mi io ol lo og gy y o o G Ga as s i ic c C Ca an nc ce e Gas ic cance is one o he mos common cance s wi h abou one million new cases es ima ed o ha e occu ed in 2008 (988 000 cases, 7.8% o he o al), making i he ou h mos common malignancy in he wo ld, behind cance s o he lung, b eas and colo- ec um. Mo e han 70% o cases (713 000 cases) occu in de eloping coun ies (467 000 in men, 246 000 in women), and hal he wo ld o al occu s in Eas e n Asia. Age-s anda dized incidence a es a e abou wice as high in men as in women, anging om 3.9 in No he n A ica o 42.4 in Eas e n Asia o men, and om 2.2 in Sou he n A ica o 18.3 in Eas e n Asia o women (Globocan 2008). The wo ldwide incidence o gas ic cance has declined apidly o e he ecen ew decades (Ande son e al. 2010, Jemal e al. 2006, Schlansky e al. 2011). Pa o he decline may be due o he dec ease o ce ain isk ac o s such as Helicobac e pylo i in ec ion and o he die a y and en i onmen al isks. The decline i s ook place in coun ies wi h low gas ic cance incidence as he Uni ed S a es (Schlansky e al. 2011), while he decline in coun ies wi h high incidence, like Japan, occu ed la e and was slowe (Hi ayama 1975). Gas ic cance used o be he leading cause o cance dea hs in he wo ld un il he 1980s when i was o e aken by lung cance (Pisani e al. 1993). Nowadays, s omach cance is he second leading cause o cance dea h in bo h sexes wo ldwide (736 000 dea hs, 9.7% o he o al) wi h only a mino i y o gas ic adenoca cinomas diagnosed a a cu able and essec able s age. Mos pa ien s die du ing he i s yea a e he diagnosis, e en i submi ed o cos ly and agg essi e he apy (Diaz De Liano e al. 2003). The highes mo ali y a es a e es ima ed in Eas e n Asia (28.1 pe 100,000 in men, 13.0 pe 100,000 in women), he lowes in No he n Ame ica (2.8 and 1.5 espec i ely). High mo ali y a es a e also p esen in bo h sexes in Cen al and Eas e n Eu ope, and in Cen al and Sou h Ame ica. In Po ugal, gas ic cance anks in 5 h place in incidence and mo ali y o bo h sexes a e p os a e, b eas , colo- ec um and lung cance s. In spi e o wo ldwide global I IA A. . G ENERAL I NTRODUCTION 40 dec ease, in 2020 (using compu ing models), he p e alence o gas ic cance is expec ed o ise in Po ugal, o bo h sexes. Figu e1. Expec ed p e alence o gas ic cance in Po ugal in 2020 using age-speci ic a es and co esponding popula ions o 10 age-g oups (F om Globocan, 2008). I IA A. . G ENERAL I NTRODUCTION 41 I IA A. .2 2. . I In n e es s i in na al l e e s su us s D Di i u us se e: : T Tw wo o P Pa a h hw wa ay ys s o o G Ga as s i ic c C Ca an nc ce e Se e al a emp s o classi y gas ic cance ha e been made o e he pas decades. The mos commonly used classi ica ions a e he Wo ld Heal h O ganiza ion (WHO) (Lauwe s GY 2010) and he Lau en´s classi ica ion, he la e encompassing wo main his ological sub ypes, di use and in es inal (Lau en 1965), which ha e di e en p o iles ega ding epidemiology, p ecu so lesions and clinic-pa hological p o ile. In es inal adenoca cinomas p edomina e in he high isk a eas whe eas he di use adenoca cinoma is mo e common in low isk a eas (Lauwe s GY 2010). Incidence o he in es inal ype has been dec easing o e he pas se e al decades (Henson e al. 2004, Locke e al. 1995); in low- isk popula ions, he equency o in es inal ype gas ic adenoca cinomas is close o he incidence o di use ype umo s. GASTRIC ADENOCARCINOMA D IFFUSE T YPE (30%) I NTESTINAL T YPE (70%) No mal Gas ic Mucosa Supe icial Gas i is Ch onic Gas i is Ch onic A ophic Gas i is In es inal Me aplasia Dysplasia Cance H. pylo i CagA;VacAs1/m1; o he … Wi hou p emalignan lesions ? Weeks Yea s En i onmen al Fac o s Diie Smoking O he E-Cadhe in (CDH1) mu a ion Soma ic Spo adic di use gas ic cance Ge mline He edi a y di use gas ic cance Family His o y o Gas ic Cance (10%) 1-3% Yea s Yea s Yea s GAPPS Gas ic adenoca cinoma and p oximal polyposis o he s omach Hos suscep ibili y P oin lamma o y In e leukins IL-1β T/T IL1-RN *2/*2 TNF- α -A -308*A Figu e2. The wo pa hways o gas ic cance and associa ed isk ac o s. I IA A. . G ENERAL I NTRODUCTION 48 loca ion, H.pylo i in ec ion, me hodologies and quali y o s udies (Pe sson e al. 2010, Yin e al. 2009). Th ee powe ed me a-analyses ound an associa ion o IL-1 β and IL- 1RN*2 isk in Caucasians bu no in Asians (Cama go e al. 2006, Wang e al. 2007, Xue e al. 2010) and ano he ound a null associa ion in bo h popula ions (Kamanga e al. 2006). Ano he ecen me a-analysis (Pe sson e al. 2010) ound an inc eased cance isk o IL-1RN*2ca ie s, a isk ha was speci ic o non-Asian popula ions and o dis al cance s; he analysis es ic ed o high-quali y s udies o H.pylo i posi i e cases and con ols obse ed associa ion wi h he ca ie and he homozygosi y s a us. Rega ding Asian popula ions, educed isk was obse ed wi h IL-1β -31C ca ie s a us (in high- quali y s udies). Caucasian ca ie s o TNF-α -308A we e a an inc eased isk o gas ic cance in a ecen me a-analysis (Loh e al. 2009). O he han he classic suscep ibili y genes ha e been conside ed o playing a ole in gas ic ca cinogenesis. Thye and colleagues pe o med a genome-wide linkage analysis in which hey iden i ied a polymo phism in he posi ion -56 o he human in e e on γ (IFNγ) ecep o 1 gene (IFNGR1), associa ed wi h an inc ease in he suscep ibili y o a human hos o be in ec ed by H.pylo i (Thye e al. 2003). A single s udy demons a ed a ele an ole o he IFNGR1 gene in he de elopmen o ea ly-onse gas ic cance (Canedo e al. 2008). The s udy o hos gene ics b ough a be e unde s anding o disease pa hogenesis and helped in con i ming wo key-poin s: he impo an ole o H.pylo i in ec ion in gas ic ca cinogenesis and he ole o ch onic in lamma ion wi h i s long- e m dele e ious e ec s on gas ic physiology. Howe e , he he e ogenei y o esul s a he p esen ime makes i di icul o ansla e hem in o ecommenda ions o daily clinical p ac ice. I IA A. . G ENERAL I NTRODUCTION 49 Die The e a e geog aphic and e hnic di e ences in he incidence o gas ic cance a ound he wo ld, as well ends in each popula ion o e he ime. Emig an s om high- incidence o low-incidence coun ies expe ience a dec eased isk o de eloping gas ic ca cinoma. Such indings s ongly sugges ha en i onmen al ac o s ha e an impo an ole in he e iology o gas ic cance and ha he exposu e o isk ac o s occu s ea ly in li e (Haenszel e al. 1972). A a ie y o die a y ac o s ha e been implica ed as isk ac o s o gas ic cance . In e es ingly, he wo ldwide decline in gas ic cance a es has coincided wi h he widesp ead use o e ige a ion which imp o ed he s o age o ood educing sal -based p ese a ion o ood and allowed o esh ood and ege ables (a sou ce o an ioxidan s o cance p e en ion) o be mo e eadily a ailable (Coggon e al. 1989, La Vecchia e al. 1990). Lowe empe a u es educe he a e o bac e ial, ungal and o he con aminan s o esh ood as well as he bac e ial o ma ion o ni i es. Sal Di e en sou ces o e idence (ecological, case-con ol and coho s udies) sugges ha he isk o gas ic cance inc eases wi h a high in ake o sal (pickled oods, soy sauce, d ied and sal ed mea and ish)(Joossens e al. 1996, Kono e al. 1996, Pele ei o e al. 2011, Shika a e al. 2006, Tsugane e al. 2007). The Ame ican Ins i u e o Cance Resea ch classi ied sal and i s consump ion as a p obable isk ac o o gas ic cance . S udies on oden s es ablished a link be ween high sal in ake and gas ic mucosa damage and suscep ibili y o ca cinogenesis (Takahashi e al. 1984). High sal in ake has been associa ed wi h highe a es o a ophic gas i is in he se ing o H.pylo i in ec ion (Fox e al. 1999). Also, he consump ion o sal ed ood appea s o inc ease he possibili y o pe sis en H.pylo i in ec ion (Fox e al. 1999, Tsugane e al. 1994). In addi ion, a syne gis ic in e ac ion be ween H.pylo i in ec ion and sal ed ood in ake o inc ease he isk o gas ic cance has also been epo ed in some case-con ol s udies (Lee e al. 2003, Machida-Mon ani e al. 2004). I IA A. . G ENERAL I NTRODUCTION 50 Ni oso compounds Much a en ion has been gi en o he e ec s o high ni a e in ake. Exposi ion o ni oso compounds come om die , smoking and o he en i onmen al sou ces as well as om endogenous syn hesis (40 o 75 pe cen o exposu e) (T icke 1997). When ni a es a e educed o ni i e by bac e ia hey can eac wi h o he ni ogena ed subs ances o o m N-ni oso compounds ha a e known mu agens and ca cinogens (Old ei e e al. 2001). S udies ying o link N-ni oso exposu e o gas ic cance ha e been inconclusi e, e lec ing he ac ha ni a e in ake does no necessa ily co ela e wi h ni osa ion le els (Knek e al. 1999). The isk o gas ic cance associa ed wi h die a y in ake o ni i es and endogenous o ma ion o ni oso compounds was in es iga ed in he EPIC s udy. While he e was no associa ion be ween in ake o ni i es and gas ic cance isk, endogenous p oduc ion o N-ni oso compounds was signi ican ly associa ed wi h non-ca dia cance isk (haza d a io – 1.42)(Jakszyn e al. 2006). Die a y sal and ni oso compounds appea o exe a syne gis ic e ec wi h H.pylo i in animal models o gas ic ca cinogenesis. Se e al case-con ol s udies in humans ha e shown a posi i e associa ion be ween gas ic cance isk and bo h sal and die a y ni i e in ake, al hough da a om p ospec i e s udies a e con lic ing (Shika a e al. 2006, Tokui e al. 2005, an Loon e al. 1998). O he die compounds Da a om a la ge Eu opean p ospec i e s udy (EPIC-EURGAST) ailed o show an o e all associa ion be ween ui o ege able consump ion and gas ic cance isk (Gonzalez e al. 2006). The e was, howe e , a s a is ically signi ican associa ion be ween o al die a y ege able con en and he in es inal his ological sub ype. A non- signi ican nega i e associa ion was obse ed be ween ca dia cance isk and ci us ui consump ion. The e ec o ui and ege able in ake appea ed o be independen o H.pylo i in ec ion. Coho s udies ha e no p o ided consis en esul s; I IA A. . G ENERAL I NTRODUCTION 51 a me a-analysis ound a weak associa ion in he educ ion o gas ic cance isk om 18 pe cen o a high in ake o ui s o 12 pe cen o a high in ake o ege ables (Lune e al. 2005). Vi amin C and o he an ioxidan compounds me i a en ion as po en ial media o s o a die a y in luence in gas ic cance isk. Vi amin C le els a e educed in he se um o H.pylo i in ec ed indi iduals and being a ee adical sca enge i educes he o ma ion o po en ially ca cinogenic ni oso compounds (Woodwa d e al. 2001). The e is some e idence om case-con ol s udies o a nega i e associa ion be ween die a y i amin C and gas ic cance isk (Mayne e al. 2001). Da a om he EPIC coho show a nega i e co ela ion be ween gas ic cance isk and se um i amin C, bu no die a y i amin C in ake, and his was una ec ed by H.pylo i s a us (Jenab e al. 2006). Smoking Smoking is an independen isk ac o o gas ic cance . Se e al s udies examined he ela ionship be ween obacco smoking and gas ic cance isk. A me a-analysis o 40 s udies ound ha compa ed wi h ne e smoke s, cu en smoke s had a 1.5- old inc eased isk o gas ic cance (ca dia and nonca dia) and was highe in man (T edaniel e al. 1997). P ospec i e s udies ha e demons a ed a signi ican dose- dependen associa ion be ween obacco smoking and gas ic cance isk (Koizumi e al. 2004, Nishino e al. 2006). In he EPIC coho , i was es ima ed ha 17.6% o gas ic cance in his Eu opean popula ion was a ibu able o ciga e e smoking (Gonzalez e al. 2003). I IA A. . G ENERAL I NTRODUCTION 52 O he isk ac o s Addi ional isk ac o s including o he in ec ious agen s besides H.pylo i, pos gas ic su ge y s a us, gas ic polyps and ho monal ac o s ha e been in es iga ed bu i s ele ance emains unclea . Eps ein-Ba (EBV) i us in ec ion is associa ed wi h a numbe o malignancies. I has been es ima ed ha be ween 5 o 10 pe cen o gas ic cance s wo ldwide a e EBV associa ed cance s ough i us media ed me hyla ion o he p omo e egion o cance -associa ed genes (Boysen e al. 2009). EBV ela ed gas ic cance s demons a e male p edominance, end o be p oximal (nea he ca dia), ha e lymphocy ic in il a ion and a a o able p ognosis (Kusano e al. 2006). The e is a ecognized inc eased isk o gas ic cance a e gas ic su ge y wi h he peak incidence 15 o 20 yea s a e he su ge y (Te sme e e al. 1990). The Bill o h II (gas ojejunos omy) wi h egu gi a ion o alkaline bile and panc ea ic juice ca ies a highe isk han Bill o h I p ocedu e (gas oduodenos omy)(Te sme e e al. 1990). Obesi y is also associa ed wi h an inc eased isk o gas ic cance (ca dia and non- ca dia). In a me a-analysis o coho s udies a body mass index > 25 ca ies a isk o gas ic cance o 1.22 among non-Asians (Yang e al. 2009). I IA A. . G ENERAL I NTRODUCTION 53 I IA A. .4 4. . P P e em ma al li ig gn na an n C Co on nd di i i io on ns s a an nd d L Le es si io on ns s o o h he e S S o om ma ac ch h In es inal- ype gas ic cance ypically a ises in he se ing o ch onic gas i is and de elops h ough in e media e s ages o a ophic gas i is, in es inal me aplasia, dysplasia and, inally, cance . This leng hy p ocess, commonly known as “Co ea Cascade”, is dependen on pe sis en ch onic in lamma ion (Co ea 1992, Co ea e al. 2007). In his mul is ep model, H. pylo i in ec ion plays a pi o al ole causing ch onic in lamma ion o he mucosa, which slowly p og esses h ough he p emalignan condi ions (a ophic gas i is and in es inal me aplasia) o p emalignan lesions (dysplasia) and inally o gas ic adenoca cinoma (Co ea 1992). A ophic gas i is (AG) is de ined as loss o glandula s uc u es o he gas ic mucosa. This is associa ed wi h a loss o specialized cells and hus a educ ion o gas ic sec e o y unc ion (Dixon e al. 1996). Va ious classi ica ions o AG ha e been p oposed o e he yea s (“A,B and C ypes”; “di use an al e sus mul i ocal”), howe e hese classi ica ions a e di icul o use in clinical p ac ice and su e om conside able in e obse e a ia ion (Co ea e al. 1992, S ickland e al. 1973, Whi ehead 1995). Cu en ly, he upda ed Sydney Sys em is gene ally used bo h in clinical p ac ice and esea ch (Dixon e al. 1996). In his classi ica ion sys em se e al ea u es o in lamma ion, a ophy and in es inal me aplasia need o be assessed indi idually. A isual analogue scale was added o acili a e g ading o he indi idual ea u es. The e alua ion o mos ea u es displays good ep oducibili y, bu ag eemen on he ecogni ion and g ading o gas ic a ophy emains inadequa e (Chen e al. 1999, el-Zimai y e al. 1996, O e haus e al. 1999). Me aplasia is de ined as “ eplacemen o one ype o cell wi h ano he ype” and in s omach, in es inal me aplasia (IM) ep esen s he eplacemen o gas ic columna epi helial cells by in es inal cells. IM is cha ac e ized by he p esence o in es inal- ype, mucin-con aining goble cells, Pane h cells and abso p i e cells. Se e al classi ica ions o IM ha e been desc ibed; i s , his ochemically-based me hods we e used allowing he de ini ion o h ee di e en ypes. Type I, o comple e IM, con aining abso p i e I IA A. . G ENERAL I NTRODUCTION 54 en e ocy es, Pane h cells, and sialomucin-sec e ing goble cells; ype II, incomple e IM, wi h co-exis ence o goble and columna cells sec e ing sialomucins; ype III, also incomple e IM, wi h p esence o goble and columna cells sec e ing sulphomucins (Filipe e al. 1994). Second, using molecula al e a ions in in es inal me aplasia in e ms o exp ession o mucins, a new classi ica ion o IM was p oposed, encompassing wo ypes: comple e o in es inal IM, cha ac e ized by comple e loss o gas ic mucin ma ke s (MUC1, MUC5AC and MUC6) and gain o he in es inal mucin MUC2 and incomple e o gas oin es inal mixed IM, whe e he in es inal mucin MUC2 is ound oge he wi h main enance o he gas ic mucins (Reis e al. 1999). In spi e o he ecogni ion o di e en ypes o gas ic in es inal me aplasia, i s di e en ia ion has no p o en ele ance o clinical p ac ice. Gas ic dysplasia is cha ac e ized by mo phologic al e a ions in cells and glandula a angemen . Assessmen o dysplasia is o en di icul and in e obse e ag eemen in g ading dysplasia is poo . In 2000, he uni ied Pado a classi ica ion was p oposed, which di ided dysplasia and adenoca cinoma in o i e ca ego ies. The Vienna classi ica ion u he subdi ided he ca ego ies o low-g ade dysplasia and high g ade dysplasia and was e ised o imp o e he co ela ion wi h clinical managemen (Dixon 2002, Schlempe e al. 2000). Recen ly, in an a emp o s anda dize e minology o he mo phological spec um o he lesions, he Wo ld Heal h O ganiza ion (WHO) p oposed a 5 ca ego y classi ica ion sys em o gas ic dysplasia/in aepi helial neoplasia(Lauwe s GY 2010). A e he ecogni ion o he mo phologic changes o gas ic mucosa ha ep esen he backg ound o gas ic cance de elopmen , se e al s udies documen ed he a e o p og ession o hese p emalignan condi ions/lesions. Ra es o p og ession o AG and IM a y be ween 0% o 1.8% and 0% o 10% pe yea , espec i ely (de V ies e al. 2007, de V ies e al. 2008). The isk o gas ic cance is, gene ally, oo low o pa ien s who simply display hese al e a ions; addi ional isk ac o s we e de ined as he in agas ic ex ension o AG and IM. Se e al s udies showed ha gas ic cance isk inc eases in I IA A. . G ENERAL I NTRODUCTION 55 pa ien s wi h ex ensi e in agas ic p emalignan condi ions (eg, de ec ion bo h in he an um and co pus)(Dinis-Ribei o 2004, Mo son 1955, Vannella e al. 2010). To de e mine he ex ension o AG and IM h ee main me hods can be used: biopsy sampling wi h his ological assessmen acco ding o Sydney Sys em (Dixon e al. 1996); se ology by de e mina ion o pepsinogen I and pespinogen I/II a io (Dinis-Ribei o e al. 2004); endoscopic assessmen using Kimu a classi ica ion (no widely used)(Kimu a e al. 1996). S aging Biopsy Sampling Biopsy specimens o he s omach a e essen ial o he classi ica ion and g ading o p eneoplas ic gas ic lesions. The Sydney and he upda ed Sydney Sys em o classi ica ion and g ading o gas i is a e he mos widely accep ed (Dixon e al. 1996). They we e p ima ily designed o p o ide s anda diza ion o epo s o gas ic biopsies. The upda ed e sion ecommended i e biopsies, one om incisu a, wo om he an um (3cm om he pylo us, g ea e and lesse cu a u es ) and wo om he co pus (one om lesse cu a u e, 4cm p oximal o he incisu a, and one om he middle o he g ea e cu a u e), si es ha we e a bi a ily chosen. Al hough his biopsy p o ocol is use ul o es ablishing H. pylo i s a us and ch onic gas i is classi ica ion, he numbe o biopsies is con o e sial o an adequa e s aging o p emalignan gas ic lesions mainly because o hei mul i ocal na u e (El-Zimai y e al. 1999, E iksson e al. 2005, Gua ne 2003, Rugge e al. 2005). This mul i ocali y in luences he abili y o de ec hem, which may a ec decisions ega ding he pa ien ´s he apy o u u e su eillance (Co ea 1988, Co ea 1992). Some s udies add essed he numbe o biopsies needed o a p ecise g ading o gas i is and p eneoplas ic lesions and concluded ha he Sydney Sys em was un eliable, unde es ima ing he p esence o in es inal me aplasia co pus a ophy and I IA A. . G ENERAL I NTRODUCTION 56 ecommended a minimum o eigh biopsies. O he s udies concluded ha he Sydney p o ocol was sensi i e o iden i ica ion o H.pylo i in ec ion and p eneoplas ic lesions (in egions o high p e alence o gas ic cance ) (de V ies e al. 2010, El-Zimai y e al. 1999, E iksson e al. 2005, Gua ne 2003, Sa oh e al. 1998). Incisu a angula is is he loca ion whe e a ophic/me aplasic changes i s appea . Howe e , he alue o biopsy o incisu a angula is has aised some con o e sy (Ricua e 2005, Rugge 2003), some s udies showing ha ew his ological indings a e de ec able in biopsies o he incisu a (E iksson e al. 2005, Sa oh e al. 1998) E en when ex ensi e biopsy p o ocols a e used ine i able sampling e o s may a ec he iden i ica ion o he p emalignan lesions which a e equen ly pa chy (Dixon e al. 1996, El-Zimai y e al. 1995, El-Zimai y e al. 1999, El-Zimai y e al. 2002) and can be missed on ollow-up (El-Zimai y e al. 2001). I is expec able ha a low numbe o biopsies will be enough o an accu a e diagnosis/s aging in high- isk popula ions whe e he ex ension o he lesions is wide (Du sun e al. 2004, Sa oh e al. 1998, You e al. 1993). Al hough he Sydney sys em and he upda ed Sydney sys em (Dixon e al. 1996) con ibu ed o he uni o mi y o he epo ing o gas ic p eneoplas ic lesions, no in o ma ion is p o ided ega ding cance isk. The ecen ly es ablished OLGA s aging sys em (Ope a i e Link o Gas i is Assessmen ) aims o ansla e he pa hological da a in o a s anda dized epo wi h in o ma ion on he gas ic condi ion ( opog aphy and ex en o he a ophic changes) and subg ouping pa ien s by cance isk-Figu e 3 (Rugge e al. 2005, Rugge e al. 2008). Ini ially, wo c oss-sec ional alida ion s udies concluded ha OLGA p o ides ele an clinical in o ma ion allowing he iden i ica ion o a subpopula ion o pa ien s (OLGA s age III/IV) wi h high isk o gas ic cance who we e amenable o su eillance(Rugge e al. 2007, Sa oh e al. 2008). Recen ly, Rugge (Rugge e al. 2010) desc ibed a 12 yea ollow-up o p emalignan gas ic lesions wi h OLGA classi ica ion a he beginning o he s udy s a i ying pa ien s acco ding o hei cance isks. The majo i y o he pa ien s we e “low-s age” (0,I,II) gas i is, and all I IA A. . G ENERAL I NTRODUCTION 57 in asi e neoplasia (n=2) we e associa ed wi h high- isk (III/IV) OLGA s ages a en olmen (P=0.001;RR=18.56). Acknowledging he ac ha se e i y and ex ension o a ophy emain he main pa ame e s o g ading and he in e obse e ag eemen is low (Dixon e al. 1996, el-Zimai y e al. 1996), Capelle and colleagues in oduced a modi ied OLGA sys em (OLGIM) based on in es inal me aplasia (Capelle e al. 2010). This sys em p o ed o ha e a high le el o in e obse e conco dance (Gua ne e al. 1999). The ag eemen be ween pa hologis s was mode a e o a ophy (k=0.6) and highe o in es inal me aplasia (k = 0.9). The cance isk was downg aded applying OLGIM wi h ewe pa ien in high isk s ages (III/IV) which, in heo y, would selec a smalle popula ion o whom su eillance would be conside ed. Mo e s udies on easibili y and ep oducibili y in di e en epidemiological con ex s a e needed o alida e hese classi ica ion sys ems (Rugge e al. 2007). Recen guidelines on managemen o p ecance ous condi ions and lesions on s omach ecommended ha a leas ou biopsies ( wo in an um and wo in co pus; g ea e and lesse cu a u e) a e adequa e o he diagnosis and su eillance o p emalignan gas ic lesions(Dinis- Ribei o e al. 2012). These guidelines s a e also ha sys ems o his opa hological s aging (e.g. OLGA and OLGIM) may be use ul o ca ego iza ion o he isk o p og ession o gas ic cance . I IA A. . G ENERAL I NTRODUCTION 64 C CH HA AP PT TE ER R I I B. R ATIONALE AND AIMS I IB B. . R ATIONALE AND AIMS 66 I IB B. . R ATIONALE AND AIMS 67 Gas ic Cance Gas ic cance is he ou h mos common malignancy in he wo ld. Nowadays, s omach cance is he second leading cause o cance dea h in bo h sexes wo ldwide (736 000 dea hs, 9.7% o he o al) wi h only a mino i y o gas ic adenoca cinomas diagnosed a a cu able and essec able s age. In Po ugal, gas ic cance anks in 5 h place in incidence and mo ali y o bo h sexes and i s incidence and mo ali y a e expec ed o ise in he nex yea s. Gas ic Cance Pa hways Lau en´s classi ica ion is he mos used o gas ic adenoca cinoma because o i s epidemiologic ele ance (Lau en 1965). I encompasses wo main his ological sub ypes, di use and in es inal, which ha e di e en clinicopa hological cha ac e is ics. In es inal ype is mo e equen ly obse ed in olde pa ien s and ollows a “cascade” ha begins wi h mul i ocal a ophic gas i is a e exposu e o en i onmen al isk ac o s like H.pylo i in ec ion. This is usually accompanied by in es inal me aplasia and leads o cance ia dysplasia. This leng hy p ocess, commonly known as “Co ea Cascade”, is dependen on pe sis en ch onic in lamma ion (Co ea 1992, Co ea e al. 2007). Unlike in es inal gas ic cance , he di use ype ypically de elops ollowing ch onic in lamma ion wi hou passing h ough he in e media e s eps wi h H.pylo i gas i is being he only uni e sal p ecu so condi ion o his sub ype o umo (Weydig e al. 2007). A de ec i e in e cellula adhesion is a p ominen molecula abno mali y o di use ca cinomas, esul ing om abno mal exp ession o he cell adhesion p o ein E- Cadhe in encoded by he CDH1 gene. I IB B. . R ATIONALE AND AIMS 68 Risk Fac o s T adi ional isk ac o s o gas ic cance de elopmen include die , sal and ni oso compounds consump ion and smoking. H. pylo i in ec ion is a pi o al isk ac o o gas ic cance de elopmen . Coloniza ion wi h he bac e ia is usually asymp oma ic and umo p og ession only occu s in a subse o indi iduals and is dependen on he hos esponse as well as gene ic a ia ion o he bac e ia (A he on 2006). Func ional di e ences exis be ween s ains o H.pylo i ha may ela e o i ulence and issue damage (Mobley 1996). The well cha ac e ized i ulence ac o s a e hose leading o he exp ession o acuola ing cy o oxin ( acA) and cy o oxin asso ia ed gene A (cagA). Gene ic hos polymo phisms di ec ly in luence in e -indi idual a ia ion in he magni ude o cy okine esponse and his clea ly con ibu es o an indi idual´s ul ima e clinical ou come. The well cha ac e ized gene ic a ia ions by popula ion-associa ed s udies a e 1 L-1β and IL1 Recep o an agonis (IL-1RN)(El-Oma e al. 2000, Figuei edo e al. 2002, Machado e al. 2003) and a single s udy poin ed a possible ele an ole o he IFNGR1 gene in he de elopmen o ea ly-onse gas ic cance (Canedo e al. 2008). P emalignan Condi ions and S aging Se e al s udies showed ha gas ic cance isk inc eases in pa ien s wi h ex ensi e in agas ic p emalignan condi ions (eg, de ec ion bo h in he an um and he co pus)(Dinis-Ribei o 2004, Mo son 1955, Vannella e al. 2010) which is de e mined by biopsy sampling wi h his ological assessmen acco ding o Sydney Sys em (Dixon e al. 1996). The Sydney upda ed e sion ecommended i e biopsies, one om incisu a, wo om he an um and wo om he co pus, si es ha we e a bi a ily chosen. Al hough his biopsy p o ocol is adequa e o a co ec e alua ion o H. pylo i s a us and ch onic gas i is, he numbe o biopsies is con o e sial o an adequa e s aging o p emalignan gas ic lesions mainly because o hei mul i ocal na u e (El-Zimai y e al. 1999, E iksson e al. 2005, Gua ne 2003, Rugge e al. 2005). The ecen ly es ablished OLGA s aging sys em (Ope a i e Link o Gas i is Assessmen ) aims o ansla e he pa hological da a in o a s anda dized epo wi h in o ma ion on he gas ic condi ion I IB B. . R ATIONALE AND AIMS 69 ( opog aphy and ex en o he a ophic changes), subg ouping pa ien s by cance isk (Rugge e al. 2005, Rugge e al. 2008). Acknowledging he ac ha se e i y and ex ension o a ophy emain he main pa ame e o g ading and he in e obse e ag eemen is low (Dixon e al. 1996, el-Zimai y e al. 1996), Capelle and colleagues (Capelle e al. 2010) in oduced a modi ied OLGA sys em (OLGIM) based on in es inal me aplasia ha p o ed o ha e a high le el o in e obse e conco dance (Gua ne e al. 1999). Familial Risk and Ea ly-Onse Gas ic Cance Familial ela i e isk is a hallma k o gene ic suscep ibili y bu amilial clus e ing may also occu because o nonhe edi a y en i onmen al ac o s, such as exposu e o H. pylo i, smoking o die . I is known ha 10% o gas ic cance s ha bo amilial agg ega ion, sugges ing some kind o amilial p edisposi ion. O hese, only 1-3% belongs o inhe i ed amilial synd omes such as He edi a y Di use Gas ic Cance (HDGC) (Fi zge ald e al. 2010, Pha oah e al. 2001). The signi icance o amily his o y and amilial clus e ing o gas ic cance is no clea ly de e mined. I was demons a ed ha ha ing a i s -deg ee ela i e wi h gas ic cance is a isk ac o o gas ic cance wi h odds a io (OR) a ying om 2 o 10, acco ding o he geog aphic egion and e hnici y (Yaghoobi e al. 2009) and Lau en in es inal ype o gas ic cance was s ongly associa ed wi h he amily his o y o gas ic cance when compa e wi h he di use ype (Be nini e al. 2006, E o e al. 2006). Case-con ol s udies demons a ed inc eased p e alence o p eneoplas ic changes and H. pylo i in ec ion a e in i s - deg ee ela i es o gas ic ca cinoma pa ien s (Rokkas e al. 2010). Ea ly-onse gas ic cance (EOCG) is de ined as gas ic cance p esen ing a he age o 45 o younge ; app oxima ely 10% o gas ic cance pa ien s all in o he EOCG ca ego y (Kokkola e al. 2001). I is pos ula ed ha gene ic ac o s may be mo e impo an in EOCG han in olde pa ien s (Co ea e al. 1994, Milne e al. 2007, Milne e al. 2009) bu en i onmen al ac o s, such as H.pylo i in ec ion, may also play a ole in he de elopmen o he disease in young pa ien s (Ha uma e al. 2000, Koshida e al. I IB B. . R ATIONALE AND AIMS 70 2000, Rugge e al. 1999). The occu ence o gas ic cance in young pa ien s emains la gely unexplained, and is p obably due o he in e -ac ion be ween a p edisposing geno ype and en i onmen al igge s (Milne e al. 2009). Rela i es o EOGC pa ien s we e seldom s udied. I IB B. . R ATIONALE AND AIMS 71 SPECIFIC AIMS • To cha ac e ize a speci ic popula ion (Fi s deg ee ela i es o pa ien s su e ing o gas ic ca cinoma i espec i e o Lau en’s sub ype, aged less han 45 yea s old a diagnosis) ega ding he his ological pa e ns o gas ic mucosa, he gene ic suscep ibili y o he indi iduals and he H.pylo i a ia ions esponsible o he inc eased isk o de eloping gas ic cance . A case-con ol app oach was used. ⋅ To de e mine and quan i y he p esence o gas ic p ecance ous condi ions and lesions (his ological pheno ype). ⋅ To cha ac e ize he H. pylo i s a us and he p esence o i ulen s ains (CagA and VacA genes). ⋅ To de e mine hos gene clus e polymo phisms in he human In e leukin 1 Be a (IL-1β), In e leukin 1 Recep o An agonis (IL-1RN) and In e e on Gamma Recep o 1 (IFNGR1) genes. • To assess OLGA and OLGIM s aging sys ems in he s a i ica ion o pa ien s acco ding o hei cance isk. I IB B. . R ATIONALE AND AIMS 72 C CH HA AP PT TE ER R I II I S ELECTION OF P ARTICIPANTS I II IB B. . S ELECTION OF C ONTROLS 80 I II IB B. . S ELECTION OF C ONTROLS 81 I II IB B. . S ELECTION OF C ONTROLS 82 I II IB B. . S ELECTION OF C ONTROLS 83 I II IB B. . S ELECTION OF C ONTROLS 84 I II IB B. . S ELECTION OF C ONTROLS 85 I II IB B. . S ELECTION OF C ONTROLS 86 I II IB B. . S ELECTION OF C ONTROLS 87 I II IB B. . S ELECTION OF C ONTROLS 88 C CH HA AP PT TE ER R I II II I P REMALIGNANT C ONDITIONS AND L ESIONS AND C LASSIFICATION S YSTEMS IN F IRST D EGREE R ELATIVES OF E ARLY -O NSET G ASTRIC C ARCINOMA P ATIENTS I II II I. . P REMALIGNANT C ONDITIONS AND L ESIONS AND C LASSIFICATION S YSTEMS IN FDR S OF EOGC P ATIENTS 96 I II II I. . P REMALIGNANT C ONDITIONS AND L ESIONS AND C LASSIFICATION S YSTEMS IN FDR S OF EOGC P ATIENTS 97 I II II I. . P REMALIGNANT C ONDITIONS AND L ESIONS AND C LASSIFICATION S YSTEMS IN FDR S OF EOGC P ATIENTS 98 I II II I. . P REMALIGNANT C ONDITIONS AND L ESIONS AND C LASSIFICATION S YSTEMS IN FDR S OF EOGC P ATIENTS 99 I II II I. . P REMALIGNANT C ONDITIONS AND L ESIONS AND C LASSIFICATION S YSTEMS IN FDR S OF EOGC P ATIENTS 100 C CH HA AP PT TE ER R I IV V H OST AND H ELICOBACTER PYLORI G ENOTYPES IN F IRST D EGREE R ELATIVES OF E ARLY -O NSET G ASTRIC C ARCINOMA P ATIENTS I IV V. . H H O OS ST T A AN ND D H H E EL LI IC CO OB BA AC CT TE ER R P PY YL LO OR RI I G GE EN NO OT TY YP PE ES S I IN N F FD DR R S S O OF F E EO OG GC C P P A AT TI IE EN NT TS 102 I IV V. . H H O OS ST T A AN ND D H H E EL LI IC CO OB BA AC CT TE ER R P PY YL LO OR RI I G GE EN NO OT TY YP PE ES S I IN N F FD DR R S S O OF F E EO OG GC C P P A AT TI IE EN NT TS S 103 I IV V. . H H O OS ST T A AN ND D H H E EL LI IC CO OB BA AC CT TE ER R P PY YL LO OR RI I G GE EN NO OT TY YP PE ES S I IN N F FD DR R S S O OF F E EO OG GC C P P A AT TI IE EN NT TS 104 I IV V. . H H O OS ST T A AN ND D H H E EL LI IC CO OB BA AC CT TE ER R P PY YL LO OR RI I G GE EN NO OT TY YP PE ES S I IN N F FD DR R S S O OF F E EO OG GC C P P A AT TI IE EN NT TS S 105 I IV V. . H H O OS ST T A AN ND D H H E EL LI IC CO OB BA AC CT TE ER R P PY YL LO OR RI I G GE EN NO OT TY YP PE ES S I IN N F FD DR R S S O OF F E EO OG GC C P P A AT TI IE EN NT TS 112 I IV V. . H H O OS ST T A AN ND D H H E EL LI IC CO OB BA AC CT TE ER R P PY YL LO OR RI I G GE EN NO OT TY YP PE ES S I IN N F FD DR R S S O OF F E EO OG GC C P P A AT TI IE EN NT TS S 113 I IV V. . H H O OS ST T A AN ND D H H E EL LI IC CO OB BA AC CT TE ER R P PY YL LO OR RI I G GE EN NO OT TY YP PE ES S I IN N F FD DR R S S O OF F E EO OG GC C P P A AT TI IE EN NT TS 114 I IV V. . H H O OS ST T A AN ND D H H E EL LI IC CO OB BA AC CT TE ER R P PY YL LO OR RI I G GE EN NO OT TY YP PE ES S I IN N F FD DR R S S O OF F E EO OG GC C P P A AT TI IE EN NT TS S 115 I IV V. . H H O OS ST T A AN ND D H H E EL LI IC CO OB BA AC CT TE ER R P PY YL LO OR RI I G GE EN NO OT TY YP PE ES S I IN N F FD DR R S S O OF F E EO OG GC C P P A AT TI IE EN NT TS 116 I IV V. . H H O OS ST T A AN ND D H H E EL LI IC CO OB BA AC CT TE ER R P PY YL LO OR RI I G GE EN NO OT TY YP PE ES S I IN N F FD DR R S S O OF F E EO OG GC C P P A AT TI IE EN NT TS S 117 I IV V. . H H O OS ST T A AN ND D H H E EL LI IC CO OB BA AC CT TE ER R P PY YL LO OR RI I G GE EN NO OT TY YP PE ES S I IN N F FD DR R S S O OF F E EO OG GC C P P A AT TI IE EN NT TS 118 I IV V. . H H O OS ST T A AN ND D H H E EL LI IC CO OB BA AC CT TE ER R P PY YL LO OR RI I G GE EN NO OT TY YP PE ES S I IN N F FD DR R S S O OF F E EO OG GC C P P A AT TI IE EN NT TS S 119 I IV V. . H H O OS ST T A AN ND D H H E EL LI IC CO OB BA AC CT TE ER R P PY YL LO OR RI I G GE EN NO OT TY YP PE ES S I IN N F FD DR R S S O OF F E EO OG GC C P P A AT TI IE EN NT TS 120 I IV V. . H H O OS ST T A AN ND D H H E EL LI IC CO OB BA AC CT TE ER R P PY YL LO OR RI I G GE EN NO OT TY YP PE ES S I IN N F FD DR R S S O OF F E EO OG GC C P P A AT TI IE EN NT TS S 121 I IV V. . H H O OS ST T A AN ND D H H E EL LI IC CO OB BA AC CT TE ER R P PY YL LO OR RI I G GE EN NO OT TY YP PE ES S I IN N F FD DR R S S O OF F E EO OG GC C P P A AT TI IE EN NT TS 128 C CH HA AP PT TE ER R V V D ISCUSSION AND C ONCLUDING R EMARKS V V. . D ISCUSSION AND C ONCLUDING R EMARKS 130 V V. . D ISCUSSION AND C ONCLUDING R EMARKS 131 D DI IS SC CU US SS SI IO ON N The amilial clus e ing o gas ic cance and he signi icance o amily his o y has been add essed in he pas (Yaghoobi e al. 2009). Familial ela i e isk is a hallma k o gene ic suscep ibili y bu his clus e ing may also be dependen on non he edi a y ac o s, such exposu e o H.pylo i, die and smoke. Gas ic cance is hough o esul om a combina ion o en i onmen al ac o s and he accumula ion o speci ic molecula al e a ions due o gene ic ins abili y, and consequen ly a ec s mainly old pa ien s. Many s udies examined he molecula gene ics and H.pylo i in ec ion o gas ic cance in gene al, bu e y ew looked a young pa ien s. Inhe i ed gas ic cance p edisposi ion synd omes accoun o app oxima ely 10% o ea ly-onse gas ic cance s, he majo i y o hem wi hou an iden i iable gene ic cause (Kokkola e al. 2001). Only a e y small pe cen age o ea ly-onse gas ic cance s can be explained by E-cadhe in ge mline mu a ions, wi h only abou 30% o all he edi a y di use gas ic cance amilies ca ying CDH1 ge mline mu a ions (Oli ei a e al. 2004). Some s udies suppo he hypo hesis ha young pa ien s de elop ca cinomas wi h a di e en molecula gene ic p o ile om ha o spo adic ca cinomas occu ing a a la e age. I is pos ula ed ha inhe i ed gene ic ac o s may be mo e impo an in ea ly onse gas ic cance han in gas ic cance s ound in olde pa ien s as hey ha e less exposu e o en i onmen al ca cinogens (Milne e al. 2007, Milne e al. 2010). To he bes o ou knowledge, his s udy epo s o he i s ime he changes in gas ic mucosa and hos /H. pylo i gene ic a ia ions o i s deg ee ela i es (FDRs) o EOGC pa ien s. A case-con ol s udy was conduc ed compa ing EOGC ela i es o h ee le els o con ol (spouses, neighbo s and dyspep ics). The objec i e in selec ing ce ain ype o con ols was o sample a ep esen a i e popula ion, om which he cases a ose, indica ing he backg ound equency o an exposu e in indi iduals who a e ee o he disease unde analysis. We analyzed p io case-con ol s udies using di e en ypes o con ols add essing he amilial agg ega ion ole o gas ic cance de elopmen . We ha e obse ed ha , independen ly o he ype o con ol, he isk o he p e alence o V V. . D ISCUSSION AND C ONCLUDING R EMARKS 132 p emalignan lesions and H pylo i in ec ion was highe o he cases which led us o conclude ha he selec ion o con ols seems o be mainly ela ed o he easibili y o ec ui men mo e han o he gene ic o en i onmen al backg ound (Ma cos-Pin o e al. 2012). His ological pheno ype A high a e o p emalignan condi ions was obse ed wi h ch onic a ophic gas i is (CAG) being diagnosed in 70% o cases and in 34% o he con ols (p<0.001). Ex ensi e a ophy (e.g. a ophy diagnosed in bo h an um and co pus) was p esen in 58% o CAG in cases and in 25% o CAG in con ols (p=0.002). The equency o in es inal me aplasia was highe in cases (43%) han in con ols (25%) (p=0.002). Also, se en cases o dysplas ic lesions we e de ec ed in cases and none in con ols (p=0.007), encompassing one high g ade dysplasia and six cases o low g ade dysplasia (mean age - 53 yea s). P emalignan condi ions we e mo e p e alen in his sample o ela i es o EOGC pa ien s han in o he se ies encompassing ela i es o gas ic cance pa ien s, ega dless o he age o onse . In hose s udies, p e alence o GAC anges om 11% o 30% (B enne e al. 2000, B enne e al. 2006, Chang e al. 2002, El-Oma e al. 2000, Jablonska e al. 2001, Leung e al. 2006, Mo a e al. 2008, Rokkas e al. 2010, Shin e al. 2010). Recen ly published guidelines on ollow-up o p emalignan condi ions ecognized he ele ance o amily his o y o gas ic cance and also ecommended ollow-up endoscopy o pa ien s wi h ex ensi e a ophic changes ( ollow-up endoscopy e e y 3 yea s)(Dinis-Ribei o e al. 2012). In ou s udy mo e han hal o cases (wi h a mean age o 43 yea s) had ex ensi e a ophy and would be amenable o ollow-up acco ding o he a o emen ioned guidelines. V V. . D ISCUSSION AND C ONCLUDING R EMARKS 133 P emalignan Condi ions S aging OLGA s aging OLGA gas i is classi ica ion sys em aims o ansla e he his opa hological da a in o a s anda dized epo (wi h in o ma ion on opog aphy and ex en o he a ophic changes) and sub g ouping pa ien s by cance isk ( hose included in s ages III and IV ha bo ing he highes isk o gas ic cance de elopmen , he e o e being eligible o ollow-up) (Rugge e al. 2008), as sugges ed in wo c oss sec ional s udies (Rugge 2003, Sa oh e al. 2008). Recen ly, a 12 yea ollow up s udy ga e addi ional suppo o he ini ial esul s (Rugge e al. 2010) and showed also a ela ionship o s ages III-IV wi h lowe pepsinogen I/II a io, a ma ke o gas ic ex ensi e a ophy (Daugule e al. 2011, Rugge e al. 2010). In es inal me aplasia sub yping was also shown o be inco po a ed in high- isk OLGA s ages (III and IV) wi h sul omucin- ype in es inal me aplasia ( ype III) being associa ed wi h an inc eased isk o gas ic cance (Rugge e al. 2011). In ou s udy, he i s case-con ol s udy applying OLGA s aging o a high- isk popula ion, 19% o cases (FDRs o EOGC pa ien s) clus e ed in s ages III-IV compa ed o 0% o he con ols (p<0.001), showing ha he e was a high numbe o pa ien s wi h ex ensi e a ophy, hus eligible o ollow-up. All pep ic ulce s we e included in low- isk s ages and 86% o dysplas ic lesions clus e ed in s ages III-IV (p<0.005). OLGIM s aging I has been ecognized ha a po en ial d awback o OLGA s aging is he ac ha i elies in he se e i y and ex en o gas ic a ophy, a pa ame e o which he e is low in e -obse e ag eemen (Chen e al. 1999, Dixon e al. 1996, el-Zimai y e al. 1996). Capelle e al p oposed a classi ica ion sys em (OLGIM) ha uses only one o he pheno ypic exp essions o a ophy (in es inal me aplasia), achie ing an highe in e - obse e ag eemen (K=0.9 o in es inal me aplasia and K=0.6 o a ophic gas i is) and a downg ade o s ages leading o a smalle popula ion sui able o su eillance (Capelle e al. 2010). Recen ly, Rugge e al conduc ed a e ospec i e, non V V. . D ISCUSSION AND C ONCLUDING R EMARKS 134 s anda dized s udy, encompassing 4,552 consecu i e biopsy se s, aiming a he compa ison o OLGA and OLGIM classi ica ion sys ems (Rugge e al. 2011). In e - obse e ag eemen was ound o be highe o OLGIM han o OLGA sys em and he use o he o me esul ed in a 6.6% downg ade o s ages in compa ison wi h OLGA classi ica ion. In bo h s aging sys ems, a signi ican associa ion was obse ed be ween s ages III-IV and gas ic neoplasia (Rugge e al. 2011). In ou s udy, 44% o cases we e sco ed as s ages I-IV acco ding o OLGIM wi h a 27% downg ade in compa ison wi h OLGA. In s ages III-IV, he e was a 3% downg ade o s aging, wi hou in e e ing wi h he clus e ing o dysplasia (86%) in high- isk s ages, which is in keeping wi h he esul s ob ained by he p oponen s o he OLGIM sys em (LG Capelle e al. 2010). Modi ied OLGA and OLGIM s aging (excluding incisu a angula is biopsy) The alue o he diagnos ic yield o he biopsy o incisu a angula is has been add essed in se e al s udies. Despi e being conside ed he loca ion a ec ed a he onse o a ophy/me aplas ic ans o ma ion (Ricua e 2005, Rugge 2003), a leas wo s udies concluded ha ew his ological indings we e de ec able only in biopsies o he incisu a angula is (E iksson e al. 2005, Sa oh e al. 1998). These esul s sugges ha mo e impo an ha he si e whe e he a ophic ans o ma ion begun is i s ex ension, he la e being he pa ame e ha con e s gas ic cance isk (Cassa o e al. 2000, Dinis-Ribei o e al. 2004, Filipe e al. 1994). Guidelines ecen ly p oposed o he ollow-up o gas ic p emalignan condi ions and lesions sugges ed he exclusion o he biopsy o he incisu a angula is o s aging, keeping wo biopsies o he an um and o he wo biopsies o he co pus (Dinis-Ribei o e al. 2012). In he g oup o FDRs o EOGC pa ien s, using modi ied OLGA and modi ied OLGIM s aging sys ems (wi h exclusion o he biopsy o incisu a angula is), we obse ed, espec i ely, 15% and 30% downg ade o s aging in compa ison wi h he o iginal OLGA sys em. Equal and less p onounced downg ade o s aging was obse ed in high- isk (5 %) o bo h o bo h V V. . D ISCUSSION AND C ONCLUDING R EMARKS 135 modi ied s aging sys ems in compa ison wi h OLGA sys em. A ele an ac is ha o all s aging sys ems, ad anced lesions (e.g.dysplasia) clus e in high- isk s ages. Helicobac e pylo i in ec ion We obse ed a highe p e alence o H. pylo i in ec ion in ela i es o gas ic cance pa ien s han in con ols (82% s. 62%) (p=0.004). These esul s a e in keeping wi h p e ious da a ha showed inc eased p e alence o in ec ion in ela i es o gas ic cance pa ien s (B enne e al. 2000, El-Oma e al. 2000, Leung e al. 2006, Mo a e al. 2008, Shin e al. 2010). Rega ding he pa hogenici y o H. pylo i s ains, we ound no global di e ence in p e alence o s ains ha bo ing cagA pa hogenic ac o o acAs1, acAm1 s ains. Howe e , a ad anced OLGA s ages (III and IV) we ound an inc eased p e alence o i ulen s ains ( acAs1, acAm1). These esul s a e also in ag eemen wi h hose ob ained by Li e al, showing a high p e alence o speci ic H. pylo i pa hogenic s ains in a se ies o 38 i s deg ee ela i es o gas ic cance pa ien s popula ion (Li e al. 2002). O he s udies demons a ed ha H. pylo i p obably play a ele an ole in he de elopmen o gas ic cance in young pa ien s bu in a smalle pe cen age han in he olde age g oup (Koshida e al. 2000, Rugge e al. 1999). Hos gene ic a ia ions Rega ding he hos geno ype no signi ican di e ences we e ound be ween cases and con ols o equency o speci ic polymo phisms o IL1B and IL1RN genes. In e es ingly, a signi ican associa ion was ound be ween IL1B-511 *T/T polymo phism and gas ic dysplasia (p<0.001). Ou esul s co obo a e hose p e iously epo ed by El-Oma e al (El-Oma e al. 2000) in ela i es o gas ic cance pa ien s, in which, simila ly o ou indings, he e was no a signi ican inc ease o p oin lamma o y gene polymo phisms. Ne e heless, among he in ec ed gas ic cance ela i es wi h low gas ic acid sec e ion, El-Oma e al ound a signi ican ly highe equency o some p oin lamma o y polymo phisms (IL-1RN *2/*2 and IL-1B-511 *T ca ie s a us)(El- V V. . D ISCUSSION AND C ONCLUDING R EMARKS 136 Oma e al. 2000). On he o he hand a Chinese s udy ound an inc eased p e alence o IL-1B-511 *T and IL-1RN *2 geno ype p e alence in i s deg ee ela i es o gas ic cance pa ien s, i espec i e o he age o onse ; he s udy did no assess gas ic his opa hology (Feng e al. 2008). Si a z e al obse ed no di e ence in he dis ibu ion o gas ic cance p edisposing IL1B polymo phisms (IL-1B-31T) be ween young and olde pa ien s (Si a z e al. 2008). We obse ed an inc eased geno ype equency o IFN-γ 1 ecep o (IFNGR1) (56C/T) – T*/*T in FDRs o EOGC pa ien s. I was demons a ed ha an up egula ed p oduc ion o IFN-γ is ele an in p omo ing H. pylo i induced mucosal in lamma ion (Smy hies e al. 2000). Genome-wide linkage analysis i s iden i ied a polymo phism o he IFNGR1gene associa ed wi h an inc ease in he suscep ibili y o H. pylo i in ec ion (Thye e al. 2003). These esul s a e consis en wi h hose ob ained by Canedo e al s udy in wo di e en popula ions showing ha homozygosi y o IFNGR1-56*T allele is a isk ac o o he de eloping o ea ly onse gas ic cance (OR: 4.1)(Canedo e al. 2008). V V. . D ISCUSSION AND C ONCLUDING R EMARKS 137 C CO ON NC CL LU UD DI IN NG G R RE EM MA AR RK KS S Ou indings showing ha p emalignan lesions and H. pylo i in ec ion a e mo e p e alen in cance ela i es suppo a ole o hese abno mali ies in he sequence o e en s leading o gas ic cance . The inc eased p e alence o p emalignan lesions was pa ially explained by he p esence o speci ic H. pylo i pa hogenic s ains in ad anced OLGA s ages and by he signi ican associa ion o IL1B *T/T hos polymo phism wi h gas ic dysplasia. Fu he mo e, ou esul s sugges ha some polymo phisms o IFNGR gene (homozygosi y o he T allele) may be a isk ac o o he de elopmen o EOGC. An al e na i e hypo hesis would be ha gene ic suscep ibili y ac o s (e.g. speci ic polymo phisms o IFNGR1gene) may play a ole in he de elopmen o EOGC, while en i onmen al ac o s (H. pylo i in ec ion, die , e c.) and hei cumula i e e ec an impo an con ibu ion o he de elopmen o gas ic cance a an olde age. Ou esul s u he suppo he impo an clinical issue o H.pylo i e adica ion in i s deg ee ela i es o gas ic cance pa ien s. I has been desc ibed o ela i es o gas ic cance pa ien s ha e adica ion o H.pylo i esol es in lamma o y gas i is and es o es no mal s uc u e and sec e o y unc ion o hal o hose wi h hypoclo id ia and low se e i y g ade o a ophy be o e ea men (El-Oma e al. 2000). O he s udies assessed he bene i o H.pylo i e adica ion o he p e en ion o gas ic cance and e en hough hey ailed o show a bene i , he subg oup analysis showed a subs an ial educ ion in he incidence o gas ic cance o pa ien s wi hou p emalignan condi ions and lesions such as a ophic gas i is, in es inal me aplasia and dysplasia (Rokkas e al. 2007, Wong e al. 2004). Taking in o accoun ha ch onic a ophic gas i is de elops in gas ic mucosa o FDRs o EGC pa ien s by he ages o 20- 30 yea s, ea ly e adica ion should be p o ided, a leas o his popula ion. A ele an issue ega ding gas ic cance isk is sc eening. Se e al uncon olled ials sugges ed ha cance mo ali y has been educed in Japan whe e a na ionwide mass sc eening p og am was implemen ed (Fukao e al. 1995, Lee e al. 2006). Howe e , a mass-sc eening p og am in coun ies wi h low incidence o gas ic cance is no A PPENDIX 1 144 A PPENDIX 1 145 A PPENDIX 1 146 A PPENDIX 1 147 A PPENDIX 1 148 A PPENDIX 1 149 A PPENDIX 1 150 A PPENDIX 1 151 A PPENDIX 1 152 A PPENDIX 1 153