| 1Background and PurposeGastric cardia adenocarcinoma(GCA)is one of the most common malignancies in northern China.The predominant epidemiological characteristic for GCA is its consistent geographic occurrence with esophageal cancer(EC).The Taihang mountain regions at the junction of Henan,Hebei and Shanxi provinces in northern China have been well recognized as the highest incidence area for EC and GCA in the world.The accumulated evidences have indicated that the incidence of GCA is increasing dramatically in western countries during the past decades.Clinically,5-year survival rate is more than90%in patients with early GCA;in contrast,less than10%in middle and advanced GCA.The early GCA patients are usually symptom-free,which results in general poor prognosis because of low detection rate for early GCA.Up to now,the risk factors affecting prognosis have been unclear,and few investigations have been performed.The other significant epidemiological characteristic of GCA is apparent familial aggregation.Family history(FH)has been documented as a risk factor for GCA,however,the relationship between FH and prognosis for GCA is largely unknown.The molecular changes under prognosis for GCA are poorly understood.Recent genome-wide association studies(GWAS)by us and other laboratories have found18high risk SNPs for EC and GCA,which offers more clues for the pathogenesis of GCA.Thus,the present study was undertaken to correlate FH,18SNPs identified from our previous GWAS studies and survival for GCA.2Materials and MethodsWe enrolled16,605patients with GCA who came from several hospitals in the high-incidence regions at the junction of Henan,Hebei and Shanxi provinces.Of the16,605cases,there were12,872males with a mean age of60.3±9.1years and3,733females with a mean age of59.9±9.2years.All the patients were confirmed GCA by pathology.The age,gender,and FH were recorded through questionnaires,especially the family number,the tumor type and relationship of blood relative(s)with cancer(s).According to the relationship and suffering tumor type,FHs were divided into four types:FH of all kinds of malignant tumors(MTFH),FH of all kinds of malignant tumors in first-degree relatives(FDMTFH),FH of upper gastrointestinal malignant tumors in first-degree relatives(FDUGIFH)and FH of GCA in first-degree relatives(FDGCFH).Of the16,605cases,2,000patients were followed by telephone or interviewed at home until November2011.In2009,through high-throughput genome-wide association study(GWAS),we screened506,666SNPs of1,077cases with esophageal squamous cell cancer(ESCC)and11,013normal controls and found18SNPs were the susceptibility loci to ESCC.We also identified these18SNPs in2,766cases with GCA.Of the2,766cases,there were1,056cases with follow-up information.Kaplan-meier(Log-rank test),multivariate Cox proportional hazard regression model and Pearson chi-square(SPSS17.0)were applied to analyze survival and related risk factors.The level of the test(α)was0.05.3Results 3.1Survival analysis of FHsThe analysis of survival and FHs with Kaplan-meier and Log-rank test showed any positive FH had better lifetime(all P<0.05).Cox model adjusted for gender,age and regions implied only positive FDMTFH was connected with survival,positive FDMTFH still had lower death risk(P=0.049and HR=0.790).The other three kinds of FHs were not signifinant(all P>0.05with HR values of0.824,0.804and0.664,respectively).3.2Hardy-weinberg genetic equilibrium test of18SNPsHardy-weinberg genetic equilibrium test showed that there were12SNPs with Hardy-Weinberg genetic equilibrium(all P>0.05)and the other6SNPs did not meet genetic equilibrium in the1,056cases,including rs5753220(χ2=453.063,P<0.05),rsl346291(χ2=41.68,P<0.05),rs7230870(χ2=42.976,P<0.05),rs462094(χ2=139.362,P<0.05),rs6140125(χ2=44.737,P<0.05),rs13042395(χ2=790.570,P<0.05).3.3Survival analysis of12SNPsKaplan-meier analysis on the relationship of12SNPs and survival presented that only rs6023640was related with GCA survival(P=0.049),the patients with GG genotype had better survival than those with TG/TT.Cox analysis adjusted for gender,age and regions demonstrated rs6023640remained statistically significant on survival(P=0.039),indicating that rs6023640might be an important independent factor for GCA survival.3.4FDMTFH and rs6023640Pearson chi-square test showed two genotypes(GG and GT/TT)for rs6023640showed different distributions in FDMTFH(P=0.022),and GG genotype occurred predominently in positive FDMTFH;otherwise,GT/TT in negative FDMTFH. 4ConclusionsBoth negative FDMTFH and the mutated genotype(GT/TT)of rs6023640are important independent factors which adverse to prognosis of patients with GCA.Furthermore,GG and GT/TT have different distributions in FDMTFH,and GT/TT predominates in negative FDMTFH,suggesting that the mutated GT/TT may be one of the indicators for poor prognosis with negative FDMTFH. |
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