Analysis Of Family History And Couples Both Suffering Cancers And Alternations Of P53 And Pcna On Esophagus And Gastric Cardia In Monozygotic Twins

1 BACKGROUND AND OBJECTIVEEsophageal cancer(EC) is one of the six most common malignant tumors worldwide and Taihang mountain areas at the junction of Henan,Hebei and Shanxi provinces has been well documented as the highest incidence areas for esophageal cancer in the world and the incidence of EC decreases from the areas centre to the edge.The remarkable geographical distribution is the striking characteristic for EC. The ratio for EC incidence between the high- and low-risk areas could be as high as 500:1.The remarkable geographical distribution suggests that environmental factors may play important roles in EC carcinogenesis.Another remarkable epidemiological characteristic for EC is the dramatic familial aggregation.Recent studies by us found that the dramatic familial aggregation in Linzhou is obviously higher than in Henan areas without Linzhou and in other provinces,our another epidemiological investigation found that after 100 years,the prevalence of EC and the prevalence of esophageal precancerous lesions in the migrated subjects is similar with Linzhou subjects.The dramatic familial aggregation,especially migrant epidemiology suggests that genetic factors may play important roles in EC carcinogenesis.At present,however,there are little understanding about the molecular mechanism and proportion of environment and heredity on EC carcinogenesis,especially the researches on the GCA genetic predisposition(family history).At present,however,there are little understanding about the molecular mechanism and proportion of environment and heredity on EC carcinogenesis.The present study was undertaken to analyze large scale of SCC samples in different areas(high- and low- incidence areas) to determine the characteristics of the SCC genetic predisposition and the proportion of environment and hereditary on SCC carcinogenesis.Couples had different genes,if they both suffering cancer,we could infer it was caused by environmental factors.The laboratory found that one of monozygotic twins suffering from esophageal cancer exist another normal,or both suffering esophageal cancer.Monozygotic twins came from the same fertilized egg, accept exactly the same chromosomes and genetic material,therefore,through comparative analysis of two members of twins phenotypic and molecular changes, would conducive to clarify the environmental and genetic factors influence the extent of tumor,also would reduce the scope of gene and protein,2 MATERIALS AND METHODS25198 patients with SCC were included in this study.Of these patients,male: 62%(15502/25198),female:38%(9696/25198).The youngest patients was 17 years old,the oldest was 93 years old,with a mean age of 58±11 years.All the SCC patients were confirmed as primary SCC by histopathology.All clinical information for 25198 patients with SCC was from hospitals in Henan,Hebei and Sichuan Provinces.795 pairs couples both suffering cancer,came from Anyang,Linzhou hospitals in Henan.p53 and PCNA protein expressions were detected by the immunohistochemical method(ABC) in 36 pairs MZ from the high incidence area for esophageal cancer in Henan,including 17 males and 19 females with median age of 43.All the resected tissues were fixed with alcohol,paraffin embedded and partial serially sectioned for histopathological diagnosis and immunostaining.Theχ~2 test,matched-pairs chi-square test and Spearman Correlation test were used for the statistic analysis,(p＜0.05 was considered significant).SCC patients with tumor family history(EC FH+) mean the families with≥2 SCC patients within continuous three generations.SCC patients without tumor family history(EC FH-) means the families with≤1 SCC patients within continuous three generations.And at the same time,no other tumors recorded.There were five different areas involved in this study:Group 1:Taihang areas(the southern of Taihang mountain at the junction of Henan,Hebei and Shanxi provinces);Group 2:Other high incidence areas in three provinces(the high incidence areas for ESCC in Henan,Hebei and Shanxi province,without Taihang high incidence areas);Group 3:Low incidence areas in three provinces(the low incidence areas for ESCC in Henan,Hebei and Shanxi provinces);Group 4:High incidence areas outside three provinces(the high incidence areas for ESCC in other province,outside the Henan,Hebei and Shanxi provinces)Group 5:Low incidence areas outside three provinces(the low incidence areas for ESCC in other province,outside the Henan,Hebei and Shanxi provinces) There were six different groups involved in couples both suffering cancers:Group 1:Both suffering SCC;Group 2:Both suffering GCA;Group 3:One person had SCC,another person had GCA;Group 4:One person had SCC;another person had other cancer;Group 5:One person had GCA;another person had other cancer;Group 6:Both had cancers which not SCC/GCA3 RESULTS3.1 25198 patients with SCC were included in this study.Of these patients,male: 62%(15502/25198),female:38%(9696/25198).The youngest patients was 17 years old,the oldest was 93 years old,with a mean age of 58±11 years.EC FH+(age 40-50) in group 1(35%,493/1429)) was higher than in group 2 24%,195/798, P＜0.001) and in group 3(20%,184/934,P＜0.001).EC FH+(age 50-60) in group 1 (28%,1289/3598) was higher than in group 2(22%,717/3200,P＜0.001) and in group 3(27%,621/2317,P＜0.001).EC FH+(age 60-70) in group 1 was higher than in group 2 and in group 3(36%,1047/2950 vs.24%,497/2033vs.20%, 628/3078),P＜0.001.EC FH+(age＞70) in group 1 was higher than in group 2 and in group 3(40%,30/826vs.28%(226/788),18%,56/1386) P＜0.001).EC FH+ (age→40→50→60) in group 1 was more than other areas(2%+15%+39%vs. 2%+12%+40%vs.1%+ 10%+40%).EC FH+ in Group 4(42%,30/72)was higher than Group 5(23%,241/1049),P＜0.001.3.2 45183 patients with SCC/GCA were included in this study.Of these patients, 795 pairs couples both suffering cancer.Those couples both suffering cancers in group who married 30-40 years(71%,561/795) was higher than in group who married 20-30 years(7%,58/795) and in group who married 40-50 years (17%,135/795),P＜0.05.Couples in group 1(69%,546/795),was higher than in group 2(1%,9/795),group 3(13.6%,108/795),group 4(13%,105/795),group 5(3%,24/795) and group 6(0.4%,3/795),P＜0.05.3.3 Out of 19 pairs of monozygotic twins,11 pairs had concordant normal esophageal pathologic result,4 pairs had inconcordant esophageal dysphasia,3 pairs had inconcordant esophageal squamous cell carcinoma,and 1 pair had concordant. Out of 17 pairs,5 pairs had concordant normal gastric cardia,12 pairs had concordant gastric cardia dysphasia.Of the 11 pairs with concordant normal esophageal tissues,4 pairs had consistent expression of p53,10 pairs had consistent expression of PCNA.In the pair with concordant SCC,the expression of p53 and PCNA were positive.Of the 5 pairs with concordant gastric cardia result,the expression of p53 was negative and that PCNA was positive.4 CONCLUSIONS 4.1 EC FH+ in Taihang areas 36%(3348/9326) is higher than in other high incidence areas within three provinces 26%(1569/6042) and in low-incidence areas in three provinces 21%(1802/8709,P＜0.001,suggesting that there may be different tumor hereditary susceptibility among different areas,SCC from Taihang areas may have higher hereditary susceptibility.4.2 Environmental factors may play an important role in molecular change in esophageal epithelial cells.