The Clinicopathological Characteristics And Whole-exome Sequencing Analysis Of AFP-producing Gastrointestinal Adenocarcinoma

BackgroundAFP-producing adenocarcinoma-gastrointestinal(APA-GI)is a rare type of gastrointestinal adenocarcinoma with abnormal ?-fetoprotein(AFP)secretion.Studies show that APA-GI of different origins displays the same pathological features of hepatoid differentiation and clinical characteristics of early metastasis and poor prognosis,which could be analyzed as the same type of diseases.However,studies on APA-GI are limited,and most are only included stomach or intestine,lacking the overall analysis of the clinicopathological features and the understanding of the genetic background of APA-GI.Consequently,this study intends to summarize the clinicopathological features of APA-GI by retrospective analysis,and understand its genetic and molecular background through whole-exome sequencing(WES)which can provide ideas for accurate diagnosis of APA-GI.MethodsIn the first part of the study,patients pathologically diagnosed with gastrointestinal adenocarcinoma with elevated serum AFP levels(>20 ng/ml)during 2010 and 2017 in our hospital were included and divided into high AFP group and low AFP group with a threshold of 200ng/ml.The clinicopathological characteristics of the two groups were compared.The pathological features of APA-GI were described through pathological image analysis and immunohistochemistry.Then,survival was compared between APA-GI and common adenocarcinoma-gastrointestinal(CA-GI)from TCGA by the Kaplan-Meier curve.Finally,Cox proportional hazards model was used to identify the prognostic risk factors of APA-GI.In the second part,WES was performed in 29 patients with APA-GI and 8 patients with CA-GI,and the differential genes were screened by GO,KEGG,and protein-protein interaction network analysis.ResultsAPA-GI was more common in middle-aged and elderly men and often occurred in the stomach.In the initial diagnosis patients with stage IV accounted for 58.2%,and the rate of final metastasis was 81.9% which liver metastasis accounted for the majority.Hepatoid adenocarcinoma is a typical pathological feature of APA-GI.Immunohistochemistry showed that the positive rate of AFP expression in APA-GI was 36.4%.The high AFP group had larger tumor diameter,a higher proportion of stage IV cases,more liver metastasis and a higher percentage of hepatoid adenocarcinoma.Survival analysis showed that the 5-year survival rate of APA-GI patients was significantly lower than that of CA-GI(17.7% vs 55.9%,P<0.001).The 5-year survival rate was lower in the high AFP group(7.5% vs.26.0%,P=0.002).Liver metastasis was an independent risk factor for APA-GI(HR,3.59,95%CI 1.28-10.02,P=0.015).AFP?200ng/ml was an independent risk factor for liver metastasis-free survival of APA-GI(HR 4.55,95%CI 1.39-14.87,P=0.012).WES observed that a total of 1,276,427 mutation sites including germline mutations in the 29 APA-GI.The 335 differentially genes were enriched in the G protein pathway,citric acid metabolism,histone modification,and other pathways.Furthermore,46 genes,including UBE2E1 and ANAPC2,formed a gene panel.After dimension reduction and visualization,CA-GI and APA-GI were clustered respectively.Conclusion 1.APA-GI often occurred in the stomach.The clinicopathological characteristics were early metastasis,high metastasis rate and the tendency of liver metastasis.Its prognosis is significantly worse than that of CA-GI.Hepatoid adenocarcinoma is the main pathological feature of APA-GI.Liver metastasis was an independent risk factor for APA-GI,while AFP?200ng/ml was an independent risk factor for liver metastasis-free survival of APA-GI;2.The analysis of WES showed that APA-GI and CA-GI could be preliminarily distinguished by the gene panel composed of 46 genes including UBE2E1 and ANAPC2.