To Distinguish Synchronous Endometrial And Ovarian Endometrioid Carcinoma With Metastatic Cancer By Next-generation Sequencing

BackgroundIn women with gynecological cancers,about 1-2%of them are found to have synchronous endometrial and ovarian cancer(SEOC).Compared with endometrial or ovarian cancers alone,SEOC generally presents different clinical characteristics and prognosis.However,the traditional pathological criteria for distinguishing synchronous tumors from metastases remains controversial and ambiguous.ObjectiveHere we are aimed to use whole-exome sequencing to elucidate the molecular features of SEOC and provide a more accurate guidance of clinical managements.MethodsSynchronous tumors of the endometrium and ovary,which are endometrioid endometrial carcinomas(EEC)and endometrioid ovarian carcinomas(EOC),from 6 patients were subjected to next-generation whole-exome sequencing.All the 6 cases fulfilled clinicopathological criteria that would lead to classification as independent endometrial and ovarian primary carcinomas,including being of FIGO stage ?,with organ-restricted growth and without surface involvement.The clonal architecture,genetic heterogeneity,and evolutionary trajectories were analyzed and reported in all the paired samples.Single nucleotide variations(SNVs)were used to reconstruct the evolutionary histories of EEC and EOC.ResultsA total of 21 matched normal tissue,cervical carcinoma,and ovarian carcinoma from 6 SEOC patients were collected and analyzed.Overall,the total somatic cell variation types and distribution of somatic mutations in EEC and EOC in each case displayed significant similarity and showed evidence of a clonal relationship.Hence,for individually paired samples,they were clonally related rather than independent multifocal tumors.To further verify the origins of the simultaneous tumors,correlation analysis of the identified SNVs were performed and Jaccard similarity was calculated in every pair of samples.The evolutionary histories showed that for P1,P2,P3,and P4,,the tumor cells were all originated from the ovary and subsequently transferred to the endometrium.One exception is for P7,where both Canopy and hierarchical clustering indicate the migration direction from EEC to EOC.The tumor origin of P6 is unresolved,since the normal cell line abundance are highly similar in all sites.The evolutionary histories were highly consistent with the stages of tumors.ConclusionsMost of the SEOC cases that had been misdiagnosed as simultaneous independent primary malignancies were actually metastatie diseases.Genetic information such as SNVs can precisely differentiate if the synchronous cancer were independent or metastasis.SNVs can also more precisely help determine the primary lesion site.In the future,more studies are required to elucidate the molecular and clinical characteristics of SEOC and provide a more precise diagnostic criteria for patients.