| BackgroundsSertoli-Leydig cell tumors(SLCTs)are one of four primary categories of gynecologic cancer in pediatric and adolescent patients.SLCTs are one of ovarian sex cord-stroma tumors,and composed of Sertoli and Leydig cells.The treatment approaches are not only related to the oncologic outcomes but also the fertility outcomes.Due to the rarity of SLCTs,there is no standard approach.Germline loss of function mutations in DICER1 have been found to predispose the carrier to human disease,named DICER1 syndrome.Pleuropulmonary blastoma,SLCTs and thyroid gland cancer are the three primary categories of malignant tumors in DICER1 syndrome.Moreover,SLCTs are the most common gynecologic tumor in DICER1 syndrome.In addition to the scarcity of data on the germline testing,the rates of germline and somatic DICER1 mutations in SLCTs vary dramatically,in previous different studies.And there are no data of SLCTs on somatic and germline mutations for Chinese populations.Moreover,previous studies of SLCTs have focused exclusively on DICER1 mutations and there are no data regarding whole exome sequencing(WES)of SLCTs.Therefore,we conducted WES of SLCTs,in order to explore not only the DICER1 mutations but also other potential mutations related to the pathogenesis and prognosis of SLCTs,which could lay a preliminary foundation for the genetic counseling.MethodsThe patients with moderately or poorly differentiated SLCTs were recruited,who underwent surgical resection between January 2012 and October 2018 in Peking Union Medical College Hospital.WES was performed on tumor formalin-fixed paraffin-embedded(FFPE)tissue and peripheral blood samples or normal FFPE tissue from these patients.ResultsTotally,17 patients were recruited with 19 tumor samples.In addition to the 17 tumor samples from 17 patients,one tumor sample was from the synchronous contralateral ovarian SLCTs and another one tumor sample from the metachronous contralateral ovarian SLCTs.The rate of tumor-associated germline mutations was 35.3%(6/17),and that of DICER1 germline mutations was 23.5%(4/17).The rate of germline DICER1 mutations in the younger patients,who were less than 18 years old at the time of diagnosis,was significantly higher than that in the other patients(3/4,75.0%vs 1/13,7.7%;P=0.022,Fisher exact test).Regarding the clinical relapse,patients with germline tumor-associated mutations had significantly poorer prognosis than those without(P=0.007,Log-rank test),and patients with germline DICER1 mutations were relatively more likely to exhibit a clinical relapse,although not to a significant degree(P=0.069,Log-rank test).Firstly,the clone evolution analysis demonstrated that synchronous and metachronous contralateral ovarian SLCTs were primary tumors respectively.Secondly,somatic mutations were most commonly found in CDC27(10/19,52.6%),DICER1(4/19,21.1%),MUC22(4/19,21.1%),MUC2(2/19,10.5%),MUC17(2/19,10.5%),RAD50(2/19,10.5%),SON(2/19,10.5%),ZNF708(2/19,10.5%),CACNA1E(2/19,10.5%),KIF1B(2/19,10.5%)and PTH2(2/19,10.5%).Furthermore,oncogenic driver mutations were found in DICER1(4/19,21.1%),BCL11A(1/19,5.3%),PRDM16(1/19,5.3%),FGFR1(1/19,5.3%),PABPC1(1/19,5.3%),MUC16(1/19,5.3%),MUC4(1/19,5.3%),QK1(1/19,5.3%),ATF1(1/19,5.3%)and FOXL2(1/19,5.3%).The analysis of the cancer cell ratio showed that DICER1 mutations were significantly correlated with the tumorigenesis of SLCTs.Moreover,the rate of somatic DICER1 mutations in the younger patients was significantly higher than that in the other patients(4/5,80.0%vs 0/14,0.0%;P=0.001,Fisher exact test).ConclusionsBilateral ovarian SLCTs are verified to be primary tumors,which supports the fertility-sparing surgery in patients with SLCTs.The rates of germline and somatic DICER1 mutations in the younger patients are significantly higher than those in the other patients.The genetic testing and counseling have important clinical significance for patients with moderately or poorly differentiated SLCTs,particularly for the younger patients. |
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