Introduction: Somatic frameshift mutations in RNF43 have previously been filtered out in cancer genome sequencing projects given that they occur in homopolymer tracts and resemble polymerase slippage errors. Two RNF43 hotspot mutations have been identified and validated in endometrioid endometrial cancer (EEC) and appear to negatively regulate Wnt signaling. These frameshift mutations occur at codons R117 and G659. Due to shared clinical and morphologic features of EEC and endometrioid ovarian cancer (EmOC), we determined the frequency of RNF43 somatic mutations in EmOC.

Methods: We reviewed the clinical and pathologic features of EmOC samples diagnosed from 2006 to 2015, retrieved from laboratory databases and institutional archives. DNA was extracted from formalin-fixed, paraffin-embedded tumor samples using standard protocols. Sanger and next-generation sequencing (NGS) were used to screen for hotspot mutations at codons R117 and G659 with custom designed primers. NGS at each hotspot was covered with a minimum sequencing depth of 400X.

Results: Forty-seven EmOC patients with available tumor specimens were identified and included in the analysis. The median age at diagnosis was 55 years old (range 34-84). The majority of patients had FIGO stage I or stage II disease (n=38, 81%). Thirteen (28%) patients had synchronous endometrial endometrioid or mixed histology tumors. Two (4.3%) RNF43 somatic mutations at codon G659 were identified in both Sanger and NGS from the EmOC tumor specimens. No mutations at codon R117 were identified. The allele fractions of the G659 mutations were 4.3% and 2.8% seen in 33 and 18 reads with a coverage of 775X and 646X, respectively. A review of pathology reports indicated that both mutated samples had synchronous EECs. These two mutated samples represent 15.4% of cases diagnosed with synchronous EmOC and EEC in this cohort.

Conclusions: RNF43 somatic mutations are uncommon in EmOCs and associated with synchronous EECs. Recent massively parallel sequencing data suggests that EmOCs in the setting of synchronous EECs are clonally related and disseminated cells are related to nearby anatomic structures. Our data supports that RNF43 somatic mutations in EmOC are clonally expanded from EECs likely through trans-tubal migration.

Citation Format: Defne L. Levine, Fanny Dao, Narciso Olvera, Katherine LaVigne, David B. Solit, Petar Jelinic. RNF43 somatic mutations in endometrioid ovarian cancers occur in the setting of synchronous endometrioid endometrial cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3415. doi:10.1158/1538-7445.AM2017-3415