Abstract
Extensive genomic profiling for endometrioid endometrial carcinoma (EEC) has pointed to genes and pathways important in uterine development as critical mediators of endometrial tumorigenesis. SOX17 is a developmental transcription factor necessary for proper endoderm formation that has been implicated as a tumor suppressor and shown to modulate WNT signaling. SOX17 mutation analysis in 539 primary EECs revealed frequent missense and frameshift mutations with an overall 11.5% mutation rate. More than half the mutations identified were frameshifts (32 of 62), and the hotspot missense changes, p.Ala96Gly and p.Ser403Ile, were seen in 14 tumors. None of the cases with a mutation had a second SOX17 mutation or evidence of allelic loss. Immunofluorescence microscopy performed on primary samples showed that there were no changes in SOX17 protein expression associated with mutation. Low/absent SOX17 staining was significantly associated with advanced stage, high tumor grade and reduced recurrence-free survival. Functional assessment of the two hotspot missense mutations and three representative frameshift mutations showed that SOX17-A96G and SOX17-S403I have transcriptional activities similar to SOX17 wild-type (WT), whereas none of the frameshift mutant proteins showed transcriptional activity. Forced expression of SOX17-WT, -A96G or -S403I in EC cell lines moderately increased β-catenin mediated transcription, which contrasts with previous data showing SOX17 is an inhibitor of TCF/β-catenin signaling. The proliferation of EC cell lines was expectedly reduced by transfection with SOX17-WT, and further reduced by SOX17-A96G and SOX17-S403I. These data implicate SOX17 mutation as a selected event in EEC, with clear differences between the missense and frameshift mutations.
Highlights
Endometrial cancer (EC) is the most common gynecologic malignancy and both the incidence and associated mortality of EC are increasing [1]
The two hotspot missense mutations previously identified by The Cancer Genome Atlas (TCGA) for EC [5] were evident: p.Ser403Ile was seen in eight tumors and p.Ala96Gly was seen in six tumors
The SOX17 mutation pattern we observed in endometrial carcinomas (EECs) is consistent with that of a tumor suppressor, in which critical regions are perturbed through single amino acid substitutions, and nonsense and frameshift mutations occur throughout the entire coding sequence
Summary
Endometrial cancer (EC) is the most common gynecologic malignancy and both the incidence and associated mortality of EC are increasing [1]. The most frequently mutated genes in type II tumors are TP53, PIK3CA, PTEN, PIK3R1, and PPP2R1A, and these tumors have many more SCNAs than type I ECs [5]. EC has one of the highest mutation rates among cancers [11], and many of the less frequently occurring mutations require biologic characterization to determine their importance in EC. The roles of these genes that are less frequently mutated in EEC, in particular those with known roles in uterine development, warrant further investigation
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