Genes differentially expressed by sex in concordance * in both the discovery and validation PNET datasets.

Genes differentially expressed by sex in concordance * in both the discovery and validation PNET datasets.

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Pancreatic neuroendocrine tumors (PNETs) occur more frequently in men and are associated with higher mortality in males; however, the molecular basis for these sexual dimorphisms is unclear. Here, we demonstrate that PNETs are associated with the emergence of unique sex-specific transcriptomic differences that are not observed in non-neoplastic pan...

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... (M)) (Supplementary Table 1) surgically resected at our institution (Discovery Dataset). To validate our results, we downloaded a publicly available PNET RNAseq data from the Sequence Read Archive (SRA), consisting of 24 primary PNETs (10 F, 14 . ...
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... was not certified by peer review) 3 Table 1). To compare PNET data to controls, we further downloaded RNAseq data from 89 non-neoplastic (control) pancreatic islet tissue samples (35 F, 54 M) (Supplementary Table 2). ...
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... the control dataset, only 173 genes were DE by sex (60.1% overexpressed in males) (Figure 1a-c). Interestingly, in both the discovery and validation PNET datasets, there were significantly more genes differentially expressed by sex as compared to control pancreatic islet tissues (discovery vs control: p = 6.5x10 -5 ; validation vs control: p = 2.0x10 -48 ), despite greater sample size (and therefore power) in the control dataset (Figure 1a and Supplementary Table 3). Additionally, there were significantly more transcription factors (TFs) differentially expressed between sexes in the PNET datasets than in control data (55 and 65 differentially expressed TFs in the discovery and validation datasets respectively; 15 TFs in the control dataset) (discovery vs control: p = 2.7x10 -6 ; validation vs control: p = 3.4x10 -8 ). ...


Introduction: Sex-based differences in survival have emerged among patients with pancreatic neuroendocrine tumors (PNETs). Mechanisms driving these differences remain poorly understood. We aimed to further characterize sex-based clinicopathologic and survival differences among patients with PNETs and correlate divergent mutational signatures in these patients. Methods: The National Cancer Database (NCDB) was queried for PNET patients diagnosed 2004-2017 who underwent surgery. Clinicopathologic features were analyzed by sex. The overall survival (OS) of men and women by disease stage was compared using the Kaplan-Meier method. Differences in PNET mutational signatures were analyzed by querying the American Association for Cancer Research Genomics Evidence Neoplasia Information (AACR-GENIE) Cohort v11.0-public. Frequencies of mutational signatures were compared by Fischer's exact (FE) test, adjusting for multiple testing via the Benjamini-Hochberg correction. Results: About 15,202 patients met inclusion criteria from the NCDB; 51.9% were men and 48.1% were women. Men more frequently had tumors > 2 cm than women and more commonly had poorly or undifferentiated tumors. Despite this, lymph node positivity and distant metastases were similar. Differences in OS were only seen among those with early stage rather than stage 3 or 4 disease. MEN1 and DAXX mutations were more frequent among men with PNETs, whereas TP53 mutations were more frequent among women when assessed by FE test. However, neither of these mutational differences maintained statistical significance when adjusted for multiple testing. Conclusion: Compared to women, men have larger tumors but similar rates of distant metastases at time of surgery. OS differences appear to be driven by patients with early-stage disease without clearly identifiable differences in mutational signatures between the sexes.