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Research Article
Genetic Analysis of Sinonasal Undifferentiated Carcinoma Discovers Recurrent SWI/SNF Alterations and a novel PGAP3-SRPK1 Fusion Gene
J Brenner
University of Michigan–Ann Arbor
Corresponding Author
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: Sinonasal Undifferentiated Carcinoma (SNUC) is a rare and aggressive skull base tumor with poor survival and limited treatment options. To date, targeted sequencing studies have identified IDH2 and SMARCB1 as potential driver alterations, but the molecular alterations found in SMARCB1 wild type tumors are unknown.
Methods: We evaluate survival outcomes in a cohort of 46 SNUC patients treated at an NCI designated cancer center and identify clinical and disease variables associated with survival on Kaplan-Meier and Cox multivariate survival analysis. We perform exome sequencing to characterize a series of SMARCB1 wild type tumors and cell line including identification of high confidence mutations, copy number alterations, microsatellite instability, and fusions. Knockdown studies using siRNA was utilized for validation of a novel PGAP3-SRPK1 gene fusion.
Results: We discover recurrent aberrations to the SWI/SNF and FAT gene families. We also validate a novel PGAP3-SRPK1 gene fusion in the SNUC cell line, and show that knockdown of the fusion is negatively associated with EGFR, E2F and MYC signaling.
Conclusion: Collectively, these data demonstrate recurrent alterations in the SWI/SNF and FAT gene families and discover a novel fusion gene (PGAP3-SRPK1). These data aim to improve understanding of possible driver mutations and guide future therapeutic strategies for this disease.
Keywords
SNUC, SWI/SNF, SMARCA
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This is a list of supplementary files associated with this preprint. Click to download.
- SupplementalFigure1.docx
Supplemental Figure 1: High confidence somatic mutations and INDELS is depicted for each sample.
- SupplementalFigure2.pdf
Supplemental Figure 2: Linked read genome sequencing identifies structural variations in the MDA8788-6 genome involving ZNF546 and AXL as well as CREB3L2 and BRAF.
- SupplementalTable1demographicstable.docx
- SupplementalTable2SnucSTRProfile.xlsx
- Supplementaltable3.docx
- SupplementalTable4primers.docx
- supplementaltable5WESqc.xlsx
- SupplementalTable6ACNVdata.xlsx
- SupplementalTable6BCNVdata.xlsx
- SupplementalTable6CCNVdata.xlsx
- SupplementalTable6DCNVdata.xlsx
- SupplementalTable6ECNVdata.xlsx
- SupplementalTable7SNV.xlsx
- SupplementalTable8Indels.xlsx
- SupplementalTable9VEST.xlsx
- SupplementalTable10MSI.xlsx
- SupplementalTable11CelllineExomeQC.xlsx
- SupplementalTable12SNUCSNVsannotatedexomefinal.xlsx
- Supplementaltable13SNUCINDELsannotatedexomefinal.xlsx
- SupplementalTable14SNUCCellLineGeneFusions.xlsx
- SupplementalTable15LongRangerData.xlsx
- Supplementaltable16SNUCknockdownGSEAsummary.xlsx
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This preprint is under consideration at BMC Cancer. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research Article
Genetic Analysis of Sinonasal Undifferentiated Carcinoma Discovers Recurrent SWI/SNF Alterations and a novel PGAP3-SRPK1 Fusion Gene
J Brenner
University of Michigan–Ann Arbor
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Revision
Version 1
Posted 28 Dec, 2020
No community comments so far
Editorial decision: Major revision
On 08 Feb, 2021
Review #5 received
Received 27 Jan, 2021
Review #6 received
Received 10 Jan, 2021
Review #8 received
Received 10 Jan, 2021
Review #11 received
Received 10 Jan, 2021
Review #7 received
Received 10 Jan, 2021
Review #1 received
Received 10 Jan, 2021
Review #2 received
Received 10 Jan, 2021
Review #3 received
Received 10 Jan, 2021
Review #10 received
Received 10 Jan, 2021
Review #9 received
Received 10 Jan, 2021
Reviewer #8 agreed
On 03 Jan, 2021
Reviewer #9 agreed
On 31 Dec, 2020
Reviewer #11 agreed
On 31 Dec, 2020
Reviewer #1 agreed
On 29 Dec, 2020
Reviewer #14 agreed
On 29 Dec, 2020
Reviewer #3 agreed
On 29 Dec, 2020
Reviewer #10 agreed
On 29 Dec, 2020
Reviewer #2 agreed
On 29 Dec, 2020
Reviewer #4 agreed
On 29 Dec, 2020
Reviewer #5 agreed
On 29 Dec, 2020
Reviewer #6 agreed
On 29 Dec, 2020
Reviewer #13 agreed
On 29 Dec, 2020
Reviewer #12 agreed
On 29 Dec, 2020
Reviewers invited
Invitations sent on 27 Dec, 2020
Editor assigned
On 27 Dec, 2020
Editor invited
On 21 Dec, 2020
Submission checks complete
On 21 Dec, 2020
First submitted
On 24 Nov, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: Sinonasal Undifferentiated Carcinoma (SNUC) is a rare and aggressive skull base tumor with poor survival and limited treatment options. To date, targeted sequencing studies have identified IDH2 and SMARCB1 as potential driver alterations, but the molecular alterations found in SMARCB1 wild type tumors are unknown.
Methods: We evaluate survival outcomes in a cohort of 46 SNUC patients treated at an NCI designated cancer center and identify clinical and disease variables associated with survival on Kaplan-Meier and Cox multivariate survival analysis. We perform exome sequencing to characterize a series of SMARCB1 wild type tumors and cell line including identification of high confidence mutations, copy number alterations, microsatellite instability, and fusions. Knockdown studies using siRNA was utilized for validation of a novel PGAP3-SRPK1 gene fusion.
Results: We discover recurrent aberrations to the SWI/SNF and FAT gene families. We also validate a novel PGAP3-SRPK1 gene fusion in the SNUC cell line, and show that knockdown of the fusion is negatively associated with EGFR, E2F and MYC signaling.
Conclusion: Collectively, these data demonstrate recurrent alterations in the SWI/SNF and FAT gene families and discover a novel fusion gene (PGAP3-SRPK1). These data aim to improve understanding of possible driver mutations and guide future therapeutic strategies for this disease.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5