Genetic analysis of sinonasal undifferentiated carcinoma discovers recurrent SWI/SNF alterations and a novel PGAP3-SRPK1 fusion gene

BMC Cancer

Jingyi Zhai¹  Hui Jiang²  Brittany M. Jewell³  Susan K. Foltin³  Aditi Kulkarni³  Molly E. Heft Neal³  Apurva D. Bhangale³  Andrew C. Birkeland³  Lisa Pinatti⁴  Megan L. Ludwig⁵  J. Chad Brenner⁶  Erin L. McKean⁷  Lawence Marentette⁷  Jonathan B. McHugh⁸ 

[1] Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA;Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA;Rogel Cancer Center, University of Michigan Medical School, 1150 E. Medical Center Dr., 9301B MSRB3, 48109-0602, Ann Arbor, MI, USA;Department of Otolaryngology – Head and Neck Surgery, University of Michigan, 1150 E. Medical Center Dr., 9301B MSRB3, 48109-0602, Ann Arbor, MI, USA;Department of Otolaryngology – Head and Neck Surgery, University of Michigan, 1150 E. Medical Center Dr., 9301B MSRB3, 48109-0602, Ann Arbor, MI, USA;Program in Cancer Biology, University of Michigan, Ann Arbor, MI, USA;Department of Otolaryngology – Head and Neck Surgery, University of Michigan, 1150 E. Medical Center Dr., 9301B MSRB3, 48109-0602, Ann Arbor, MI, USA;Program in Cellular and Molecular Biology, University of Michigan, 1150 E. Medical Center Dr., 9301B MSRB3, 48109-0602, Ann Arbor, MI, USA;Department of Otolaryngology – Head and Neck Surgery, University of Michigan, 1150 E. Medical Center Dr., 9301B MSRB3, 48109-0602, Ann Arbor, MI, USA;Program in Cellular and Molecular Biology, University of Michigan, 1150 E. Medical Center Dr., 9301B MSRB3, 48109-0602, Ann Arbor, MI, USA;Rogel Cancer Center, University of Michigan Medical School, 1150 E. Medical Center Dr., 9301B MSRB3, 48109-0602, Ann Arbor, MI, USA;Department of Pharmacology, University of Michigan, 1150 E. Medical Center Dr., 9301B MSRB3, 48109-0602, Ann Arbor, MI, USA;Department of Otolaryngology – Head and Neck Surgery, University of Michigan, 1150 E. Medical Center Dr., 9301B MSRB3, 48109-0602, Ann Arbor, MI, USA;Rogel Cancer Center, University of Michigan Medical School, 1150 E. Medical Center Dr., 9301B MSRB3, 48109-0602, Ann Arbor, MI, USA;Rogel Cancer Center, University of Michigan Medical School, 1150 E. Medical Center Dr., 9301B MSRB3, 48109-0602, Ann Arbor, MI, USA;Department of Pathology, University of Michigan, Ann Arbor, MI, USA;

关键词: SNUC;    SWI/SNF;    SMARCA;   

DOI  :  10.1186/s12885-021-08370-x

来源: Springer

【 摘 要 】

BackgroundSinonasal 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.MethodsWe evaluated 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 performed exome sequencing to characterize a series of SNUC tumors (n = 5) and cell line (MDA8788–6) to identify high confidence mutations, copy number alterations, microsatellite instability, and fusions. Knockdown studies using siRNA were utilized for validation of a novel PGAP3-SRPK1 gene fusion.ResultsOverall survival analysis revealed no significant difference in outcomes between patients treated with surgery +/− CRT and CRT alone. Tobacco use was the only significant predictor of survival. We also confirmed previously published findings on IDH and SMARC family mutations and identified novel recurrent aberrations in the JAK/STAT and PI3K pathways. We also validated 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.ConclusionCollectively, these data demonstrate recurrent alterations in the SWI/SNF family as well as IDH, JAK/STAT, and PI3K pathways 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.

【 授权许可】

CC BY