The origins and consequences of UPF1 variants in pancreatic adenosquamous carcinoma

eLife

Gokce Askan¹  Dylan B Udy¹  Robert K Bradley²  Ram Kannan³  Steven D Leach⁴  Jacob T Polaski⁵  Luisa F Escobar-Hoyos⁵  Andrea Ventura⁶ 

[1] Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States;Department of Pathology, Stony Brook University, New York, United States;Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States;Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, United States;Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States;David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, United States;

关键词: pancreatic cancer;    cancer genomics;    cancer genetics;   

DOI  :  10.7554/eLife.62209

来源: DOAJ

【 摘 要 】

Pancreatic adenosquamous carcinoma (PASC) is an aggressive cancer whose mutational origins are poorly understood. An early study reported high-frequency somatic mutations affecting UPF1, a nonsense-mediated mRNA decay (NMD) factor, in PASC, but subsequent studies did not observe these lesions. The corresponding controversy about whether UPF1 mutations are important contributors to PASC has been exacerbated by a paucity of functional studies. Here, we modeled two UPF1 mutations in human and mouse cells to find no significant effects on pancreatic cancer growth, acquisition of adenosquamous features, UPF1 splicing, UPF1 protein, or NMD efficiency. We subsequently discovered that 45% of UPF1 mutations reportedly present in PASCs are identical to standing genetic variants in the human population, suggesting that they may be non-pathogenic inherited variants rather than pathogenic mutations. Our data suggest that UPF1 is not a common functional driver of PASC and motivate further attempts to understand the genetic origins of these malignancies.

【 授权许可】

Unknown