The origins and consequences of UPF1 variants in pancreatic adenosquamous carcinoma

被引：12

作者：

Polaski, Jacob T. ^{[1
,2
]}

Udy, Dylan B. ^{[1
,2
,3
]}

Escobar-Hoyos, Luisa F. ^{[4
,5
,6
,7
]}

Askan, Gokce ^{[4
]}

Leach, Steven D. ^{[4
,5
,8
,9
]}

Ventura, Andrea ^{[10
]}

Kannan, Ram ^{[10
]}

Bradley, Robert K. ^{[1
,2
]}

机构：

[1] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Computat Biol Program, 1124 Columbia St, Seattle, WA 98104 USA

[2] Fred Hutchinson Canc Res Ctr, Div Basic Sci, 1124 Columbia St, Seattle, WA 98104 USA

[3] Univ Washington, Mol & Cellular Biol Grad Program, Seattle, WA 98195 USA

[4] Mem Sloan Kettering Canc Ctr, David M Rubenstein Ctr Pancreat Canc Res, 1275 York Ave, New York, NY 10021 USA

[5] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA

[6] SUNY Stony Brook, Dept Pathol, New York, NY USA

[7] Yale Univ, Sch Med, New Haven, CT USA

[8] Mem Sloan Kettering Canc Ctr, Dept Surg, 1275 York Ave, New York, NY 10021 USA

[9] Dartmouth Norris Cotton Canc Ctr, Lebanon, NH USA

[10] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, 1275 York Ave, New York, NY 10021 USA

来源：

ELIFE | 2021年 / 10卷

关键词：

MESSENGER-RNA DECAY;

D O I：

10.7554/eLife.62209

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

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.

引用

页码：1 / 19

页数：19

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