Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States.
Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States.
Elife. 2021 Jan 6;10:e62209. doi: 10.7554/eLife.62209.
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 mutations are important contributors to PASC has been exacerbated by a paucity of functional studies. Here, we modeled two mutations in human and mouse cells to find no significant effects on pancreatic cancer growth, acquisition of adenosquamous features, splicing, UPF1 protein, or NMD efficiency. We subsequently discovered that 45% of 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 is not a common functional driver of PASC and motivate further attempts to understand the genetic origins of these malignancies.
胰腺腺鳞癌（PASC）是一种侵袭性癌症，其突变起源尚不清楚。一项早期研究报道了 PASC 中影响 UPF1 的高频体细胞突变，UPF1 是一种无义介导的 mRNA 降解（NMD）因子，但随后的研究并未观察到这些病变。由于缺乏功能研究，关于突变是否是 PASC 的重要贡献者的争议更加激烈。在这里，我们在人类和小鼠细胞中模拟了两种 突变，没有发现它们对胰腺癌细胞生长、获得腺鳞特征、剪接、UPF1 蛋白或 NMD 效率有显著影响。随后我们发现，据报道存在于 PASCs 中的 45%的 突变与人群中的常见遗传变异相同，这表明它们可能是无致病性的遗传变异，而不是致病性突变。我们的数据表明 不是 PASC 的常见功能驱动因素，并促使我们进一步努力了解这些恶性肿瘤的遗传起源。
