WWP1 Gain-of-Function Inactivation of PTEN in Cancer Predisposition.

Abstract

Patients with <i>PTEN</i> hamartoma tumor syndrome (PHTS) have germline mutations in the tumor-suppressor gene encoding phosphatase and tensin homologue (<i>PTEN</i>). Such mutations have been associated with a hereditary predisposition to multiple types of cancer, including the Cowden syndrome. However, a majority of patients who have PHTS-related phenotypes have tested negative for <i>PTEN</i> mutations. In a previous study, we found that the E3 ubiquitin ligase WWP1 negatively regulates the function of PTEN. In a prospective cohort study conducted from 2005 through 2015, we enrolled 431 patients with wild-type <i>PTEN</i> who met at least the relaxed diagnostic criteria of the International Cowden Consortium. Patients were scanned for <i>WWP1</i> germline variants. We used the Cancer Genome Atlas (TCGA) data set as representative of apparently sporadic cancers and the Exome Aggregation Consortium data set excluding TCGA (non-TCGA ExAC) and the noncancer Genome Aggregation Database (gnomAD) as representative of population controls without a reported cancer diagnosis. We established both in vitro and murine in vivo models to functionally characterize representative <i>WWP1</i> variants. The existence of germline <i>WWP1</i> variants was first established in a family with wild-type <i>PTEN</i> who had oligopolyposis and early-onset colon cancers. A validation series indicated that <i>WWP1</i> germline variants occurred in 5 of 126 unrelated patients (4%) with oligopolyposis as a predominant phenotype. Germline <i>WWP1</i> variants, particularly the <i>WWP1</i> K740N and N745S alleles, were enriched in patients who did not have PHTS but had prevalent sporadic cancers, including <i>PTEN-</i>related cancer types in TCGA (odds ratio, 1.5; 95% confidence interval, 1.1 to 2.1; P = 0.01). The prioritized <i>WWP1</i> variants resulted in gain-of-function effects, which led to aberrant enzymatic activation with consequent PTEN inactivation, thereby triggering hyperactive growth-promoting PI3K signaling in cellular and murine models. In this study involving patients with disorders resulting in a predisposition to the development of multiple malignant neoplasms without <i>PTEN</i> germline mutations, we confirmed the function of <i>WWP1</i> as a cancer-susceptibility gene through direct aberrant regulation of the PTEN-PI3K signaling axis. (Funded by the National Institutes of Health and others.).