Letter to the Editor: Prevalence of WWP1 Gene Mutations in Patients with Thyroid Nodules

Dear Editor:

In a recent prospective cohort study, Lee et al. demonstrated that specific missense variants in WWP1 gene, coding for the E3 ubiquitin ligase that negatively regulates phosphatase and tensin homolog (PTEN), are associated with phenotypes that together comprise the PTEN hamartoma tumor syndrome (PHTS) (1). The authors then showed that germline WWP1 variants were over-represented in numerous tumors included in The Cancer Genome Atlas (TCGA). Furthermore, they reported that two germline variants in exon 20 of WWP1, K740N and N745S, accounted for just more than half of all the WWP1 variants detected in these TCGA cancers (1).

PTEN is a well-known tumor suppressor with loss-of-function alterations occurring as germline mutations in patients with PHTS, who are predisposed to multiple cancer types, and as somatic mutations in sporadic cancers (2,3). Considering thyroid cancer is a common manifestation of PHTS and somatic PTEN mutations occur in thyroid tumors (4), the article by Lee et al. (1) raises the question whether WWP1 may also predispose to thyroid cancer development through germline or somatic occurrence.

To investigate this possibility, with the approval by the University of Pittsburgh Institutional Review Board, we searched for mutations in exon 20 of WWP1 in a series of 713 consecutive thyroid tumors and hyperplastic nodules (median age 47 years, range 10–95 years) with DNA available in our database. Using Sanger sequencing, we identified 6 (0.84%) positive cases (median age 36 years, range 26–59 years), including five with N745S and one with K740N. Specifically, we detected WWP1 mutations in 2 out of 174 (1.14%) hyperplastic nodules, 3 out of 387 (0.77%) papillary thyroid carcinomas (PTCs), and 1 out of 39 (2.56%) Hürthle cell carcinomas (HCCs). To confirm the germline origin of both variants, we analyzed five available normal thyroid tissue samples from the positive cases, all of which yielded the same variants. Furthermore, when analyzed for additional molecular alterations using ThyroSeq v3 targeted next-generation sequencing panel (5), three of the WWP1 mutation-positive cases were found to also carry well-known driver mutations for PTC, including BRAF V600E in classic PTC and ETV6/NTRK3 fusion or EML4/ALK fusion in follicular variants PTC. No thyroid cancer-associated somatic mutations were found in HCC or hyperplastic nodules.

To determine whether the prevalence of germline WWP1 variants in patients with nodular thyroid lesions found in this series is comparable with the general population, we investigated the incidence of these two variants in patients without a reported cancer diagnosis in the population databases, including the 1000 Genomes, Exome Aggregation Consortium, Genome Aggregation Database/non-cancer, and Exome Sequencing Project. We found a significantly higher frequency of the WWP1 variants in our cohort as compared with those reported in each of these four databases (Table 1).

In summary, our findings suggest that germline WWP1 variants, and specifically N745S, are more common in patients with thyroid nodules as compared with the general population and raise a possibility that WWP1 may play a role in predisposition to thyroid nodules. However, WWP1 N745S is likely to be insufficient by itself to drive thyroid cancer development.