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Germ-line mutations in WDR77 predispose to familial papillary thyroid cancer.

ABSTRACT: The inheritance of predisposition to nonsyndromic familial nonmedullary thyroid cancer (FNMTC) remains unclear. Here, we report six individuals with papillary thyroid cancer (PTC) in two unrelated nonsyndromic FNMTC families. Whole-exome sequencing revealed two germ-line loss-of-function variants occurring within a 28-bp fragment of WDR77, which encodes a core member of a transmethylase complex formed with the protein arginine methyltransferase PRMT5 that is responsible for histone H4 arginine 3 dimethylation (H4R3me2) in frogs and mammals. To date, the association of WDR77 with susceptibility to cancer in humans is unknown. A very rare heterozygous missense mutation (R198H) in WDR77 exon 6 was identified in one family of three affected siblings. A heterozygous splice-site mutation (c.619+1G > C) at the 5' end of intron 6 is present in three affected members from another family. The R198H variant impairs the interaction of WDR77 with PRMT5, and the splice-site mutation causes exon 6 skipping and results in a marked decrease in mutant messenger RNA, accompanied by obviously reduced H4R3me2 levels in mutation carriers. Knockdown of WDR77 results in increased growth of thyroid cancer cells. Whole-transcriptome analysis of WDR77 mutant patient-derived thyroid tissue showed changes in pathways enriched in the processes of cell cycle promotion and apoptosis inhibition. In summary, we report WDR77 mutations predisposing patients to nonsyndromic familial PTC and link germ-line WDR77 variants to human malignant disease.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC8346892 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Many physiological effects of thyroid hormone (TH) are mediated by its canonical action via nuclear receptors (TH receptor α and β [TRα and TRβ]) to regulate transcription of target genes. Heterozygous dominant negative mutations in human TRα mediate resistance to thyroid hormone alpha (RTHα), characterized by features of hypothyroidism (e.g., skeletal dysplasia, neurodevelopmental retardation, constipation) in specific tissues, but near-normal circulating TH concentrations. Hitherto, 41 RTHα cases have been recorded worldwide. Methods: RTHα cases (n = 10) attending a single center underwent cutaneous assessment, recording skin lesions. Lesions excised from different RTHα patients were analyzed histologically and profiled for cellular markers of proliferation and oncogenic potential. Proliferative characteristics of dermal fibroblasts and inducible pluripotent stem cell (iPSC)-derived keratinocytes from patients and control subjects were analyzed. Results: Multiple skin tags and nevi were recorded in all cases, mainly in the head and neck area with a predilection for flexures. The affected patients had highly deleterious mutations (p.E403X, p.E403K, p.F397fs406X, p.A382PfsX7) involving TRα1 alone or mild/moderate loss-of-function mutations (p.A263V, p.L274P) common to TRα1 and TRα2 isoforms. In four patients, although lesions excised for cosmetic reasons were benign intradermal melanocytic nevi histologically, they significantly overexpressed markers of cell proliferation (K17, cyclin D1) and type 3 deiodinase. In addition, oncogenic markers typical of basal cell carcinoma (Gli-1, Gli-2, Ptch-1, n = 2 cases) and melanoma (c-kit, MAGE, CDK4, n = 1) were markedly upregulated in skin lesions. Cell cycle progression and proliferation of TRα mutation-containing dermal fibroblasts and iPSC-derived keratinocytes from patients were markedly increased. Conclusions: Our observations highlight frequent occurrence of skin tags and benign melanocytic nevi in RTHα, with cutaneous cells from patients being in a hyperproliferative state. Such excess of skin lesions, including nevi expressing oncogenic markers, indicates that dermatologic surveillance of RTHα patients, monitoring lesions for features that are suspicious for neoplastic change, is warranted.

Project description:BackgroundCurrently, less aggressive treatment or even active surveillance of papillary thyroid microcarcinoma (PTMC) is widely accepted and recommended as a therapeutic management option. However, there are some concerns about these approaches. We investigated whether there are any demographic, clinical and ultrasound characteristics of PTMC patients that are easy to obtain and clinically available before surgery to help clinicians make proper therapeutic decisions.MethodsWe performed a retrospective chart review of 5,021 patients with thyroid tumors surgically treated in one center in 2008-2018. Finally, 182 (3.62%) PTMC patients were selected (158 (86.8%) females and 24 (13.2%) males, mean age 48.8±15.4 years). We analyzed the disease-free survival (DFS) time of the PTMC patients according to demographic and histopathological parameters. Univariate and multivariate logistic regression analyses were used to assess the relationships of demographic, clinical and ultrasound characteristics with aggressive histopathological features.ResultsAge ≥55 years, hypoechogenicity, microcalcifications, irregular tumor shape, smooth margins and high vascularity significantly increased the risk for minimal extrathyroidal extension (minETE), lymph node metastasis (LNM), and capsular and vascular invasion (p<0.0001). Multivariate logistic regression analysis demonstrated a statistically significant risk of LNM (OR = 5.98, 95% CI: 2.32-15.38, p = 0.0002) and trends toward significantly higher rates of minETE and capsular and vascular invasion (OR = 2.24, 95% CI: 0.97-5.19, p = 0.056) in patients ≥55 years than in their younger counterparts. The DFS time was significantly shorter in patients ≥55 years (p = 0.015), patients with minETE and capsular and vascular invasion (p = 0.001 for all), patients with tumor size >5 mm (p = 0.021), and patients with LNM (p = 0.002).ConclusionsThe absence of microcalcifications, irregular tumor shape, blunt margins, hypoechogenicity and high vascularity in PTMC patients below 55 years and with tumor diameters below 5 mm may allow clinicians to select individuals with a low risk of local recurrence so that they can receive less aggressive management.

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Germ-line mutations in WDR77 predispose to familial papillary thyroid cancer.

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