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

Abstract

Significance Familial nonmedullary thyroid cancer (FNMTC) accounts for up to 15% of all thyroid tumors. Here, we report two germ-line loss-of-function variants in WDR77 in two unrelated families with NMTC. WDR77 is expressed in diverse human tissues. It forms a complex with the protein arginine methyltransferase PRMT5 and mediates H4R3me2 in frogs and mammals. Functional analyses show that WDR77 variants impair formation of the complex of WDR77–PRMT5, resulting in reduced H4R3me2 in patients. Knockdown of WDR77 results in increased growth of thyroid cancer cells. Taken together, our findings reveal a predisposing gene of FNMTC and expand the variant profile predisposing to FNMTC. Additionally, this report presents germ-line variants in WDR77 associated with human disease. 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.