title: Germline compound heterozygous poly-glutamine deletion in USF3 may be involved in predisposition to heritable and sporadic epithelial thyroid carcinoma.
abstract: Cowden syndrome (CS) is an autosomal dominant disorder that predisposes to breast, thyroid, and other epithelial cancers. Differentiated thyroid carcinoma (DTC), as one of the major component cancers of CS, is the fastest rising incident cancer in the USA, and the most familial of all solid tumours. To identify additional candidate genes of CS and potentially DTC, we analysed a multi-generation CS-like family with papillary thyroid cancer (PTC), applying a combined linkage-based and whole-genome sequencing strategy and identified an in-frame germline compound heterozygous deletion, p.[Gln1478del];[Gln1476-Gln1478del] in USF3 (previously known as KIAA2018). Among 90 unrelated CS/CS-like individuals, 29% were found to have p.[Gln1478del];[Gln1476-Gln1478del]. Of 497 TCGA PTC individuals, 138 (27%) were found to carry this germline compound deletion, with somatically decreased tumour USF3 expression. We demonstrate an increased migration phenotype along with enhanced epithelial-to-mesenchymal transition (EMT) signature after USF3 knockdown or USF3 p.[Gln1478del];[Gln1476-Gln1478del] overexpression, which sensitizes cells to the endoplasmic reticulum (ER) stress. Loss of USF3 function induced cell necrosis-like features and impaired respiratory capacity while providing a glutamine-dependent cell survival advantage, strongly suggests a metabolic survival and migration-favouring microenvironment for carcinogenesis. Therefore, USF3 may be involved in the predisposition of thyroid cancer. Importantly, the results that glutamine-dependent survival and sensitivity to ER stress in USF3-deficient cells provide avenues for therapeutic and adjunct preventive interventions for both sporadic cancer as well as cancer predisposition syndromes with similar mechanisms.
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, OH, USA.|Department of Genetics and Genome Sciences.|Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, Ohio, OH, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ni
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, OH, USA.
authors.forename: Spencer
authors.initials: S
authors.lastname: Seballos
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, OH, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Fletcher
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, OH, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Romigh
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, OH, USA.
authors.forename: Lamis
authors.initials: L
authors.lastname: Yehia
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, OH, USA.|Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, OH, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Mester
authors.affiliation: Division of Human Genetics.|Thyroid Center Unit, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, OH, USA.
authors.forename: Leigha
authors.initials: L
authors.lastname: Senter
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, OH, USA.
authors.forename: Farshad
authors.initials: F
authors.lastname: Niazi
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, The Ohio State University School of Medicine, Columbus, Ohio, OH, USA.|Thyroid Center Unit, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, OH, USA.
authors.forename: Motoyasu
authors.initials: M
authors.lastname: Saji
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, The Ohio State University School of Medicine, Columbus, Ohio, OH, USA.|Thyroid Center Unit, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, OH, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Ringel
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, OH, USA.|Department of Genetics and Genome Sciences.|Germline High Risk Focus Group, CASE Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, OH, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: LaFramboise
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, OH, USA.|Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, OH, USA.|Stanley Shalom Zielony Nursing Institute, Cleveland Clinic, Cleveland, Ohio, OH, USA.|Department of Genetics and Genome Sciences.|Germline High Risk Focus Group, CASE Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, OH, USA.
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D002291:Carcinoma, Papillary; D002465:Cell Movement; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D005838:Genotype; D018095:Germ-Line Mutation; D006223:Hamartoma Syndrome, Multiple / Q000235:genetics* / Q000473:pathology; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D010375:Pedigree; D010455:Peptides / Q000235:genetics; D017384:Sequence Deletion; D000077273:Thyroid Cancer, Papillary; D013961:Thyroid Gland / Q000473:pathology; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology; D059016:Tumor Microenvironment / Q000235:genetics; D051720:Upstream Stimulatory Factors / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D010455:Peptides; D051720:Upstream Stimulatory Factors; C000622661:USF3 protein, human; C097188:polyglutamine