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Hum Mol Genet. 2017 Jan 15;26(2):243-257. doi: 10.1093/hmg/ddw382.

Germline compound heterozygous poly-glutamine deletion in USF3 may be involved in predisposition to heritable and sporadic epithelial thyroid carcinoma.

Author information

1
Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, OH, USA.
2
Department of Genetics and Genome Sciences.
3
Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, Ohio, OH, USA.
4
Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, OH, USA.
5
Division of Human Genetics.
6
Thyroid Center Unit, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, OH, USA.
7
Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, The Ohio State University School of Medicine, Columbus, Ohio, OH, USA.
8
Germline High Risk Focus Group, CASE Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, OH, USA.
9
Stanley Shalom Zielony Nursing Institute, Cleveland Clinic, Cleveland, Ohio, OH, USA.

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.

PMID:
28011713
PMCID:
PMC5351935
DOI:
10.1093/hmg/ddw382
[Indexed for MEDLINE]
Free PMC Article

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