Familial medullary thyroid carcinoma secondary to an SLC30A9 intragenic deletion and translation reinitiation

Abstract While most individuals with familial medullary thyroid carcinoma (fMTC) carry RET mutations, in some instances the causative mutations remain unknown. We studied two related families with RET -negative fMTC in 21 affected individuals through linkage analysis, exome/genome sequencing, and high-density array comparative genomic hybridization. We identified a novel heterozygous 40kb intragenic SLC30A9 deletion which segregated with the disease in all affected individuals. The mutant transcript escaped nonsense-mediated decay and resulted in the production of N-terminally truncated proteins via translation reinitiation from in-frame AUG codons located downstream of the deletion. These proteins localized to the endoplasmic reticulum suggesting protein misfolding. Introducing the deletion in an MTC cell line resulted in significant upregulation of genes involved in the unfolded protein response, ER-associated degradation, and the PI3K-Akt pathway. Furthermore, the deletion was associated with increased cell proliferation, migration, and clonogenic capacity, supporting an oncogenic role. These findings expand the genetic background of fMTC beyond RET mutations and implicate translation reinitiation in the etiology of cancer susceptibility syndromes secondary to structural genomic variants.