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Identification of Rare Germline Variants in Familial Patients with Non-medullary Thyroid Cancer

As the most common malignancy of the endocrine system, thyroid cancer is classified into two major categories, non-medullary thyroid cancer (NMTC) and medullary thyroid cancer (MTC) according to the origins and clinical features. NMTC includes papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), and anaplastic thyroid cancer (ATC). Sporadic non-medullary thyroid cancer (SNMTC) accounts for ~90% of all thyroid cancers. Compared to SNMTC, familial non-medullary thyroid cancer (FNMTC) is rare, constituting only 3 - 9%. FNMTC is a complex genetic disease that often shows an autosomal dominant mode of inheritance. Characterization of the germline variants causing the disease is still challenging given the heterogeneity of affected families.

In recent years, some mutations in known cancer susceptive coding genes have been reported using targeted DNA sequencing method in FNMTC cases. Still, little is known for the novel mutations in other thyroid cancer predisposition genes. With the decreasing cost and rapid development of next generation sequencing technology, more rare germline mutations underlying different types of cancer susceptibility in families had been discovered by whole genome sequencing (WGS). In this study, we performed WGS in familial NMTC patients in the U.S. Our aim is to identify rare germline variants with high penetrance that may contribute to thyroid cancer predisposition in NMTC families.