Thyroid Cancer, Nonmedullary, 2

A number sign (#) is used with this entry because of evidence that susceptibility to nonmedullary thyroid cancer-2 (NMTC2) is conferred by heterozygous mutation in the SRGAP1 gene (606523) on chromosome 12q14.

Description

Nonmedullary thyroid cancer (NMTC) comprises thyroid cancers of follicular cell origin and accounts for more than 95% of all thyroid cancer cases. The remaining cancers originate from parafollicular cells (medullary thyroid cancer, MTC; 155240). NMTC is classified into 4 groups: papillary, follicular, Hurthle cell (607464), and anaplastic. Approximately 5% of NMTC is hereditary, occurring as a minor component of a familial cancer syndrome (e.g., familial adenomatous polyposis, 175100, Carney complex, 160980) or as a primary feature (familial NMTC or FNMTC). Papillary thyroid cancer (PTC) is the most common histologic subtype of FNMTC, accounting for approximately 85% of cases (summary by Vriens et al., 2009).

Follicular thyroid cancer (FTC) accounts for approximately 15% of NMTC and is defined by invasive features that result in infiltration of blood vessels and/or full penetration of the tumor capsule, in the absence of the nuclear alterations that characterize papillary carcinoma. FTC is rarely multifocal and usually does not metastasize to the regional lymph nodes but tends to spread via the bloodstream to the lung and bones. An important histologic variant of FTC is the oncocytic (Hurthle cell, oxyphilic) follicular carcinoma composed of eosinophilic cells replete with mitochondria (summary by Bonora et al., 2010).

For a general phenotypic description and a discussion of genetic heterogeneity of NMTC, see NMTC1 (188550).

Molecular Genetics

He et al. (2013) performed genomewide linkage analysis in 38 families with PTC and identified SRGAP1 in the linkage peak as a candidate gene. Two missense mutations in the Fes/CIP4 homology domain (Q149H, 606523.0001 and A275T, 606523.0002) segregated with disease in 1 family each; 1 missense variant in the RhoGAP domain (R617C; 606523.0003) occurred in 1 family. Biochemical assays demonstrated that the ability to inactivate CDC42 (116950), a key function of SRGAP1, was severely impaired by the Q149H and R617C variants.