Familial non-medullary thyroid cancer: unraveling the genetic maze

Abstract

Familial non-medullary thyroid cancer (FNMTC) constitutes 3-9% of all thyroid cancers. Out of all FNMTC cases, only 5% in the syndromic form has well-studied driver germline mutations. These associated syndromes include Cowden syndrome, familial adenomatous polyposis, Gardner syndrome, Carney complex type 1, Werner syndrome and DICER1 syndrome. It is important for the clinician to recognize these phenotypes so that genetic counseling and testing can be initiated to enable surveillance for associated malignancies and genetic testing of family members. The susceptibility chromosomal loci and genes of 95% of FNMTC cases remain to be characterized. To date, 4 susceptibility genes have been identified (SRGAP1 gene (12q14), TITF-1/NKX2.1 gene (14q13), FOXE1 gene (9q22.33) and HABP2 gene (10q25.3)), out of which only the FOXE1 and the HABP2 genes have been validated by separate study groups. The causal genes located at the other 7 FNMTCassociated chromosomal loci (TCO (19q13.2), fPTC/ PRN (1q21), FTEN (8p23.1-p22), NMTC1 (2q21), MNG1 (14q32), 6q22, 8q24) have yet to be identified. Increasingly, gene regulatory mechanisms (miRNA and enhancer elements) are recognized to affect gene expression and FNMTC tumorigenesis. With newer sequencing technique, along with functional studies, there has been progress in the understanding of the genetic basis of FNMTC. In our review, we summarize the FNMTC studies to date and provide an update on the recently reported susceptibility genes including novel germline SEC23B variant in Cowden syndrome, SRGAP1 gene, FOXE1 gene and HABP2 genes in non-syndromic FNMTC.

Multi-omics Signatures and Translational Potential to Improve Thyroid Cancer Patient Outcome

“…Functional studies have shown the mutant variant increased tumor colony formation and cell migration consistent with the loss of tumor suppressor effect. The HABP2 G534E variant has also been reported in another cohort in the U.S. [106] but not in the Middle Eastern or UK, or Chinese cohorts [102]. The TTF1 germline mutation has been reported in two families with PTC and coexisting multinodular goiter.…”

“…Known familial tumor syndromes that feature thyroid cancer account for only 5% of all familial non-medullary thyroid cancer (FNMTC). These syndromes include familial adenomatous polyposis (Gardner's syndrome), Cowden syndrome, Werner syndrome, Carney complex, and DICER1 mutation syndrome [102]. Much effort to identify susceptibility genes involved in non-syndromic familial thyroid cancer has resulted in the identification of FOXE1, HABP2, and TITF1.…”

Clinical implications of GWAS variants associated with differentiated thyroid cancer

“…If the genetic background of DTC is strong, linkage analyses should easily uncover predisposing loci in affected families. However, such linkage analyses have identified only a handful of genes; driver mutations existed in single families and they were absent in sporadic DTC [12]. Therefore, it seems that the genetic predisposition to DTC is probably polygenic with low-penetrance genes involved.…”

Syndrome mit breitem Tumorspektrum

“…Die Diagnosestellung erfolgt meist im jungen Erwachsenenalter, selten früher oder nach dem 50. LJ [4,22] Bis zu 60 % der Patienten zeigen insbesondere in Kindheit/Adoleszenz eine Schilddrüsenbeteiligung in Form von unspezifischen zystischen Veränderun-gen (75 %), meist follikulären Adenomen (25 %) und selten (<10 %) papillären oder follikulären Karzinomen [19,21].…”