Identification of Rare Variants Predisposing to Thyroid Cancer

Abstract

Background: Familial non-medullary thyroid cancer (NMTC) accounts for a relatively small proportion of thyroid cancer cases, but it displays strong genetic predisposition. So far, only a few NMTC susceptible genes and low-penetrance variants contributing to NMTC have been described. This study aimed to identify rare germline variants that may predispose individuals to NMTC by sequencing a cohort of 17 NMTC families. Methods: Whole-genome sequencing and genome-wide linkage analysis were performed in 17 NMTC families. MendelScan and BasePlayer were applied to screen germline variants followed by customized filtering. The remaining candidate variants were subsequently validated by Sanger sequencing. A panel of 277 known cancer predisposition genes was also screened in these families. Results: A total of 41 rare coding candidate variants in 40 genes identified by whole-genome sequencing are reported, including 24 missense, five frameshift, five splice change, and seven nonsense variants. Sanger sequencing confirmed all 41 rare variants and proved their co-segregation with NMTC in the extended pedigrees. In silico functional analysis of the candidate genes using Ingenuity Pathway Analysis showed that cancer was the top category of ''Diseases and Disorders.'' Additionally, a targeted search displayed six variants in known cancer predisposition genes, including one frameshift variant and five missense variants. Conclusions: The data identify rare germline variants that may play important roles in NMTC predisposition. It is proposed that in future research including functional characterization, these variants and genes be considered primary candidates for thyroid cancer predisposition.

Inherited Follicular Epithelial-Derived Thyroid Carcinomas: From Molecular Biology to Histological Correlates

“…CHEK2 variants may be associated with NSFNMTC [ 70 , 72 , 103 ]. CHEK2 (22q12.1) gene mutations may contribute to tumorigenesis through the haploinsufficiency mechanism due to low CHEK2 protein levels [ 70 ].…”

Genetic Mutations and Variants in the Susceptibility of Familial Non-Medullary Thyroid Cancer

“…There are even controversial observations for the same polymorphism [ 26 , 27 , 59 , 60 , 63 ]. Despite these controversies, consistent ATM variants ( ATM p.P1054R-rs1800057- and rs149711770) were recently described in families with FNMTC and other cancers (as kidney, lung, stomach, and prostate) [ 11 ]. Nonetheless, in A-T Syndrome´s patient, the only screening recommended is for breast cancer [ 15 ].…”

“…In a large series including 17 families with isolated FNMTC and FNMTC associated with other malignancies, 41 rare candidate variants were identified in TDRD6, IDE, TINF2, RNF213, AGK, NHLH1, TMCC1, ALB, THBS4, C5orf15, KLH3, FGFR4, SMARCD3, GPR107, NSMF, SVIL, EIF3, RNF169, NFRB, CIS, CDH11, EDC4, FOXA3, CDS2, NAPB, SALL4, ATG14, UNC79, LZTR1, ATP13A2, CTDSP1, MAPKAPK3, AARS, KDSR, ZNF302, ZNF17, ITGAD, FGD6, PDPR , and EFCAB8 genes. Cancer susceptibility genes ( CHEK2, PRF1, ATM, AKAP13, SLC26A11 ) were also observed [ 11 ]. As described before, the authors further correlated the presence of TINF2 (a shelterin gene) to families with PTC and melanoma.…”

“…The initial FNMTC studies were performed by linkage analysis and described some specific loci, although they did not identify a precise gene associated with FMNTC [ 5 , 6 , 7 , 8 , 9 , 10 ]. Furthermore, despite the efforts of many groups in investigating FNMTC using Sanger sequencing, no conclusive information was found, suggesting genetic heterogeneity, multigenic inheritance, and multifactorial inheritance [ 11 ]. However, a new genomic perspective emerged with the application of Next Generation Sequencing (NGS) technology that covered the entire genome.…”

A novel essential splice site variant in SPTB in a large hereditary spherocytosis family

“…There are eight individuals with both NMTC and HS. This family was included in our previous genomic analysis of NMTC families (Wang et al, 2019). As is suggested by the data in the pedigree, HS and NMTC are genetically different and presumably unrelated (Wang et al, 2019).…”