TY - JOUR
T1 - Identification of Rare Variants Predisposing to Thyroid Cancer
AU - Wang, Yanqiang
AU - Liyanarachchi, Sandya
AU - Miller, Katherine E.
AU - Nieminen, Taina T.
AU - Comiskey, Daniel F.
AU - Li, Wei
AU - Brock, Pamela
AU - Symer, David E.
AU - Akagi, Keiko
AU - Delap, Katherine E.
AU - He, Huiling
AU - Koboldt, Daniel C.
AU - De La Chapelle, Albert
N1 - Publisher Copyright:
© Copyright 2019, Mary Ann Liebert, Inc., publishers 2019.
PY - 2019/7
Y1 - 2019/7
N2 - 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.
AB - 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.
KW - candidate genes
KW - familial non-medullary thyroid carcinoma
KW - germline predisposition variants
KW - rare variants
KW - whole-genome sequencing
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U2 - 10.1089/thy.2018.0736
DO - 10.1089/thy.2018.0736
M3 - Article
C2 - 30957677
AN - SCOPUS:85069233268
SN - 1050-7256
VL - 29
SP - 946
EP - 955
JO - Thyroid
JF - Thyroid
IS - 7
ER -