Identification of Rare Variants Predisposing to Thyroid Cancer

Yanqiang Wang, Sandya Liyanarachchi, Katherine E. Miller, Taina T. Nieminen, Daniel F. Comiskey, Wei Li, Pamela Brock, David Eric Symer, Keiko Akagi, Katherine E. Delap, Huiling He, Daniel C. Koboldt, Albert De La Chapelle

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)946-955
Number of pages10
JournalThyroid
Volume29
Issue number7
DOIs
StatePublished - Jul 1 2019

Fingerprint

Thyroid Neoplasms
Neoplasm Genes
Genome
Penetrance
Genetic Association Studies
Pedigree
Genetic Predisposition to Disease
Computer Simulation
Genes

Keywords

  • candidate genes
  • familial non-medullary thyroid carcinoma
  • germline predisposition variants
  • rare variants
  • whole-genome sequencing

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Wang, Y., Liyanarachchi, S., Miller, K. E., Nieminen, T. T., Comiskey, D. F., Li, W., ... De La Chapelle, A. (2019). Identification of Rare Variants Predisposing to Thyroid Cancer. Thyroid, 29(7), 946-955. https://doi.org/10.1089/thy.2018.0736

Identification of Rare Variants Predisposing to Thyroid Cancer. / Wang, Yanqiang; Liyanarachchi, Sandya; Miller, Katherine E.; Nieminen, Taina T.; Comiskey, Daniel F.; Li, Wei; Brock, Pamela; Symer, David Eric; Akagi, Keiko; Delap, Katherine E.; He, Huiling; Koboldt, Daniel C.; De La Chapelle, Albert.

In: Thyroid, Vol. 29, No. 7, 01.07.2019, p. 946-955.

Research output: Contribution to journalArticle

Wang, Y, Liyanarachchi, S, Miller, KE, Nieminen, TT, Comiskey, DF, Li, W, Brock, P, Symer, DE, Akagi, K, Delap, KE, He, H, Koboldt, DC & De La Chapelle, A 2019, 'Identification of Rare Variants Predisposing to Thyroid Cancer', Thyroid, vol. 29, no. 7, pp. 946-955. https://doi.org/10.1089/thy.2018.0736
Wang Y, Liyanarachchi S, Miller KE, Nieminen TT, Comiskey DF, Li W et al. Identification of Rare Variants Predisposing to Thyroid Cancer. Thyroid. 2019 Jul 1;29(7):946-955. https://doi.org/10.1089/thy.2018.0736
Wang, Yanqiang ; Liyanarachchi, Sandya ; Miller, Katherine E. ; Nieminen, Taina T. ; Comiskey, Daniel F. ; Li, Wei ; Brock, Pamela ; Symer, David Eric ; Akagi, Keiko ; Delap, Katherine E. ; He, Huiling ; Koboldt, Daniel C. ; De La Chapelle, Albert. / Identification of Rare Variants Predisposing to Thyroid Cancer. In: Thyroid. 2019 ; Vol. 29, No. 7. pp. 946-955.
@article{beed733c03e24dd1a970563485ab6f18,
title = "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.",
keywords = "candidate genes, familial non-medullary thyroid carcinoma, germline predisposition variants, rare variants, whole-genome sequencing",
author = "Yanqiang Wang and Sandya Liyanarachchi and Miller, {Katherine E.} and Nieminen, {Taina T.} and Comiskey, {Daniel F.} and Wei Li and Pamela Brock and Symer, {David Eric} and Keiko Akagi and Delap, {Katherine E.} and Huiling He and Koboldt, {Daniel C.} and {De La Chapelle}, Albert",
year = "2019",
month = "7",
day = "1",
doi = "10.1089/thy.2018.0736",
language = "English (US)",
volume = "29",
pages = "946--955",
journal = "Thyroid",
issn = "1050-7256",
publisher = "Mary Ann Liebert Inc.",
number = "7",

}

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 Eric

AU - Akagi, Keiko

AU - Delap, Katherine E.

AU - He, Huiling

AU - Koboldt, Daniel C.

AU - De La Chapelle, Albert

PY - 2019/7/1

Y1 - 2019/7/1

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

UR - http://www.scopus.com/inward/record.url?scp=85069233268&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85069233268&partnerID=8YFLogxK

U2 - 10.1089/thy.2018.0736

DO - 10.1089/thy.2018.0736

M3 - Article

C2 - 30957677

AN - SCOPUS:85069233268

VL - 29

SP - 946

EP - 955

JO - Thyroid

JF - Thyroid

SN - 1050-7256

IS - 7

ER -