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Title: Germline and somatic SDHx alterations in apparently sporadic differentiated thyroid cancer
Authors: Ni, Y
Seballos, S
Ganapathi, S
Gurin, D
Fletcher, B
Ngeow, J 
Nagy, R
Kloos, R.T
Ringel, M.D
LaFramboise, T
Eng, C
Keywords: protein
SDHx protein
unclassified drug
membrane protein
SDHB protein, human
SDHC protein, human
SDHD protein, human
succinate dehydrogenase
breast adenocarcinoma
cancer staging
chromosome 1
chromosome duplication
comparative study
controlled study
copy number variation
differentiated thyroid cancer
gene expression
gene loss
genetic association
genetic variability
germline mutation
invasive carcinoma
major clinical study
middle aged
sdhx gene
somatic mutation
thyroid carcinoma
thyroid follicular carcinoma
breast tumor
Paget nipple disease
thyroid tumor
very elderly
Adenocarcinoma, Follicular
Aged, 80 and over
Breast Neoplasms
Carcinoma, Ductal, Breast
Genetic Variation
Membrane Proteins
Middle Aged
Succinate Dehydrogenase
Thyroid Neoplasms
Issue Date: 2015
Publisher: BioScientifica Ltd.
Citation: Ni, Y, Seballos, S, Ganapathi, S, Gurin, D, Fletcher, B, Ngeow, J, Nagy, R, Kloos, R.T, Ringel, M.D, LaFramboise, T, Eng, C (2015). Germline and somatic SDHx alterations in apparently sporadic differentiated thyroid cancer. Endocrine-Related Cancer 22 (2) : 121-130. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: Along with breast and endometrial cancers, thyroid cancer is a major component cancer in Cowden syndrome (CS). Germline variants in SDHB/C/D (SDHx) genes account for subsets of CS/CS-like cases, conferring a higher risk of breast and thyroid cancers over those with only germline PTEN mutations. To investigate whether SDHx alterations at both germline and somatic levels occur in apparently sporadic breast cancer and differentiated thyroid cancer (DTC), we analyzed SDHx genes in the following four groups: i) 48 individuals with sporadic invasive breast adenocarcinoma for germline mutation; ii) 48 (expanded to 241) DTC for germline mutation; iii) 37 pairs DTC tumor-normal tissues for germline and somatic mutation and mRNA expression levels; and iv) data from 476 patients in the Cancer Genome Atlas thyroid carcinoma dataset for validation. No germline SDHx variant was found in a pilot series of 48 breast cancer cases. As germline SDHx variants were found in our pilot of 48 thyroid cancer cases, we expanded to three series of DTC comprising a total 754 cases, and found 48 (6%) with germline SDHx variants (P<0.001 compared with 0/350 controls). In 513 tumors, we found 27 (5%) with large somatic duplications within chromosome 1 encompassing SDHC. Both papillary and follicular thyroid tumors showed consistent loss of SDHC/D gene expression (P<0.001), which is associated with earlier disease onset and higher pathological-TNM stage. Therefore, we conclude that both germline and somatic SDHx mutations/variants occur in sporadic DTC but are very rare in sporadic breast cancer, and overall loss of SDHx gene expression is a signature of DTC. © 2015 The authors.
Source Title: Endocrine-Related Cancer
ISSN: 1351-0088
DOI: 10.1530/ERC-14-0537
Rights: Attribution 4.0 International
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