Germline and somatic SDHx alterations in apparently sporadic differentiated thyroid cancer

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 if SDHx alterations at both germline and somatic levels occur in apparently sporadic breast cancer and differentiated thyroid cancer (DTC), we analyzed SDHx genes in following 4 groups: 1) 48 individuals with sporadic invasive breast adenocarcinoma for germline mutation; 2) 48 (expanded to 241) DTC for germline mutation; 3) 37 pairs DTC tumor-normal tissues for germline and somatic mutation and mRNA expression levels; and 4) 476 TCGA thyroid carcinoma dataset for validation. No germline SDHx variant was found in a pilot series of 48 breast cancer cases. Because germline SDHx variants were found in our pilot of 48 thyroid cancer cases, we expanded to 3 series of DTC comprising a total 754 cases, and found 48 (6%) with germline SDHx variants (p<0.001 compared to 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.

Coexistence of paraganglioma/pheochromocytoma and papillary thyroid carcinoma: a four-case series analysis

“…During the process of revision of the present manuscript, a new publication by Ni et al [10] documented a significant frequency of germline mutations in SDHx genes among patients with differentiated thyroid carcinoma. Actually, the authors observed 48 cases among 754 (6 %) with germline SDHx mutations contrasting with 0/350 controls.…”

“…Papillary histology is the major subtype among SDHx variant carriers with thyroid cancer in Cowden syndrome like cases, in contrast to the over-presentation of follicular histology in PTEN mutation carriers [9,10].…”

Familiar Papillary Thyroid Carcinoma in a Large Brazilian Family Is Not Associated with Succinate Dehydrogenase Defects

“…By analyzing the expression of the SDHx gene in differentiated carcinoma samples, a classic PTC histology was overrepresented among patients with low overall SDHx expression compared with those with other histologic types, especially the follicular variant form of PTC [42]. …”

Succinate Dehydrogenase Complex: An Updated Review

“…About 6% of thyroid cancers have a germline mutation of SDHB or SDHD and a further 5% have somatic SDHC mutations. 30 Consistent loss of either SDHC or SDHD gene expression is associated with earlier disease onset and higher pathologic TNM stage in both papillary and follicular thyroid tumors. 30 Although further studies focusing on the SDH transcript levels and immunohistochemical SDHB protein expression are to be fully explored, early studies point toward papillary histology as the major subtype.…”