Inherited Thyroid Tumors With Oncocytic Change

Abstract

Familial non-medullary thyroid carcinoma (FNMTC) corresponds to 5-10% of all follicular cell-derived carcinoma (FCDTC). Oncocytic thyroid tumors have an increased incidence in the familial context in comparison with sporadic FCDTC, encompassing benign and malignant tumors in the same family presenting with some extent of cell oxyphilia. This has triggered the interest of our and other groups to clarify the oncocytic change, looking for genetic markers that could explain the emergence of this phenotype in thyroid benign and malignant lesions, focusing on familial aggregation. Despite some advances regarding the identification of the gene associated with retinoic and interferon-induced mortality 19 (GRIM-19), as one of the key candidate genes affected in the “Tumor with Cell Oxyphilia” (TCO) locus, most of the mutations follow a pattern of “private mutations”, almost exclusive to one family. Moreover, no causative genetic alterations were identified so far in most families. The incomplete penetrance of the disease, the diverse benign and malignant phenotypes in the affected familial members and the variable syndromic associations create an additional layer of complexity for studying the genetic alterations in oncocytic tumors. In the present review, we summarized the available evidence supporting genomic-based mechanisms for the oncocytic change, particularly in the context of FNMTC. We have also addressed the challenges and gaps in the aforementioned mechanisms, as well as molecular clues that can explain, at least partially, the phenotype of oncocytic tumors and the respective clinico-pathological behavior. Finally, we pointed to areas of further investigation in the field of oncocytic (F)NMTC with translational potential in terms of therapy.

Molecular Alterations and Comprehensive Clinical Management of Oncocytic Thyroid Carcinoma

“…Evidence of genotype or phenotype correlation between chromosomal alterations and tumor aggressiveness has been found, with diploid tumors having a better outcome than those with haploidy or polysomy with massive loss of heterozygosity (LOH). Heterozygosity can be maintained in chromosomes 7, 5, 12, and 20; in particular, chromosome 7 evades LOH, suggesting that the normal gene dosage of this chromosome (containing EGFR , BRAF , and MET genes) may be important for tumor progression . Consistently, tumors that display massive LOH and chromosome 7 duplication have the worst outcome .…”

“…mtDNA variations include truncating variants, missense variations, and large deletions, and can affect almost all cellular mtDNAs, with a major incidence in gene-encoding proteins of the mitochondrial respiratory complex I . These variations have been associated with partial or complete loss of function of the proteins forming the mitochondrial respiratory complex, with altered energy production by the Krebs cycle and the overproduction of reactive oxygen species.…”

“…mtDNA variations include truncating variants, missense variations, and large deletions, and can affect almost all cellular mtDNAs, with a major incidence in gene-encoding proteins of the mitochondrial respiratory complex I. 2,8,19 These variations have been associated with partial or complete loss of function of the proteins forming the mitochondrial respiratory complex, with altered energy production by the Krebs cycle and the overproduction of reactive oxygen species. It has been hypothesized (ie, the compensatory theory) that the tumor cells try to compensate for this reduced or absent activity by increasing the number of mitochondria, as typically observed in OTC, which in turn is responsible for the oncocytic staining avidity.…”

Susceptibility Genes and Chromosomal Regions Associated With Non-Syndromic Familial Non-Medullary Thyroid Carcinoma: Some Pathogenetic and Diagnostic Keys

“…NADH:ubiquinone oxidoreductase subunit A13 ( NDUFA13 ) gene, also known as GRIM19 , is located at 19p13.11. NDUFA13 as well as the TIMM44 and MYO1F genes have been associated to the oncocytic phenotype and the TCO (thyroid tumors with cell oxyphilia) locus at 19q13.2 (reviewed by Correia M et al ( 49 ). NDUFA13 encodes a protein that exerts a dual function: (i) it is essential for assembly and function of the complex I of the mitochondrial respiratory chain, and (ii) it induces apoptosis in a number of cell lines upon treatment with interferon-beta and retinoic acid ( 94 ).…”

“…$ Thyroid tumor with cell oxyphilia TCO MNG, PTC (including the oncocytic variant), HCC, FTA, oncocytic nodules(48,49) MNG, multinodular goiter; PTC, papillary thyroid carcinoma; FTC, follicular thyroid carcinoma; HCC, oncocytic (Hürthle cell) carcinoma; FTA, follicular thyroid adenoma.…”