The thyroid is the most common site of endocrine cancer. One type of thyroid cancer, non-medullary thyroid cancer (NMTC), develops from follicular cells and represents approximately 90% of all thyroid cancers. Approximately 5%–15% of NMTC cases are thought to be of familial origin (FNMTC), which is defined as the occurrence of the disease in three or more first-degree relatives of the patient. It is often divided into two groups: Syndrome-associated and non-syndromic. The associated syndromes include Cowden syndrome, familial adenomatous polyposis, Gardner syndrome, Carney complex and Werner syndrome. The hereditary factors contributing to the unfavorable course of FNMTC remain poorly understood; therefore, considerable effort is being expended to identify contributing loci. Research carried out to date identifies fourteen genes (DICER1, FOXE1, PTCSC2, MYH9, SRGAP1, HABP2, BRCA1, CHEK2, ATM, RASAL1, SRRM2, XRCC1, TITF-1/NKX2.1, PTCSC3) associated with vulnerability to FNMTC that are not related to hereditary syndromes. In this review, we summarize FNMTC studies to date, and provide information on genes involved in the development of non-syndromic familial non-medullary thyroid cancers, and the significance of mutations in these genes as risk factors. Moreover, we discuss whether the genetic polymorphism rs966423 in DIRC3 has any potential as a prognostic factor of papillary thyroid cancer.

Medullary thyroid cancer (MTC) is a rare malignancy, and the treatment of metastatic MTC is challenging. In previous work, immune profiling (RNA-Seq) of MTC identified CD276 as a potential target for immunotherapy. CD276 expression was 3-fold higher in MTC cells than in normal tissues. Paraffin blocks from patients with MTC were analyzed by immunohistochemistry to confirm the results of RNA-Seq. Serial sections were incubated with anti-CD276 antibody, and scored according to staining intensity and the percentage of immunoreactive cells. The results showed that CD276 expression was higher in MTC tissues than in controls. A lower percentage of immunoreactive cells correlated with the absence of lateral node metastasis, lower levels of calcitonin after surgery, no additional treatments, and remission. There were statistically significant associations of intensity of immunostaining and percentage of CD276 immunoreactive cells with clinical factors and the course of the disease. These results suggest that targeting this immune checkpoint molecule CD276 could be a promising strategy for the treatment of MTC.

Medullary thyroid cancer (MTC) is a rare malignancy that arises from calcitonin-producing C-cells. Curative treatment for patients with metastatic MTC is challenging. Identifying the mechanisms by which cancer cells inhibit the activity of immune cells provides an opportunity to develop new therapies that restore anticancer activity. Little is known about the immunological phenomena underlying MTC. Here, we examined the expression profile of 395 genes associated with MTC. The study included 51 patients diagnosed with MTC at a single center. Bioinformatical analysis revealed that CD276 expression in MTC cells was at least three-fold higher than that in normal tissue. The expression of CD276 showed a weak but statistically significant positive correlation with tumor diameter, but we did not find a significant association between CD276 expression and other histopathological clinical factors, or the response to initial therapy. A search of published data identified the monoclonal antibody (inhibitor) enoblituzumab as a potential drug for patients diagnosed with MTC overexpressing CD276.

Succinate dehydrogenase (SDH)-deficient renal cancer is a rare renal cancer subtype recently accepted by the World Health Organization as a unique subtype of renal cell carcinoma (RCC). Here we report a case of 17-year-old man. The detailed evaluation indicated occurrence of the SDHB-deficient RCC. The genetic testing revealed no germline mutation in SDH genes. Immunohistochemistry showed SDHB deficiency, overexpression of pyruvate kinase M2 and dramatic downregulation of fructose-1,6-bisphosphatase metabolic enzymes, and unaltered levels of phosphorylated AMP-activated protein kinase and mammalian target of rapamycin. Strong upregulation of INI1 and BRG1 and overexpression of BAF180, subunits of SWI/SNF ATP-dependent chromatin remodeling complex, were also found. The identified tumor pathologically did not resemble clear cell renal cell carcinoma (ccRCC), but some metabolic alterations are common for both cancer types. Thus, we postulate that the phenotypical differences between ccRCC and SDHB-deficient RCC may be related to distinct molecular and metabolic alterations. Implications for Practice Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) is a rare renal tumor occurring even in young patients. Until now, in all described and genetically tested cases, mutations and deletions in SDH genes have been found. This article describes SDHB-deficient RCC without any germline mutations in SDH genes. Therefore, genetic analysis for germline mutations in SDH genes in SDH-deficient RCC, especially in young individuals, should be strongly recommended, although as of now it is not obligatory. This knowledge will allow improvement of patient monitoring including both disease recurrence and new cancer appearance.

Thyroid cancer (TC) is the most common cancer of the endocrine system. Most new diagnoses are of low-grade papillary thyroid cancer (PTC), suggesting that PTC may be over-diagnosed. However, the incidence of advanced-stage PTC has increased in recent years. It is therefore very important to identify prognostic factors for advanced PTC. Somatic mutation of the BRAF gene at V600E, or the coexistence of the BRAF V600E mutation and mutations in the TERT promoter are associated with more aggressive disease. It would also be valuable to identify genetic risk factors affecting PTC prognosis. We therefore evaluated the impact of the rs966423 polymorphism in the DIRC3 gene, including its relationship with unfavorable histopathological and clinical features and mortality, in differentiated thyroid cancer (DTC). The study included 1466 patients diagnosed with DTC from one center. There was no significant association between the DIRC3 genotype at rs966423 (CC, CT, or TT) and any histopathological or clinic factor examined, including initial response to therapy, response at follow-up, or overall mortality, in DTC patients.

Background: Multiple endocrine neoplasia type 2A (MEN2A) is a rare, hereditary syndrome resulting from a germline mutation in the RET proto-oncogene and characterized primarily by medullary thyroid cancer (MTC), pheochromocytoma (PHEO), and hyperparathyroidism. Types of RET mutation have been associated with age at onset, clinical outcomes of MTC, and the penetrance of other components. Patients classified as ‘high-risk’ by the American Thyroid Association (ATA), based on the aggressiveness of MTC and the penetrance of other components, are recommended to undergo early prophylactic thyroidectomy at age ≤ 5 years and to be screened for PHEO at age ≥ 11 years. Patients with RET codon C634R mutations have been classified as high-risk. Case presentation: The present study describes a 71-year-old woman newly diagnosed with hereditary MTC related to a RET C634R germline mutation. Her basal serum calcitonin level was high, but there was no evidence of distant metastases. Surgery revealed bilateral MTC with two metastatic lymph nodes. Because microscopic resection was incomplete and extranodal extension was observed, the patient underwent adjuvant external beam radiotherapy. Response to therapy was excellent. Follow-up after 1.5 years showed no evidence of disease or other manifestations of MEN2A. Conclusion: Despite RET C634R carriers being classified as high-risk by the ATA, this patient did not present with either distant MTC or PHEO until her seventies. To our knowledge, only one other patient has shown a similar late identification of a RET C634R mutation, but MTC could not be diagnosed because the patient was lost to follow-up. Further research is required to develop optimal protocols that could allow patients requiring prophylactic thyroidectomy to be differentiated from those who can be monitored closely without early surgery.