Follicular Thyroid Adenoma and Follicular Thyroid Carcinoma—A Common or Distinct Background? Loss of Heterozygosity in Comprehensive Microarray Study
Martyna BorowczykPaula DoboszEwelina Szczepanek‐ParulskaBartłomiej BudnySzymon DębickiDorota FilipowiczElżbieta WrotkowskaMichalina OszywaFrederik A. VerburgMałgorzata Janicka‐JedyńskaKatarzyna ZiemnickaMarek Ruchała
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Pre- and postsurgical differentiation between follicular thyroid adenoma (FTA) and follicular thyroid cancer (FTC) represents a significant diagnostic challenge. Furthermore, it remains unclear whether they share a common or distinct background and what the mechanisms underlying follicular thyroid lesions malignancy are. The study aimed to compare FTA and FTC by the comprehensive microarray and to identify recurrent regions of loss of heterozygosity (LOH). We analyzed formalin-fixed paraffin-embedded (FFPE) samples acquired from 32 Caucasian patients diagnosed with FTA (16) and FTC (16). We used the OncoScan™ microarray assay (Affymetrix, USA), using highly multiplexed molecular inversion probes for single nucleotide polymorphism (SNP). The total number of LOH was higher in FTC compared with FTA (18 vs. 15). The most common LOH present in 21 cases, in both FTA (10 cases) and FTC (11 cases), was 16p12.1, which encompasses many cancer-related genes, such as TP53, and was followed by 3p21.31. The only LOH present exclusively in FTA patients (56% vs. 0%) was 11p11.2-p11.12. The alteration which tended to be detected more often in FTC (6 vs. 1 in FTA) was 12q24.11-q24.13 overlapping FOXN4, MYL2, PTPN11 genes. FTA and FTC may share a common genetic background, even though differentiating rearrangements may also be detected.Keywords:
Follicular thyroid cancer
Tissue microarray
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To highlight the magnitude and distribution of thyroid cancer at the largest cancer center in Tanzania and to correlate patient region of residence with regions of dietary iodine adequacy and deficiency in the country.A retrospective cross-sectional chart review to characterize patients with thyroid cancer and regions of residence.Ocean Road Cancer Institute (ORCI), the largest cancer center in Tanzania.Subjects had histologically confirmed thyroid cancer and no history of cancer treatment. Between January 2006 and April 2016, the cases of 139 consecutive patients with thyroid cancer at ORCI were retrospectively reviewed. Patients were grouped into those from iodine-adequate and iodine-deficient regions, based on the Tanzania demographic and health survey.Patients' median age was 47 years (range, 17-73 years), and the male:female ratio was 1:5. The number of people with thyroid cancer seen at ORCI increased steadily during the study period, with no significant difference between papillary (46%) and follicular (45%) diagnoses. Nonpapillary cancers occurred more frequently among males and patients ≥45 years of age, but these did not reach statistical significance. Seventy-five percent of all thyroid cancers were from areas of iodine deficiency, and this was similar in papillary and follicular cancer subtypes.The incidence of differentiated thyroid cancer is increasing at the largest cancer center in Tanzania, whereby papillary and follicular subtypes were significantly higher in regions with long-standing dietary iodine deficiency.
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Abstract Objectives To analyze the variant‐specific survival benefits and usage patterns of standardized treatment combinations of surgery (S), radioactive iodine ablation (RAI), and thyroid‐stimulating hormone suppression therapy (THST) for high‐risk differentiated thyroid cancer. Study Design Retrospective cohort study. Setting National Cancer Database. Methods The 2004‐2017 National Cancer Database was queried for patients receiving definitive surgery for high‐risk papillary, follicular, or Hurthle cell thyroid cancer. Cox proportional hazards and Kaplan‐Meier analyses assessed for treatment‐associated survival. Results Of 21,076 cases, 18,214 underwent survival analysis with a mean ± SD age of 50.6 ± 17.1 years (71.3% female). When compared with surgery alone, S + RAI was associated with reduced mortality in papillary (hazard ratio [HR], 0.574; P < .001) and follicular (HR, 0.489; P = .004) thyroid cancer. S + RAI + THST was associated with reduced mortality in papillary (HR, 0.514; P < .001), follicular (HR, 0.602; P = .016), and Hurthle cell (HR, 0.504; P = .021) thyroid cancer. In papillary thyroid cancer, S + RAI (91.3%), S + THST (89.2%), and S + RAI + THST (92.7%) were associated with higher 5‐year overall survival rates than surgery (85.4%, all P < .001). Papillary thyroid cancer treatments involving THST were associated with higher 5‐year overall survival rates than corresponding regimens without THST (all P < .001). In follicular thyroid cancer, S + RAI (73.9%) and S + RAI + THST (78.7%) were associated with higher 5‐year overall survival rates than surgery (65.6%, all P < .05). In Hurthle cell thyroid cancer, S + RAI (66.5%) and S + RAI + THST (73.4%) were associated with higher 5‐year overall survival rates than surgery (53.7%, all P < .05). On linear regression, THST usage increased by 77.5% ( R 2 = 0.944, P < .001), while RAI usage declined by 11.3% ( R 2 = 0.320, P = .035). Conclusions High‐risk differentiated thyroid cancer exhibited varying susceptibilities to different treatment combinations depending on histology, with greatest responses to regimens that included RAI. Physician practices have trended toward decreased RAI and increased THST usage.
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Background: Thyroid cancer is the most common endocrine tumor and is increasing in incidence. The aim of this study was to review mouse models of differentiated thyroid cancer and how they elucidate human thyroid cancer biology. Summary: Differentiated thyroid cancer, primarily papillary and follicular, comprises the majority of thyroid cancers. There has been tremendous growth in the cross-talk between basic science and clinical practice for thyroid cancer management. Insight into the framework of genes responsible for differentiated thyroid cancer has been gained through the use of mouse models. Common genetic alterations found in human papillary thyroid cancer such as RET/PTC rearrangements or the BRAFV600E mutation have genetically modified mouse counterparts. These and other preclinical mouse models have validated the importance of the cyclic adenosine monophosphate (cAMP)/protein kinase A and mitogen-activated protein kinase (MAPK) signaling pathways in papillary thyroid cancer (PTC). RAS mutations have a role in both papillary and follicular thyroid cancer development. Mice with overactivation of the phosphatidylinol-3-kinase (PI3K)–AKT and/or thyrotropin-regulated signaling pathways have been found to develop follicular thyroid cancer. Additional mouse models of thyroid cancer that utilize inducible expression systems are in development or are being characterized and will better reflect the majority of human thyroid cancers which are non-hereditary. Advances in in vivo imaging of mice allow for earlier detection of metastasis and the ability to follow tumor growth or regression which may be used in evaluation of pharmaceutical agents. Conclusions: Mouse models have expanded our understanding of the altered signaling pathways that contribute to thyroid cancer tumorigenesis and provide a powerful tool to develop novel diagnostic approaches and therapies.
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Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy. RET/PTC rearrangement is the most common genetic modification identified in this category of cancer, increasing proliferation and dedifferentiation by the activation of the RET/PTC-RAS-BRAF-MAPK-ERK signaling pathway. Recently, let-7 miRNA was found to reduce RAS levels, acting as a tumor suppressor gene. Circulating miRNA profiles of the let-7 family may be used as novel noninvasive diagnostic, prognostic, treatment and surveillance markers for PTC.
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Abstract Thyroid cancer is the most common endocrine malignancy, and incidence has been steadily increasing, suggesting occurrence will exceed that of colon cancer by 2030. Papillary and follicular thyroid cancer subtypes are most common, which are activated by BRAF and HRAS mutations, respectively. Interestingly, papillary and follicular thyroid cancers are associated with different pathologies and metastases. Currently, both papillary and follicular thyroid cancers are treated by surgical removal of the thyroid, followed by radioactive iodine treatment to eliminate any remaining tumor cells. Unfortunately, for individuals with progressive thyroid cancer, these treatment options are not effective, highlighting a need for increased investigation into mechanisms of drug sensitivity. In this study, we sought to evaluate mechanisms of differential drug sensitivity through RNA-seq analysis of cell lines derived from mouse models of papillary and follicular thyroid cancer. Additionally, we evaluated the effects of MAPK, AKT, and mTOR inhibitors on murine papillary and follicular thyroid cancer cell proliferation. To accurately assess drug efficacy, we calculated GR50 concentrations for each inhibitor in six papillary and follicular thyroid cancer cell lines. We discovered that papillary and follicular thyroid cancer cell lines responded differently to MAPK and AKT inhibitors, suggesting that treatment approaches should be tailored to subtype despite having mutations in the same signaling pathway. Citation Format: Brianna LeBoeuf, Braxton Anderson, Margaret Young, Aime Franco, Laura MacDonald. Evaluating the effectiveness of MAPK, AKT, and mTOR inhibitors in reducing proliferation in cellular models of papillary and follicular thyroid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2887.
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Thyroid cancer (TC) includes tumors of follicular cells; it ranges from well differentiated TC (WDTC) with generally favorable prognosis to clinically aggressive poorly differentiated TC (PDTC) and undifferentiated TC (UTC). Papillary thyroid cancer (PTC) is a WDTC and the most common type of thyroid cancer that comprises almost 70-80% of all TC. PTC can present as a solid, cystic, or uneven mass that originates from normal thyroid tissue. Prognosis of PTC is excellent, with an overall 10-year survival rate >90%. However, more than 30% of patients with PTC advance to recurrence or metastasis despite anti-cancer therapy; consequently, systemic therapy is limited, which necessitates expansion of improved clinical approaches. We strived to elucidate genetic distinctions due to patient-derived anti-cancer drug-sensitive or -resistant PTC, which can support in progress novel therapies. Patients with histologically proven PTC were evaluated. PTC cells were gained from drug-sensitive and -resistant patients and were compared using mRNA-Seq. We aimed to assess the in vitro and in vivo synergistic anti-cancer effects of a novel combination therapy in patient-derived refractory PTC. This combination therapy acts synergistically to promote tumor suppression compared with either agent alone. Therefore, genetically altered combination therapy might be a novel therapeutic approach for refractory PTC.
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