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Impact of Age-Related Genetic Differences on the Therapeutic Outcome of Papillary Thyroid Cancer.

ABSTRACT: The incidence of papillary thyroid carcinoma (PTC) has been increasing worldwide. PTC is the most common type of differentiated thyroid cancer and usually shows good prognosis. However, some PTC is driven to advanced stage by epithelial-mesenchymal transition (EMT)-mediated drug resistance, which is particularly noticeable in pediatric patients. There are limited options for systemic treatment, necessitating development of new clinical approaches. Here, we aimed to clarify genetic differences due to age of patients with PTC, and thereby aid in developing novel therapeutics. Patients with biochemically and histologically confirmed PTC were included in this study. PTC cells were acquired from young and older patients showing drug resistance, and were compared via microarray analysis. Cellular proliferation and other properties were determined after treatments with lenvatinib and sorafenib. In vivo, tumor volume and other properties were examined using a mouse xenograft model. Lenvatinib-treated group showed obvious suppression of markers of anti-apoptosis, EMT, and the FGFR signaling pathway, compared with control and Sorafenib-treated group. In the xenograft models, lenvatinib treatment induced significant tumor shrinkage and blocked the proto-oncogene Bcl-2 (B cell lymphoma/leukemia gene-2) and FGFR signaling pathway, along with reduced levels of EMT markers, compared with control and Sorafenib-treated group. Our findings clarify the age-dependent characteristics of pediatric PTC, giving insights into the relationship between young age and poor prognosis. Furthermore, it provides a basis for developing novel therapeutics tailored to the age at diagnosis.

SUBMITTER: Kim SM

PROVIDER: S-EPMC7072359 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Impact of Age-Related Genetic Differences on the Therapeutic Outcome of Papillary Thyroid Cancer.

Kim Seok-Mo SM Kim Soo Young SY Park Cheong Soo CS Chang Hang-Seok HS Park Ki Cheong KC

Cancers 20200214 2

The incidence of papillary thyroid carcinoma (PTC) has been increasing worldwide. PTC is the most common type of differentiated thyroid cancer and usually shows good prognosis. However, some PTC is driven to advanced stage by epithelial-mesenchymal transition (EMT)-mediated drug resistance, which is particularly noticeable in pediatric patients. There are limited options for systemic treatment, necessitating development of new clinical approaches. Here, we aimed to clarify genetic differences du ...[more]

PMID: 32075109

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Project description:ContextThyroid cancer predominately affects women, carries a worse prognosis in older age, and may have higher mortality in men. Superimposed on these observations is the fact that most women have attained menopause by age 55 yr.ObjectiveThe objective of the study was to determine whether men contribute disproportionately to papillary thyroid cancer (PTC) mortality or whether menopause affects PTC prognosis.DesignGender-specific mortality was normalized using age-matched subjects from the U.S. population. Multivariate Cox proportional hazard regression models incorporating gender, age, and National Thyroid Cancer Treatment Cooperative Study Group stage were used to model disease-specific survival (DSS).Participants and settingPatients were followed in a prospective registry.Main outcome measureThe relationships between gender, age, and PTC outcomes were analyzed.ResultsThe unadjusted hazard ratio (HR) for DSS for women was 0.40 [confidence interval (CI) 0.24-0.65]. This female advantage diminished when DSS was adjusted for age at diagnosis and stage with a HR encompassing unity (HR 0.72, CI 0.44-1.19). Additional multivariate models of DSS considering gender, disease stage, and various age groupings showed that the DSS for women diagnosed at under 55 yr was improved over men (HR 0.33, CI 0.13-0.81). However, the HR for DSS increased to become similar to men for women diagnosed at 55-69 yr (HR 1.01, CI 0.42-2.37) and at 70 yr or greater (HR 1.17, CI 0.48-2.85).ConclusionsAlthough the overall outcome of women with PTC is similar to men, subgroup analysis showed that this composite outcome is composed of two periods with different outcomes. The first period is a period with better outcomes for women than men when the diagnosis occurs at younger than 55 yr; the second is a period with similar outcomes for both women and men diagnosed at ages greater than 55 yr. These data raise the question of whether an older age cutoff would improve current staging systems. We hypothesize that older age modifies the effect of gender on outcomes due to menopause-associated hormonal alterations.

Project description:ImportanceFear is commonly experienced by individuals newly diagnosed with papillary thyroid cancer (PTC).ObjectiveTo explore the association between gender and fears of low-risk PTC disease progression, as well as its potential surgical treatment.Design, setting, and participantsThis single-center prospective cohort study was conducted at a tertiary care referral hospital in Toronto, Canada, and enrolled patients with untreated small low risk PTC (<2 cm in maximal diameter) that was confined to the thyroid. All patients had a surgical consultation. Study participants were enrolled between May 2016 and February 2021. Data analysis was performed from December 16, 2022, to May 8, 2023.ExposuresGender was self-reported by patients with low-risk PTC who were offered the choice of thyroidectomy or active surveillance. Baseline data were collected prior to the patient deciding on disease management.Main outcomes and measuresBaseline patient questionnaires included the Fear of Progression-Short Form and Surgical Fear (referring to thyroidectomy) questionnaires. The fears of women and men were compared after adjustment for age. Decision-related variables, including Decision Self-Efficacy, and the ultimate treatment decisions were also compared between genders.ResultsThe study included 153 women (mean [SD] age, 50.7 [15.0] years) and 47 men (mean [SD] age, 56.3 [13.8] years). There were no significant differences in primary tumor size, marital status, education, parental status, or employment status between the women and men. After adjustment for age, there was no significant difference observed in the level of fear of disease progression between men and women. However, women reported greater surgical fear compared with men. There was no meaningful difference observed between women and men with respect to decision self-efficacy or the ultimate treatment choice.Conclusions and relevanceIn this cohort study of patients with low-risk PTC, women reported a higher level of surgical fear but not fear of the disease compared with men (after adjustment for age). Women and men were similarly confident and satisfied with their disease management choice. Furthermore, the decisions of women and men were generally not significantly different. The context of gender may contribute to the emotional experience of being diagnosed with thyroid cancer and its treatment perception.

Project description:BackgroundAlthough the most thyroid carcinoma patients have good prognosis, around 20% of papillary thyroid carcinoma (PTC) patients have a high rate of metastasis and recurrence after routine treatment, which causes high lethality with these patients. Tumor proliferation, metastasis, and invasion are important predictors of PTC invasiveness and are key factors in cancer-related death. Angiopoietin-like 2 (ANGPTL2), a secreted protein which belongs to the angiopoietin (ANGPTL) family, was reported to be involved in the regulation of several different type of cancer cell proliferation and metastasis. However, whether ANGPTL2 plays a role in the progression of PTC, particularly in metastasis and recurrence of PTC, remains unclear. Hence, the purpose of this study was to evaluate the level of ANGPTL2 in PTC and normal thyroid, as well as para-cancerous tissue. Furthermore, the impact of ANGPTL2 on PTC cell proliferation, metastasis, recurrence and invasion was assessed to investigate the possibility whether ANGPTL2 may become a novel target for PTC therapy and cancer prognosis.Materials and methodsThe level of ANGPTL2 in PTC and para-cancerous tissue was assessed by immunohistochemistry. The biological effect of ANGPTL2 on thyroid cancer cell proliferation and metastasis was investigated by the Cell Counting Kit-8 (CCK8) assay, cell scratch test, and transwell assay. Correlations of ANGPTL2 expression levels with proliferation, migration, and metastasis of thyroid cancer were assessed with the TCGA data set and analyzed by gene set enrichment analysis. Receiver operating characteristic analysis was used to evaluate the utility of ANGPTL2 as a biomarker for prediction of thyroid cancer. Survival analysis was performed using the thyroid cancer database in K-M Plotter to detect correlations between survival time and ANGPTL2 levels.ResultsCurrent study revealed that: (1) ANGPTL2 was highly expressed in thyroid cancer in comparison with adjacent normal thyroid tissue; (2) ANGPTL2 expression was increased with thyroid tumor progression; (3) ANGPTL2 increased proliferation of thyroid cancer cells; (4) ANGPTL2 promoted migration and invasion of thyroid cancer cells; (5) high level of ANGPTL2 in thyroid cancer patients were significantly associated with a poor prognosis. The patients showed a higher metastasis and recurrence rate.ConclusionANGPTL2 promoted and enhanced proliferation, metastasis, and invasion of thyroid cancer cells. ANGPTL2 may be considered as a potential biomarker for diagnosis and prognosis of thyroid cancer patients. Further evaluation needs to be done to analyze the possibility of taking ANGPTL2 as a prognostic marker and therapeutic target for papillary thyroid cancer.

Dataset Information

Impact of Age-Related Genetic Differences on the Therapeutic Outcome of Papillary Thyroid Cancer.

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Impact of Age-Related Genetic Differences on the Therapeutic Outcome of Papillary Thyroid Cancer.

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