Richard Armos, Bence Bojtor, Janos Podani, Ildiko Illyes, Bernadett Balla, Zsuzsanna Putz, Andras Kiss, Andrea Kohanka, Erika Toth, Istvan Takacs, Janos P Kosa, Peter Lakatos
{"title":"匈牙利甲状腺乳头状癌常见融合突变的描述性分析","authors":"Richard Armos, Bence Bojtor, Janos Podani, Ildiko Illyes, Bernadett Balla, Zsuzsanna Putz, Andras Kiss, Andrea Kohanka, Erika Toth, Istvan Takacs, Janos P Kosa, Peter Lakatos","doi":"10.3390/ijms251910787","DOIUrl":null,"url":null,"abstract":"<p><p>Thyroid cancer is the most common type of endocrine malignancy. Papillary thyroid carcinoma (PTC) is its predominant subtype, which is responsible for the vast majority of cases. It is true that PTC is a malignant tumor with a very good prognosis due to effective primary therapeutic approaches such as thyroidectomy and radioiodine (RAI) therapy. However, we are often required to indicate second-line treatments to eradicate the tumor properly. In these scenarios, molecular therapies are promising alternatives, especially if specifically targetable mutations are present. Many of these targetable gene alterations originate from gene fusions, which can be found using molecular diagnostics like next-generation sequencing (NGS). Nonetheless, molecular profiling is far from being a routine procedure in the initial phase of PTC diagnostics. As a result, the mutation status, except for <i>BRAF V600E</i> mutation, is not included in risk classification algorithms either. This study aims to provide a comprehensive analysis of fusion mutations in PTC and their associations with clinicopathological variables in order to underscore certain clinical settings when molecular diagnostics should be considered earlier, and to demonstrate yet unknown molecular-clinicopathological connections. We conducted a retrospective fusion mutation screening in formalin-fixed paraffin-embedded (FFPE) PTC tissue samples of 100 patients. After quality evaluation by an expert pathologist, RNA isolation was performed, and then NGS was applied to detect 23 relevant gene fusions in the tumor samples. Clinicopathological data were collected from medical and histological records. To obtain the most associations from the multivariate dataset, we used the <i>d</i>-correlation method for our principal component analysis (PCA). Further statistical analyses, including Chi-square tests and logistic regressions, were performed to identify additional significant correlations within certain subsets of the data. Fusion mutations were identified in 27% of the PTC samples, involving nine distinct genes: <i>RET</i>, <i>NTRK3</i>, <i>CCDC6</i>, <i>ETV6</i>, <i>MET</i>, <i>ALK</i>, <i>NCOA4</i>, <i>EML4</i>, and <i>SQSTM1</i>. <i>RET</i> and <i>CCDC6</i> fusions were associated with type of thyroidectomy, RAI therapy, smaller tumor size, and history of Hashimoto's disease. <i>NCOA4</i> fusion correlated with sex, multifocality, microcarcinoma character, history of goiter, and obstructive pulmonary disease. <i>EML4</i> fusion was also linked with surgical procedure type and smaller tumor size, as well as the history of hypothyroidism. <i>SQSTM1</i> fusion was associated with multifocality and a medical history of thyroid/parathyroid adenoma. <i>NTRK3</i> and <i>ETV6</i> fusions showed significant associations with Hashimoto's disease, and <i>ETV6,</i> also with endometriosis. Moreover, fusion mutations were linked to younger age at the time of diagnosis, particularly the fusion of <i>ETV6</i>. The frequent occurrence of fusion mutations and their associations with certain clinicopathological metrics highlight the importance of integrating molecular profiling into routine PTC management. Early detection of fusion mutations can inform surgical decisions and therapeutic strategies, potentially improving clinical outcomes.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":5.6000,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11477448/pdf/","citationCount":"0","resultStr":"{\"title\":\"Descriptive Analysis of Common Fusion Mutations in Papillary Thyroid Carcinoma in Hungary.\",\"authors\":\"Richard Armos, Bence Bojtor, Janos Podani, Ildiko Illyes, Bernadett Balla, Zsuzsanna Putz, Andras Kiss, Andrea Kohanka, Erika Toth, Istvan Takacs, Janos P Kosa, Peter Lakatos\",\"doi\":\"10.3390/ijms251910787\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Thyroid cancer is the most common type of endocrine malignancy. Papillary thyroid carcinoma (PTC) is its predominant subtype, which is responsible for the vast majority of cases. It is true that PTC is a malignant tumor with a very good prognosis due to effective primary therapeutic approaches such as thyroidectomy and radioiodine (RAI) therapy. However, we are often required to indicate second-line treatments to eradicate the tumor properly. In these scenarios, molecular therapies are promising alternatives, especially if specifically targetable mutations are present. Many of these targetable gene alterations originate from gene fusions, which can be found using molecular diagnostics like next-generation sequencing (NGS). Nonetheless, molecular profiling is far from being a routine procedure in the initial phase of PTC diagnostics. As a result, the mutation status, except for <i>BRAF V600E</i> mutation, is not included in risk classification algorithms either. This study aims to provide a comprehensive analysis of fusion mutations in PTC and their associations with clinicopathological variables in order to underscore certain clinical settings when molecular diagnostics should be considered earlier, and to demonstrate yet unknown molecular-clinicopathological connections. We conducted a retrospective fusion mutation screening in formalin-fixed paraffin-embedded (FFPE) PTC tissue samples of 100 patients. After quality evaluation by an expert pathologist, RNA isolation was performed, and then NGS was applied to detect 23 relevant gene fusions in the tumor samples. Clinicopathological data were collected from medical and histological records. To obtain the most associations from the multivariate dataset, we used the <i>d</i>-correlation method for our principal component analysis (PCA). Further statistical analyses, including Chi-square tests and logistic regressions, were performed to identify additional significant correlations within certain subsets of the data. Fusion mutations were identified in 27% of the PTC samples, involving nine distinct genes: <i>RET</i>, <i>NTRK3</i>, <i>CCDC6</i>, <i>ETV6</i>, <i>MET</i>, <i>ALK</i>, <i>NCOA4</i>, <i>EML4</i>, and <i>SQSTM1</i>. <i>RET</i> and <i>CCDC6</i> fusions were associated with type of thyroidectomy, RAI therapy, smaller tumor size, and history of Hashimoto's disease. <i>NCOA4</i> fusion correlated with sex, multifocality, microcarcinoma character, history of goiter, and obstructive pulmonary disease. <i>EML4</i> fusion was also linked with surgical procedure type and smaller tumor size, as well as the history of hypothyroidism. <i>SQSTM1</i> fusion was associated with multifocality and a medical history of thyroid/parathyroid adenoma. <i>NTRK3</i> and <i>ETV6</i> fusions showed significant associations with Hashimoto's disease, and <i>ETV6,</i> also with endometriosis. Moreover, fusion mutations were linked to younger age at the time of diagnosis, particularly the fusion of <i>ETV6</i>. The frequent occurrence of fusion mutations and their associations with certain clinicopathological metrics highlight the importance of integrating molecular profiling into routine PTC management. Early detection of fusion mutations can inform surgical decisions and therapeutic strategies, potentially improving clinical outcomes.</p>\",\"PeriodicalId\":14156,\"journal\":{\"name\":\"International Journal of Molecular Sciences\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.6000,\"publicationDate\":\"2024-10-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11477448/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"International Journal of Molecular Sciences\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.3390/ijms251910787\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Molecular Sciences","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.3390/ijms251910787","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Descriptive Analysis of Common Fusion Mutations in Papillary Thyroid Carcinoma in Hungary.
Thyroid cancer is the most common type of endocrine malignancy. Papillary thyroid carcinoma (PTC) is its predominant subtype, which is responsible for the vast majority of cases. It is true that PTC is a malignant tumor with a very good prognosis due to effective primary therapeutic approaches such as thyroidectomy and radioiodine (RAI) therapy. However, we are often required to indicate second-line treatments to eradicate the tumor properly. In these scenarios, molecular therapies are promising alternatives, especially if specifically targetable mutations are present. Many of these targetable gene alterations originate from gene fusions, which can be found using molecular diagnostics like next-generation sequencing (NGS). Nonetheless, molecular profiling is far from being a routine procedure in the initial phase of PTC diagnostics. As a result, the mutation status, except for BRAF V600E mutation, is not included in risk classification algorithms either. This study aims to provide a comprehensive analysis of fusion mutations in PTC and their associations with clinicopathological variables in order to underscore certain clinical settings when molecular diagnostics should be considered earlier, and to demonstrate yet unknown molecular-clinicopathological connections. We conducted a retrospective fusion mutation screening in formalin-fixed paraffin-embedded (FFPE) PTC tissue samples of 100 patients. After quality evaluation by an expert pathologist, RNA isolation was performed, and then NGS was applied to detect 23 relevant gene fusions in the tumor samples. Clinicopathological data were collected from medical and histological records. To obtain the most associations from the multivariate dataset, we used the d-correlation method for our principal component analysis (PCA). Further statistical analyses, including Chi-square tests and logistic regressions, were performed to identify additional significant correlations within certain subsets of the data. Fusion mutations were identified in 27% of the PTC samples, involving nine distinct genes: RET, NTRK3, CCDC6, ETV6, MET, ALK, NCOA4, EML4, and SQSTM1. RET and CCDC6 fusions were associated with type of thyroidectomy, RAI therapy, smaller tumor size, and history of Hashimoto's disease. NCOA4 fusion correlated with sex, multifocality, microcarcinoma character, history of goiter, and obstructive pulmonary disease. EML4 fusion was also linked with surgical procedure type and smaller tumor size, as well as the history of hypothyroidism. SQSTM1 fusion was associated with multifocality and a medical history of thyroid/parathyroid adenoma. NTRK3 and ETV6 fusions showed significant associations with Hashimoto's disease, and ETV6, also with endometriosis. Moreover, fusion mutations were linked to younger age at the time of diagnosis, particularly the fusion of ETV6. The frequent occurrence of fusion mutations and their associations with certain clinicopathological metrics highlight the importance of integrating molecular profiling into routine PTC management. Early detection of fusion mutations can inform surgical decisions and therapeutic strategies, potentially improving clinical outcomes.
期刊介绍:
The International Journal of Molecular Sciences (ISSN 1422-0067) provides an advanced forum for chemistry, molecular physics (chemical physics and physical chemistry) and molecular biology. It publishes research articles, reviews, communications and short notes. Our aim is to encourage scientists to publish their theoretical and experimental results in as much detail as possible. Therefore, there is no restriction on the length of the papers or the number of electronics supplementary files. For articles with computational results, the full experimental details must be provided so that the results can be reproduced. Electronic files regarding the full details of the calculation and experimental procedure, if unable to be published in a normal way, can be deposited as supplementary material (including animated pictures, videos, interactive Excel sheets, software executables and others).