RET/PTC Gene Rearrangements in Thyroid Carcinogenesis: Assessment and Clinico-Pathological Correlations

Khan, Mosin Saleem; Qadri, Qurteeba; Makhdoomi, Mudasir J; Wani, Mudassir Maqbool; Malik, Aejaz A; Niyaz, Madiha; Masoodi, Shariq Rashid; Andrabi, Khurshid Iqbal; Ahmad, Rauf; Mudassar, Syed

doi:10.1007/s12253-018-0540-3

Cited by 35 publications

(32 citation statements)

References 32 publications

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“…In PTC, RET rearrangements appear to be an early event in tumourigenesis (Viglietto et al, 1995). Although not essential for PTC formation, presence of a RET fusion protein or increased expression is linked to more malignant phenotypes including regional invasion and lymph node metastasis (Miki et al, 1999; Wang et al, 2008; Yip et al, 2015; Khan et al, 2018). Thus, RET rearrangements are an important marker for risk of malignancy in fine needle aspirates of thyroid nodules with indeterminate cytology.…”

Section: Ret Dependent Gfl Independent Cancersmentioning

confidence: 99%

GDNF and the RET Receptor in Cancer: New Insights and Therapeutic Potential

Mulligan

2019

Front. Physiol.

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The Glial cell line-derived neurotrophic Family Ligands (GFL) are soluble neurotrophic factors that are required for development of multiple human tissues, but which are also important contributors to human cancers. GFL signaling occurs through the transmembrane RET receptor tyrosine kinase, a well-characterized oncogene. GFL-independent RET activation, through rearrangement or point mutations occurs in thyroid and lung cancers. However, GFL-mediated activation of wildtype RET is an increasingly recognized mechanism promoting tumor growth and dissemination of a much broader group of cancers. RET and GFL expression have been implicated in metastasis or invasion in diverse human cancers including breast, pancreatic, and prostate tumors, where they are linked to poorer patient prognosis. In addition to directly inducing tumor growth in these diseases, GFL-RET signaling promotes changes in the tumor microenvironment that alter the surrounding stroma and cellular composition to enhance tumor invasion and metastasis. As such, GFL RET signaling is an important target for novel therapeutic approaches to limit tumor growth and spread and improve disease outcomes.

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Section: Ret Dependent Gfl Independent Cancersmentioning

confidence: 99%

GDNF and the RET Receptor in Cancer: New Insights and Therapeutic Potential

Mulligan

2019

Front. Physiol.

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“…RET fusions are among the many RTK fusions described in human neoplasia. RET rearrangements have been well described in epithelial neoplasms including lung, thyroid, breast, and colorectal cancers and salivary gland tumours 9–17 . RET ‐rearranged mesenchymal neoplasms are an emerging group, with only single case reports and small series published under a variety of nosological terms (Table 1).…”

Section: Introductionmentioning

confidence: 99%

Recurrent RET gene fusions in paediatric spindle mesenchymal neoplasms*

et al. 2020

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Aims: The classification of paediatric spindle mesenchymal tumours is evolving, and the spectrum of socalled 'infantile fibrosarcoma' has expanded to include tumours with NTRK, BRAF and MET gene fusions. RETrearranged paediatric spindle cell neoplasms are an emerging group; there is sparse literature on their clinical, pathological and genetic features, and their nosological place in the canon of soft tissue tumours is uncertain. In this study, we report five RET-rearranged paediatric spindle cell tumours with fusion partners MYH10, KIAA1217 and CLIP2. Methods and results: The tumours occurred in the pelvic region, paraspinal region, kidney and subcutaneous tissue of hand and abdomen. The patients' ages ranged from 6 months to 13 years (median 1 year). The tumours were composed of monomorphic spindle cells arranged in a fascicular pattern. Lesional cells had minimally atypical ovoid or tapered nuclei and pale cytoplasm with indistinct borders. Necrosis was not identified. Mitoses numbered three to 12 per 10 high-power field. Cases showed inconsistent and variable expression of S100, CD34 and SMA. Clinical behaviour ranged from small lesions potentially cured by simple resection to large lesions exhibiting metastasis, but responsive to kinase inhibitor therapy. Conclusions: Our findings help to define RET-rearranged spindle cell tumours. Although it is likely that these tumours comprise part of the morphological and clinical spectrum of infantile fibrosarcoma (IFS), identification of RET gene alteration is important for its unique therapeutic implications.

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“…On the other hand, this panel was not designed to detect large sequential alterations and structural rearrangements of the genome. This restriction should be considered, especially as chromosomal translocations (e.g., RET/PTC) appear to be clinically significant in thyroid tumors, primarily in the classical papillary variant [25]. In the present study, however, we were principally interested in SNVs in HT-related carcinoma and, further, in the potential clonal correlations characteristic of multifocality.…”

Section: Discussionmentioning

confidence: 99%

High Genetic Diversity and No Evidence of Clonal Relation in Synchronous Thyroid Carcinomas Associated with Hashimoto’s Thyroiditis: A Next-Generation Sequencing Analysis

et al. 2020

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The close association between pre-existing Hashimoto’s thyroiditis and thyroid cancer is well established. The simultaneous occurrence of multiple neoplastic foci within the same organ suggests a common genotoxic effect potentially contributing to carcinogenesis, the nature of which is still not clear. Next-generation sequencing (NGS) provides a potent tool to demonstrate and compare the mutational profile of the independent neoplastic foci. Our collection of 47 cases with thyroid carcinoma and Hashimoto’s thyroiditis included 14 with at least two tumorous foci. Detailed histological analysis highlighted differences in histomorphology, immunoprofile, and biological characteristics. Further, a 67-gene NGS panel was applied to demonstrate the mutational diversity of the synchronic tumors. Significant differences could be detected with a wide spectrum of pathogenic gene variants involved (ranging between 5 and 18, cutoff >5.0 variant allele frequencies (VAF)). Identical gene variants represented in both synchronous tumors of the same thyroid gland were found in only two cases (BRAF and JAK3 genes). An additional set of major driver mutations was identified at variable allele frequencies in a highly individual setup suggesting a clear clonal independence. The different BRAF statuses in coincident thyroid carcinoma foci within the same organ outline a special challenge for molecular follow-up and therapeutic decision-making.

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RET/PTC Gene Rearrangements in Thyroid Carcinogenesis: Assessment and Clinico-Pathological Correlations

Cited by 35 publications

References 32 publications

GDNF and the RET Receptor in Cancer: New Insights and Therapeutic Potential

GDNF and the RET Receptor in Cancer: New Insights and Therapeutic Potential

Recurrent RET gene fusions in paediatric spindle mesenchymal neoplasms*

High Genetic Diversity and No Evidence of Clonal Relation in Synchronous Thyroid Carcinomas Associated with Hashimoto’s Thyroiditis: A Next-Generation Sequencing Analysis

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