Deep Small RNA Sequencing of BRAF V600E Mutated Papillary Thyroid Carcinoma With Lymph Node Metastasis.

Abstract

Papillary thyroid carcinoma (PTC) is the most predominant subtype of thyroid cancer, contributing to more than 80% of all thyroid or endocrine malignancies. Its prognosis is relatively good compared to other cancers, with more than 90% overall 10-year survival rate (Haugen et al., 2016). However, despite the favorable prognosis, some cases exhibit aggressive phenotype. On average, 50% of the patients are presented with lymph node metastases (LNM) at diagnosis (Saiselet et al., 2015). LNM in PTC confers various poor prognostic indicators; it increases recurrence risk and decreases long term survival predominantly in patients older than 45 years old (Lundgren et al., 2006; Xing, 2013). Treating recurrent PTCs is still a challenge (Pasternak and Shen, 2017) and one of the important issues yet to be solved in PTC patient management is the mortality and morbidity associated with the recurrent disease (Lee et al., 2013). MicroRNAs (miRNAs) are short, endogenous noncoding RNAs first identified in Caenorhabditis elegans which regulate gene expression by binding to the 3′-UTR of target messenger RNA (mRNAs). Their post-transcriptional regulatory functions are involved in controlling the level of proteins involved in numerous biological processes, including embryogenesis, organogenesis, tissue homeostasis, immune system function and cell cycle control (Tafrihi and Hasheminasab, 2019). Relationship between miRNAs and tumor growth, tumor progression and metastasis has been demonstrated by many studies, indicating the ability of these molecules to be used as biomarkers for diagnosis and prognosis (Iorio and Croce, 2012). MiRNA also plays a role as biomarker in predicting lymph nodes metastasis (LNM) in thyroid cancer (Ab Mutalib et al., 2016; Mutalib et al., 2016; Mohamad Yusof et al., 2018). P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are a quite recently discovered class of RNAs and more than 30,000 piRNA genes been identified within the human genome (Zhang et al., 2014; Wang et al., 2019). Originally described as key regulators for the germline maintenance and transposon silencing, these short RNAs were disregarded for a long time due to our limited knowledge regarding their function (Weng et al., 2019). However, emergent of new data reveals that unusual expression of piRNAs is a distinct feature Fin many diseases, including cancers (Weng et al., 2019). This has changed our perspectives on their significance in various diseases. Epigenetically, piRNAs are also the post-transcriptional regulators of the expression of specific downstream target genes (Watanabe and Lin, 2014), and accumulating evidence demonstrates that similarly to miRNAs, piRNAs also possess both oncogenic and tumor-suppressive roles (Weng et al., 2019). BRAF is a serine-threonine kinase that is activated by RAS binding and protein recruitment to the cell membrane. Activation of MEK along with the MAPK signaling pathway is activated by BRAF phosphorylation (Nikiforov and Nikiforova, 2011). The most frequent genetic changes in PTC are point mutations of BRAF which are observed in 35 to 70% of PTC cases (Li et al., 2012; Xing, 2013). More than 95% of BRAF mutations in thyroid cancers are thymine to adenine transversion at position 1799 (T1799A) which result in the substitution of glutamate from valine at residue 600 (V600E) (Xing et al., 2015). Various studies have also shown that the BRAF V600E mutation is related to LNM, as further presented by a meta-analysis by Song et al. (2018). In the past years, the evolution of next-generation sequencing technologies has enabled global transcriptome expression profiling and the discovery of novel human miRNAs (Kozomara and Griffiths-Jones, 2011; Kozomara and Griffiths-Jones, 2014; Kozomara et al., 2019) and piRNAs (Weng et al., 2019). Coincidentally, PTC has a relatively lower overall mutation burden hence termed as quiet genome (Cancer Genome Atlas Research Network, 2014; Siraj et al., 2016), therefore investigating the regulatory molecules such as the miRNAs and piRNAs has the potential to deepen our understanding of this cancer. This Data Report aims to provide the readers a comprehensive dataset of small RNAs expression derived from next-generation sequencing in an unbiased manner. For detailed analysis of this dataset focusing on miRNAs with biological insights in PTC, please refer to our original article published in Frontiers of Endocrinology (Mohamad Yusof et al., 2018).