Contribution of CGP in the treatments of Thyroid cancer

Keerthi Ranganathan

Scientific Content Developer
4baseCare

Thyroid carcinoma is one of the most prevalent cancers of the endocrine system in humans and it is also a rare type of cancer. Differentiated thyroid cancers (DTCs) develop from thyroid follicular cells and are the most common kind of thyroid cancer. The majority of thyroid malignancies are papillary thyroid cancer (PTC; 80–85 %) and follicular thyroid cancer (FTC; 10%–15 %), and most patients have a favorable prognosis. Patients with advanced thyroid cancer, such as poorly-differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC), have a poorer prognosis than DTC patients. Anaplastic thyroid cancer is the most lethal human cancer form, with a median survival of only 5 months, yet there is still no effective treatment for this fatal cancer.

Early identification of predictive and prognostic molecular markers is critical for preventing and forecasting the progression of the disease. Plenty of research has effectively revealed the underlying genetic basis of human cancers due to the recent boom in next-generation sequencing (NGS) technology. The development of molecularly targeted therapeutics has resulted from significant advances in understanding the genetic and biologic aspects of the disease, and we are now entering an era of precision oncology for thyroid cancer management. With a single test – and from a single sample – Comprehensive genomic profiling (CGP) can identify all kinds of genomic alterations (SNVs/InDels, CNAs, Gene Fusions) across thousands of genes. Understanding the molecular processes during thyroid cancer growth would give an efficient treatment approach since numerous genetic variables impact therapeutic sensitivity or drug resistance. Studies have reported that point mutations for proto-oncogenes (BRAF, NRAS, HRAS, KRAS, RET) and chromosomal rearrangements (RET/PTC1, RET/PTC3, PAX8/PPARG) are common in thyroid malignancies and vary by histologic subtype.

Papillary carcinoma:
NGS has been used to study varied subgroups of PTCs in several studies.  Nikiforova et al. investigated FFPE or frozen tissue from 27 classic PTCs and 30 FVPTCs using the ThyroSeq NGS panel. The findings revealed that 70 % of classic PTCs had mutant genes, with BRAF (59 %) being the most common, followed by PIK3A (11%), TP53 (7%), and NRAS (4%).  In contrast, 83% of FVPTCs had altered genes, the most common of which was RAS (73%), followed by BRAF (7%), and TSHR (3%). Smallridge et al. performed RNA sequencing (RNA-Seq) on frozen tissue from 12 BRAF V600E-mutated PTCs and 8 BRAF-wild type PTCs.  560 genes were differently expressed between BRAF V600E-mutated PTCs and BRAF-wild type PTCs among the 13,085 genes examined. Among the 560 genes studied, 67 were linked to immune function pathways, 51 were found to be underexpressed in BRAF V600E-mutated PTCs, whereas HLAG, CXCL14, TIMP1, and IL1RAP were found to be overexpressed. Four immune function genes (IL1B, CCL19, CCL21, and CXCR4) were considerably differently expressed in BRAF-wild type PTCs and showed a strong connection with lymphocytic infiltration. RET gene alteration has a profound effect in the tumorigenesis of PTC and it accounts for almost 70% PTC cases.

Follicular carcinoma:
Follicular carcinoma (FC) is the second most prevalent thyroid cancer after PTC. It is a well-differentiated thyroid carcinoma. One of the most common genetic events in follicular thyroid cancer is the gene fusion of PAX8/PPARγ or PPFP oncoprotein gene. In FTC, as in PTC, overexpression of TMPRSS4 is observed in 53.6% (15/28) of the samples, as shown by Guan et al.

Sun et al., found a positive correlation between FTC tumorigenesis and low levels of miR-199a-5p expression [131]. MiR-199a-5p was identified as a regulator of the connective tissue growth factor (CTFG), which acts as an inhibitor of the cell cycle in healthy tissue. In tumor conditions, both fusion proteins appear to possess binding domains that retain their function in the correct cellular context Recent work used the ThyroSeq panel to analyse 12 cancer genes and 34 amplicons utilising FFPE or fresh frozen tissue samples from 36 FCs. NRAS (N = 9), KRAS (N = 2), HRAS (N = 1), TSHR (N = 4), TP53 (N = 4), and PTEN (N = 1) mutations were discovered. The conventional type (N = 18) and oncocytic type (N = 18) samples both revealed distinct genetic changes. NRAS was the most frequently impacted gene in conventional type FCs, followed by TSHR and KRAS. The most frequently mutated gene in oncocytic type FCs was TP53, followed by HRAS, KRAS, and PTEN.

Poorly differentiated carcinoma and anaplastic carcinoma:
Poorly differentiated carcinoma (PDC) and anaplastic carcinoma (AC) are two rare types of thyroid cancer, each having a 10% occurrence and a 1–2% overall prevalence. PDC and AC have poor prognoses, with survival rates of 51% and 0%, respectively, after five years. Because many malignancies do not react well to conventional therapies (such as radioiodine therapy, chemotherapy, and radiation), clinical trials for molecular-targeted therapies are currently underway. It may be feasible to uncover targetable gene modifications that can enhance the course of patient therapy using next-generation sequencing. In a study 12 genes with 34 amplicons were examined in FFPE or fresh frozen tissue from 10 PDCs and 27 ACs. According to the findings, 30% of PDCs had mutations, whereas 74% of ACs had mutations. NRAS, PIK3CA, GNAS, and BRAF were altered in PDCs, whereas TP53, BRAF, RAS, PIK3CA, PTEN, and CTNNB1 were altered in ACs.

Medullary carcinoma:
Medullary carcinoma (MC) is a type of neuroendocrine tumor that develops from C-cells and accounts for around 5% of all thyroid malignancies. MC is made up of 75% sporadic and 25% hereditary forms, the latter of which is caused by a RET proto-oncogene mutation. Using FFPE or fresh frozen tissue samples from 15 sporadic MCs, Nikiforova et al. examined 12 genes and 34 amplicons. In 11 (73%) of the MCs, mutations were found, with 7 (47%) being RET mutations, 3 (20%) being HRAS mutations, and 1 (7%) being a KRAS mutation.

In the future, NGS might be used to detect circulating tumor cells or cell-free plasma DNA to detect early relapse and/or residual disease in thyroid cancer. In addition, NGS may detect tumor-specific genomic changes, which are employed in patient follow-ups.  BRAF V600E is the most prevalent and early genetic event in PTC in thyroid cancer and it looks to be a suitable candidate gene for monitoring. New mutation variations other than the initial tumor can also be identified in NGS analysis of either circulating tumor cells or cell-free plasma DNA following radioactive iodine and/or drug treatment of thyroid cancer. This idea can be used to discover genetic alterations linked to treatment resistance acquired during the clinical course.