Follicular cell-derived thyroid tumors originate from follicular cells in the thyroid gland. These tumors encompass 95% of all thyroid malignancies and include well-differentiated, poorly differentiated and anaplastic thyroid cancers. The molecular landscape of follicular cell-derived thyroid cancer is variable according to the different tumor subtypes.
Thyroid tumors originated from follicular cells, namely non-medullary thyroid cancers, encompass 95% of all thyroid malignancies [1]. A primary gross distinction can be made between well-differentiated thyroid carcinomas (WDTC), which include papillary thyroid carcinomas (PTC), follicular thyroid carcinomas (FTC), and Hürthle cell thyroid carcinomas (HCC), and less differentiated forms, i.e., poorly differentiated thyroid carcinomas (PDTC) and anaplastic, or undifferentiated, thyroid carcinomas (ATC). PTC is the most common endocrine malignancy, accounting for approximately 85% of all follicular-derived thyroid cancers, while FTC occurs in less than 10% of all thyroid tumors [2]. In general, WDTC patients have excellent 10-year survival rates, but prognosis highly depends on molecular and clinico-pathological characteristics. For instance, the noninvasive follicular neoplasm with papillary-like nuclear features, NIFTP, is a borderline lesion introduced in 2016 from the reclassification of a specific, indolent subtype of PTC [3]. On the other hand, there are PTC variants, such as the hobnail variant, which often present with gross local invasion as well as lymph node and distant metastases, and has a high recurrence rate, therefore representing a non-negligible threat to patients’ survival [4].
The molecular hallmarks among and within histological subtypes can be highly variable and may impact on patients’ prognosis. In particular, the presence of secondary mutations defines a subgroup of aggressive tumors, which are often resistant to standard treatment [5]. In this context, targeted therapies have been emerging in the clinical management of thyroid cancer, in the light of which molecular tumor characterization will acquire even more significance. This review describes the molecular landscape of follicular-derived thyroid cancers, highlighting the differences among histological subtypes, with a particular focus on advanced tumors.
BRAF
BRAFV600E
RAS
NRAS
HRAS
KRAS
HRAS
EIF1AX
KRAS
PPM1D
CHEK2
BRAF
PPARG
THADA
NTRK fusions were also rare, being found in 2% of cases, although some authors had previously reported them in up to 3–5% of sporadic adult PTC [7][10]. It is worth noting that in thyroid cancer almost only
NTRK1
NTRK3
BRAFV600E
RAS
BRAFV600E
RAS
BRAFV600E
BRAFV600E
RET/PTC
BRAF
RAS
RAS
BRAFK601E
PPARG
THADA
EIF1AX
BRAF
RAS
BRAFV600E
BRAFV600E
BRAF
RET
NTRK
FTCs, follicular-patterned tumors that lack PTC nuclear alterations, are usually encapsulated and show tumor capsule and/or vascular invasion. They represent 6–10% of follicular-derived thyroid tumors [2]. Unlike PTCs, which cause lymph node involvement in many patients, FTCs often show hematogenous spread to distant organs (mainly to the bones and lungs). The TCGA study results on PTC have been confirmed by several subsequent studies, where FTCs were also included [7][13][14]. Apart from the already known high prevalence of RAS (in up to 50% of cases) [15] and of
RAS
BRAF
RAS
BRAF
RAS
PPARG
EIF1AX
Finally, the HCCs are a group of encapsulated tumors predominantly composed of oncocytic cells and characterized by capsular/vascular invasion. The classification of these neoplasms as a subtype of follicular tumors has been a hotly-debated issue; according to the current indications of WHO, HCCs are independent histo-pathological entities belonging to the DTC [2]. HCCs account for 3–5% of all non-medullary thyroid tumors [16][17]. Similarly to FTC, HCCs show a higher incidence of distant metastases compared to PTCs. The molecular frame of HCCs is completely different from that of the rest of the WDTCs, being characterized by three main types of alterations: (1) mitochondrial DNA mutations, occurring as early events in genes encoding complex I subunits; (2) point mutations recurring in genes that are not typically mutated in thyroid cancer, with the exception of few
RAS
EIF1AX mutations; (3) karyotype alterations, with tumors having a near-haploid state, a polysomic state and/or duplication of chromosomes 7, 5, and 12 [16][17].
TERT promoter mutations show a frequency of about 10% in PTCs and 15% in FTCs [7][9][18]. However, a difference across PTC variants has been observed, with tall cell PTCs reaching a frequency of 25%. Similarly,
TERT promoter mutations have been reported in 15–20% of HCCs, with a higher occurrence in widely invasive (32%), versus minimally invasive (5%) tumors [17][18]. Since
TERT
TERT promoter mutations and distant metastases, disease persistence and recurrence, advanced stage and also patients’ survival have been demonstrated in WDTC patients [19][20][21]. The influence of
TERT
RAS
RAS mutations in 40–70% of cases [22][23] in the same way as their invasive counterparts. NIFTPs should lack
BRAF
BRAFV600E
RAS
BRAF
TP53
EIF1AX
PTEN
PIK3CA
Table 1. Most frequent molecular alterations reported in PDTC and ATC [5][14][30][31][32][33][34][35][36].
Gene | PDTC | ATC | |||||
---|---|---|---|---|---|---|---|
n° Mutant/n° Total | Frequency Range | Pooled Frequency | n° Mutant/n° Total | Frequency Range | Pooled Frequency | ||
BRAF | 57/220 | 15–33% | 26% | 166/395 | 20–56% | 42% | |
RAS | 48/220 | 9–39% | 22% | 100/395 | 20–33% | 25% | |
EIF1AX | 11/125 | 5–11% | 9% | 22/181 | 8–14% | 12% | |
PIK3CA | 15/220 | 2–20% | 7% | 65/395 | 9–44% | 16% | |
PTEN | 6/220 | 4–33% | 3% | 45/395 | 11–20% | 11% | |
TERT | 43/125 | 22–40% | 34% | 242/355 | 56–75% | 68% | |
TP53 | 45/220 | 8–67% | 20% | 244/395 | 25–80% | 62% | |
RET | fusion | ||||||
0% | |||||||
0% | |||||||
NTRK | fusion | 1/41 | 0–2% | 2% | 5/322 | 1–4% | 2% |
Considering the differences between PDTCs and ATCs, it has been reported that ATCs show significantly higher frequencies of TP53, TERT promoter, PIK3CA and PTEN mutations compared to PDTCs [30][31]. Moreover, ATCs also harbor ATM, NF1, NF2, CDKN2A, CDKN2B and RB1 mutations [5][30][32][33][37]. On the other hand, PDTCs more frequently display gene fusions (RET, ALK, NTRK1, NTRK3) compared to ATCs [30][31].
Considering the differences between PDTCs and ATCs, it has been reported that ATCs show significantly higher frequencies of TP53, TERT promoter, PIK3CA and PTEN mutations compared to PDTCs [30,31]. Moreover, ATCs also harbor ATM, NF1, NF2, CDKN2A, CDKN2B and RB1 mutations [5,30,32,33,37]. On the other hand, PDTCs more frequently display gene fusions (RET, ALK, NTRK1, NTRK3) compared to ATCs [30,31].Table 2. Gene mutations and rearrangements described in advanced well-differentiated thyroid carcinomas [5][35][37][38][39][40].
Gene | Advanced PTC | Advanced FTC | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
n° Mutant/n° Total | Frequency Range | Pooled Frequency | n° Mutant/n° Total | Frequency Range | Pooled Frequency | |||||
BRAF | 583/894 | 45–71% | 65% | 6/136 | 1 | 0–8% | 4% | |||
RAS2 | 68/890 | 1–23% | 8% | 83/136 | 8–90% | 61% | ||||
EIF1AX | 3/62 | 0–10% | 5% | 5/88 | 0–40% | 6% | ||||
PIK3CA | 36/669 | 3–6% | 5% | 2/100 | 0–3% | 2% | ||||
PTEN | 10/669 | 0–2% | 1% | 9/100 | 0–14% | 9% | ||||
TERT | 314/651 | 13–62% | 48% | 68/103 | 50–82% | 66% | ||||
TP53 | 64/669 | 3–13% | 10% | 9/100 | 0–12% | |||||
11/125 | 6–15% | 9% | 5/355 | 0–2% | 1% | |||||
9% | ||||||||||
RET | fusion | 37/558 | 3–7% | 7% | 0/89 | 0% | 0% | PPARG | fusion | 4/125 |
PPARG | 2–4% | 3% | 0/159 | fusion | 0/590% | 0%0% | ||||
0% | 0/89 | 0% | 0% | ALK | fusion | 4/125 | 2–4% | 3% | 0/355 | |
ALK | fusion | 3/527 | <1–2% | 1% | 0/89 | 0% | 0% | |||
NTRK | fusion | 8/527 | 1–5% | 2% | 0/89 | 0% | 0% | |||
BRAF | fusion | 14/527 | 0–3% | 3% | 0/89 | 0% | 0% |
1
V600E
2
BRAF
BRAFV600E ATCs [41]. The administration of multi-target thyrosine kinase inhibitors (TKI) such as sorafenib and lenvatinib, approved in many countries, has improved the progression-free survival of radioiodine-resistant DTCs [42][43]. Indeed, a recent meta-analysis reports that treatment with lenvatinib in DTC patients achieved a pooled partial response rate of 69%, and a progression-free survival of 19 months [44]. However, prognosis in ATC patients remained poor even with TKI therapy (pooled progression-free survival was 5 months), and a complete response was rarely achieved (0.3%). Moreover, owing to its inhibitory effects against multiple targets, TKI treatment causes adverse events involving fatigue, gastrointestinal symptoms, hypertension, liver disfunction and affecting also thyroid function and metabolism [45].
With regard to immunotherapy, it has been demonstrated that ATCs express PD-L1, but evidences of the efficacy of immune check-point inhibitors in the treatment of thyroid cancer patients are still limited [29][46]. The use of the anti-PD-1 drug pembrolizumab in combination with lenvatinib is currently being evaluated in clinical trials enrolling DTC, PDTC and ATC patients (NCT02973997; NCT04731740).
NTRK
NTRK
NTRK
ALK
ROS1-altered receptors [47][48]. Preliminary data on thyroid cancer show that larotrectinib is effective, demonstrating an overall response rate of 75% [49]. In spite of the rarity of
NTRK fusions in non-pediatric thyroid cancers (2–5%) [9][10], these targeted drugs might represent a promising strategy of treatment in advanced tumors lacking the most common molecular alterations.
RET
RET
CCDC6/RET
RET
MiRNAs are small non-coding RNA molecules that regulate the expression of specific transcripts in an epigenetics manner. Several miRNAs have been reported as being involved in thyroid cancer pathogenesis as well as in cancer progression. Some of them (for example miR-146b, miR-221 and miR-222) have been consistently and widely reported as up-regulated in PTC by many authors, and could therefore serve as PTC markers [53][54][55]. It has been demonstrated that up-regulated miRNAs target suppressor genes, such as
PTEN, belonging to the MAPK and the PI3K/AKT pathways [54]. On the contrary, suppressor miRNAs have been frequently reported as down-regulated in thyroid cancer (for instance miR-375, miR-7 and miR204) [55][56]. Moreover, since miRNAs are differentially expressed in thyroid tumors versus benign lesions and in different histotypes of thyroid cancer, the development of miRNA-based molecular test is an appealing strategy for the diagnostic and prognostic definition of thyroid tumors [57].