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Anaplastic (ATC) and poorly differentiated thyroid cancer (PDTC) are very aggressive cancers whose histological diagnosis is not always straightforward. Clinical, pathological and genetic features may be useful to improve the identification of these rare histotypes. In the present study the clinical, pathological and genetic features of two groups of ATC (n=21) and PDTC (n=21) patients were analyzed. Clinical data were retrieved from a computerized database. The oncogenic profiles were studied using the Sanger sequencing method of a selected series of oncogenes and/or tumor suppressor genes known to be altered in these tumors. The presence of macrophages in both series of tissues was evaluated by immunohistochemistry. Patients with ATC were older and affected by a more advanced disease at diagnosis than those with PDTC. The median survival was significantly shorter in ATC compared with PDTC patients (P=0.0014). ATC showed a higher prevalence of TP53 and TERT mutations (10/21, 47.6% and 9/21, 42.8%, respectively) while TERT and BRAF mutations were the most prevalent in the PDTC group (7/21, 33.3% and 4/23, 19% respectively). Genetic heterogeneity (i.e., >2 mutations) was more frequent in ATC (10/21, 28.6%) compared with in PDTC (3/21, 4.7%) (P=0.03). Macrophages were more frequently present in ATC, particularly in those cases with TP53 mutations. In conclusion, these data indicate that ATC and PDTC may be characterized by different clinical, pathological and genetic profiles. In particular ATC, but not PDTC, were positive for TP53 and PTEN alterations. Complex mutations were also found in ATC but not in PDTC. Moreover, genetic heterogeneity was more frequent in ATC than PDTC. Finally, TP53 mutation and the accumulation of several mutations correlated with a shorter survival time. [ABSTRACT FROM AUTHOR]

Background: The follicular variant (FV) of papillary thyroid cancer (PTC) is one of the most common variants of PTC. Clinically, non-infiltrative FVPTC is considered a low-risk variant of PTC, and the non-invasive encapsulated forms of FVPTC represent a group of thyroid tumors with a particularly good prognosis. Consequently, these neoplasms have been very recently reclassified as non-invasive follicular neoplasms with papillary-like nuclear features (NIFTP). From a molecular standpoint, NIFTP appears to be similar to follicular neoplasms. However, only limited data are currently available regarding their gene expression profile. Methods: The aim of this study was to identify specific molecular signatures of 26 NIFTPs compared to those of 19 follicular adenomas (FAs) and 18 infiltrative FVPTCs (IFVPTCs). A nanoString custom assay was used to perform mRNA expression analysis. All cases were also genotyped for BRAF, N-, H-, and K-RAS mutations. Samples were grouped on the basis of gene expression profiles by Pearson's correlation and non-negative matrix factorization clustering analysis. Finally, the uncorrelated shrunken centroid machine-learning algorithm was used to classify the samples. Results: The results revealed distinct expression profiles of FAs and IFVPTCs. NIFTP samples can exhibit different expression profiles, more similar to FAs (FA-like) or to IFVPTCs (IFVPTC-like), and these different expression profiles largely depend on the presence of different mutations ( RAS or BRAF). Conclusion: In conclusion, although further validation of the model is required by using a larger group of prospective cases, these data reinforce the hypothesis that IFVPTC-like NIFTPs might represent precursors of IFVPTC. [ABSTRACT FROM AUTHOR]

BRAF mutations represent the most common genetic alteration in papillary thyroid carcinoma (PTC). The p.V600E mutation is specific for the classic and tall-cell variants of PTC and has been associated with a more aggressive biologic behavior. On the other hand, the p.K601E mutation is peculiar to the follicular variant of PTC, and seems to be a favorable prognostic indicator. A 12-year-old boy presented with a 10-mm left-sided thyroid nodule. Fine-needle aspiration cytology reported the lesion as suspicious for a follicular neoplasm (Bethesda category IV). The patient underwent lobectomy, and histopathology revealed a follicular adenoma with normal surrounding tissue. The cytological smear was found to be positive for BRAF p.K601E mutation, and this was later confirmed on the corresponding paraffin block. This case was independently revised by 4 expert pathologists, all of whom confirmed the benign nature of the thyroid lesion. This article describes the presence of a BRAF mutation in a benign thyroid lesion. To the authors' knowledge, this is the fourth case of follicular adenoma carrying BRAFK601E reported in literature to date. BRAFK601E mutation can occur in benign thyroid lesions. This finding, in the context of the current literature and the recently proposed reclassification of the noninvasive encapsulated follicular variant of papillary thyroid carcinoma into a benign lesion, confirms the importance of preoperative BRAF p.K601E testing in offering patients a tailored treatment plan and avoiding overtreatment. [ABSTRACT FROM AUTHOR]

Background: Approximately 60% of sporadic medullary thyroid carcinomas (sMTC) remain orphan of a recognized genetic cause. Recently, a high percentage of RAS point mutations have been described in RET-negative sMTC. The aim of this study was to assess the prevalence of RAS point mutations in a large series of MTC collected in four Italian centers. Methods: For this purpose, we studied codons 12, 13, and 61 of H-, K-, and N- RAS genes in 188 MTC samples, either hereditary or sporadic, by direct sequencing. Correlations between the RAS mutational status and the clinical-pathological features of MTC patients as well as a meta-analysis of all published data were performed. Results: The prevalence of RAS mutations in the present series of MTC was 10.1%, and 17.6% when considering only RET-negative cases. RAS mutations were found in MTC tumoral tissue, but not in peripheral blood indicating their somatic origin. A novel mutation in codon 72 (M72I) was found, but with a low or null transforming potential. No association was found between the presence of RAS mutations and the clinical-pathological features of the patients. Although not statistically significant, a positive association between the presence of RAS mutations and a better outcome was observed. The meta-analysis of all published studies confirmed a prevalence of 8.8% for RAS mutations in MTC. Conclusions: The prevalence of RAS mutations in our MTC series was relatively low and consistent with the meta-analysis data. Only somatic RAS mutations were found and only in RET-negative sMTC. Likewise, MTCs that harbor a RAS mutation identify a subgroup of tumors with less aggressive behavior. To our knowledge, this is the largest series of MTCs studied for the presence of mutations in RAS genes and the first meta-analysis on this specific topic. [ABSTRACT FROM AUTHOR]

Background: The prevalence of RET somatic mutations in sporadic medullary thyroid cancer (MTCs) is ∼40%-50%, and the most frequent somatic mutation is M918T. RET-positive MTCs have been demonstrated to have a more advanced stage at diagnosis and a worse outcome. Aims: The aim of the present work was to compare the prevalence of RET somatic mutations in sporadic microMTCs (<1 cm) and in larger MTCs. Patients: We analyzed the M918T RET point mutation in 160 sporadic MTC cases. Tumors were classified according to their size: group A, <1 cm; group B, >1 and <2 cm; group C, >2 and <3 cm; and group D, >3 cm. Results: The overall prevalence of the somatic M918T RET mutation was 19.4% (31/160). RET mutations were distributed differently among the four groups. The prevalence was 11.3% (6/53) in group A, 11.8% (8/68) in group B, 31.8% (7/22) in group C, and 58.8% (10/17) in group D, exhibiting an increase with increasing size of the tumor. When comparing the prevalence of mutations in the four groups, we found a lower prevalence in microMTCs ( p<0.0001). Conclusions: The overall prevalence of RET somatic mutations was lower than expected, and the prevalence of the somatic M918T RET mutation was significantly lower in microMTCs than in larger tumors. To explain this finding, we can hypothesize either that other oncogene(s) might be responsible for the majority of microMTC, thus identifying a tumor subset, or that the RET mutation might, or might not, occur later during tumor progression. [ABSTRACT FROM AUTHOR]

Simple Summary: Papillary thyroid carcinoma (PTC) in pediatric patients shows different characteristics compared with PTC in adults. In this large mono-institutional cohort of pediatric PTCs, tumor tissue samples have been analyzed for point mutations and fusions. Overall, molecular alterations were detected in 131 out of 163 PTCs (80%). Fusion-driven PTCs showed more aggressive clinico-pathological features compared to mutation-driven and wild-type cases. These results highlight the importance of testing pediatric PTCs for gene rearrangement in routine characterization of tumors. Papillary thyroid carcinoma (PTC) presents distinct clinico-pathological and molecular differences in children compared with adult patients. Whether the presence of rearrangements or point mutations is associated with aggressive PTC clinical presentation is still controversial. In this study, PTCs diagnosed in patients aged less than 18 years were retrospectively searched from the institutional archive and tumor tissue was tested for point mutations in BRAF and RAS genes and for rearrangements in RET, NTRK1, NTRK3, ALK, PPARG, BRAF and THADA. A total of 163 PTCs were analyzed. Point mutations were found in 83 (51%) and gene fusions in 48 cases (30%). The most frequent alteration was the BRAFV600E mutation (36.8%), followed by NTRK3 fusion (11%), NRAS mutation (10.4%) and RET fusion (10.4%). Fusion-driven PTCs showed more frequently infiltrative growth, larger tumors, extrathyroidal extension and N1b disease. PTCs showing solid growth pattern were significantly enriched in gene fusions. This is one of the largest cohorts of pediatric PTCs. Fusion-driven tumors most frequently show aggressive pathological features; the search for rearrangements, especially in tumors with solid areas, could improve the characterization of pediatric PTCs and offer possible therapeutic options. [ABSTRACT FROM AUTHOR]

We performed a comprehensive genomic profiling of tumour samples from metastatic colorectal cancer (mCRC) patients enrolled in the TRIBE2 study to assess the concordance among different techniques to evaluate mismatch repair (MMR) and microsatellite instability (MSI) status, to characterize tumours according to the tumour mutational burden (TMB) and explore the clinical relevance of different TMB cutpoints, and to investigate the prevalence of alterations actionable with targeted approaches or immune checkpoint inhibitors. Tumour samples of 296 (44%) of 679 enrolled patients underwent 592-gene DNA next-generation sequencing (NGS). MMR status was assessed by immunohistochemistry (MMR-IHC), and MSI status was assessed by NGS (MSI-NGS). TMB was defined as low, intermediate, or high if <7, 7–16, or ≥17 mutations/megabase (mut/Mb) were found. The performance of TMB to predict MSI status was tested by receiver operating characteristic (ROC) curve. Actionable alterations included BRAF V600E, KRAS G12C, POLE mutations, HER2 amplification and mutations, and MSI-H. Of 216 paired cases, concordance between MMR-IHC and MSI-NGS was 98.6%. Among 11 TMB-high tumours, eight (73%) were MSI-H and three (27%) were microsatellite stable and harboured POLE or MSH6 mutations. High TMB had a trend for a better outcome than low/intermediate TMB (hazard ratio for overall survival 0.45, 95% confidence interval 0.28–1.33; P = 0.106). No interaction effect between TMB and treatment arm was observed. Seventeen mut/Mb was identified as the optimal threshold of TMB for predicting MSI status. Actionable alterations were found in 62 (21%) of 296 patients. Genomic profiling provides an overview of the genomic landscape of mCRC in a single analysis, including actionable targets and markers of immune sensitivity. • Microsatellite testing by next-generation sequencing is higly concordant with immunohistochemistry. • High tumour mutational burden (TMB) defines a clinical and molecular subtype of mCRC. • Alterations in DNA damage repair are rare in microsatellite stable mCRC with high TMB. • Potentially actionable alterations are detectable in a small percentage of mCRC. • Molecular characterisation of mCRC is helpful in adopting personalised treatments. [ABSTRACT FROM AUTHOR]

Recent data from the TRIBE2 study have failed to suggest a higher magnitude of benefit from upfront FOLFOXIRI/bevacizumab in patients with BRAF -mutant metastatic colorectal cancer (mCRC) as previously reported in the TRIBE study. Clinical characteristics and gene expression signatures of patients with BRAF-mutant mCRC enrolled in the TRIBE2 study were evaluated with the aim of understanding that patients may derive benefit from the intensification of the upfront chemotherapy. Of 46 BRAF-mutant tumour samples analysed, 24 (52%) and 22 (48%) were classified as BM1 and BM2, respectively, and 27 (59%) and 19 (41%) were assigned to ligand-independent (LI) and ligand-dependent (LD) Wnt pathway subgroups, respectively. No prognostic impact was shown for both BM1/BM2 and LI/LD subtypes. No interaction was evident between BM1/BM2 or LI/LD signatures and the benefit provided by FOLFOXIRI/bevacizumab. Significant interaction effect was evident in terms of progression-free survival between treatment arm and primary tumour sidedness (P = 0.05) and Eastern Cooperative Oncology Group performance status (ECOG-PS; P < 0.001). Gene expression analysis failed to identify patients with BRAF-mutant mCRC candidate to upfront FOLFOXIRI/bevacizumab. ECOG-PS >0 and left-sidedness seem associated with no benefit from the intensified treatment. • A restricted panel of 44 genes discerns BM1/BM2 subtypes of BRAF mut mCRC. • AXIN2 expression distinguishes LI versus LD Wnt pathway activation of BRAF mut mCRC. • No prognostic impact was shown for both BM1/BM2 and LI/LD subtypes. • No predictive effect of both BM1/BM2 and LI/LD subtypes was shown for FOLFOXIRI/bev. • ECOG-PS >0 and left-sidedness seem associated with no benefit from FOLFOXIRI/bev. [ABSTRACT FROM AUTHOR]

Abstract: About 30% of hereditary Medullary Thyroid Carcinoma (MTC) have been demonstrated to harbour imbalance between mutant and wild-type RET alleles. We studied the RET copy number alterations (RET CNA) in 65 MTC and their correlation with RET mutation and patients’ outcome. Fluorescence in situ Hybridization and Real-time PCR revealed RET CNA in 27.7% MTC but only in a variable percentage of cells. In sporadic MTC, RET CNA were represented by chromosome 10 aneuploidy while in hereditary MTC by RET amplification. A significant higher prevalence of RET CNA was observed in RET mutated MTC (P =0.003). RET CNA was also associated to a poorer outcome (P =0.005). However, the multivariate analysis revealed that only RET mutation and advanced clinical stage correlated with the worst outcome. In conclusion, 30% MTC harbour RET CNA in variable percentage of cells suggesting cell heterogeneity. RET CNA can be considered a poor prognostic factor potentiating the poor prognostic role of RET mutation. [Copyright &y& Elsevier]