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PubMed2026

TERT promoter mutations and recurrence patterns in differentiated thyroid carcinoma.

Telomerase reverse transcriptase promoter mutations (TERT) are known prognostic factors associated with poor outcomes in differentiated thyroid carcinoma (DTC). We analyzed differences in DTC recurrence patterns over time according to TERT. A retrospective review was conducted on DTC patients who achieved remission after total thyroidectomy and/or radioactive iodine treatment at Samsung Medical Center between 1994 and 2004. The sites and patterns by time of recurrence in the patients were reviewed. In total, 367 patients with a median follow-up of 14 years (interquartile range, 12-17 years) were included. Recurrence occurred in 91 patients, wherein 56 had lymph node recurrence and 35 had either local or distant recurrence. TE RT and tumor size <2 cm were independent factors for recurrence in the Cox proportional hazards analysis. In cases of TERT-wild type (WT), the recurrence rate decreased significantly over time after diagnosis, whereas in TERT-mutant type (MT), a consistently high recurrence rate was observed. In the Kaplan-Meier analysis, TERT-MT exhibited a significantly poorer disease-free survival, with continuous recurrence over time, whereas in TERT-WT, the curve showed a gradual decline. Further analysis of the overall survival among the 91 patients revealed that TERT-MT was significantly associated with a higher risk of mortality, whereas TERT-WT exhibited a slowly decreasing curve. In conclusion, TERT-MT was a significant adverse prognostic factor wherein continuous recurrence necessitates long-term follow-up. For TERT-WT, the recurrence rate decreased compared to TERT-MT, and even in cases of recurrence, the treatment outcomes are favorable.

Humans↗

PubMed2026

Value of TERT promoter mutations for early outcomes in papillary thyroid cancer.

Telomerase reverse transcriptase (TERT) promoter mutations are associated with aggressive clinicopathological features of papillary thyroid cancer (PTC). However, their independent prognostic value remains unclear. This study aimed to evaluate the prognostic significance of TERT promoter mutations (TPMs) in predicting early treatment outcomes and event-free survival (EFS) in patients with PTC. We retrospectively analyzed a prospective cohort; patients underwent surgery at a single tertiary referral center between 2019 and 2022. Patients underwent thyroidectomy, selective postoperative radioactive iodine ablation, and levothyroxine suppression therapy. Propensity score matching (PSM, 1:1) was applied to adjust for baseline clinicopathological differences. Of 10,642 patients with available molecular data, 115 (1.1%) harbored TPMs. After PSM, 90 matched pairs of patients with TERT-wild-type and TERT-mutant tumors were analyzed. Early treatment responses at 1 and 2 years post-treatment and EFS were evaluated. Early treatment responses did not differ significantly between groups at 1 year (P = 0.212) and 2 years (P = 0.571). However, patients with TERT-mutant tumors had fewer excellent responses and higher rates of structural incomplete response. During follow-up, the TERT-mutant group experienced more recurrences and one disease-specific death. Cumulative EFS was significantly poorer in the TERT-mutant group than in the TERT-wild-type group (P = 0.022). Despite their low prevalence, TPMs were independently associated with adverse oncological outcomes, including higher rates of recurrence and mortality. TPMs may serve as valuable prognostic markers for early risk stratification in PTC.

Humans↗

PubMed2026

Machine Learning-Based Preoperative Predicting TERT Promoter Mutation and EGFR Gene Amplification Phenotype in IDH Wild-Type Glioblastoma Using Advanced MR Habitat Imaging.

BACKGROUND AND PURPOSE: The telomerase reverse transcriptase (TERT) gene promoter mutation is a crucial factor for identifying an isocitrate dehydrogenase (IDH) wild-type glioblastoma with poor prognosis, and the epidermal growth factor receptor (EGFR) amplification may be a potential prognostic factor. The purpose of this study was to investigate the value of the tumor habitats imaging model on advanced MRI in predicting TERT promoter mutation and EGFR gene amplification phenotype of IDH wild-type glioblastoma. MATERIALS AND METHODS: One hundred seventy-nine patients with pretreatment conventional MRI, DWI, and DSC-PWI were included. The data were divided into the training set (n=112), test set (n=29), and time-independent validation set (n=38). Based on the ADC and CBV map, the solid tumor area was split into several habitat subregions using the k-means clustering algorithm (hypovascular hypercellular area, hypervascular area, and hypovascular hypocellular area). In the training set, TERT promoter mutation and EGFR gene amplification phenotype prediction models were constructed using the random forest method. The reliability of prediction models was validated in the test and the time-independent validation sets. Receiver operating characteristic (ROC) curve analysis, calibration curve, and decision curve analysis (DCA) were used. RESULTS: The area under the curve (AUC) of the training, test, and validation sets of the TERT promoter prediction model was 0.877, 0.783, and 0.796, respectively. The accuracy of the TERT promoter prediction model was 82.1%, 75.9%, and 76.3%, respectively. The AUCs of the 3 sets for the EGFR gene amplification status prediction model were 0.877, 0.784, and 0.878, respectively. The accuracy of the EGFR gene amplification status prediction model was 79.5%, 75.9%, and 89.5%, respectively. Moreover, the prediction probability of these models was in good agreement with the actual result. CONCLUSIONS: The tumor habitat imaging model based on advanced MRI was useful for accurately predicting TERT promoter mutation and EGFR amplification status in IDH wild-type glioblastoma.

Humans↗

PubMed2025

The effect of TERT promoter mutation on predicting meningioma outcomes: a multi-institutional cohort analysis.

BACKGROUND: Molecular aberrations have been incorporated into tumour classification guidelines of meningioma. TERT-promoter (TERTp) mutation is associated with worse prognosis and is designated a WHO grade 3 biomarker. However, it remains unclear whether TERTp mutation is context-dependent, with other co-occurring genetic alterations potentially driving its association with prognosis. We sought to characterise the role of TERTp mutation in meningioma and guide TERTp sequencing. METHODS: We identified 1492 patients of all ages who had previously received surgery for meningioma across 14 medical centres in the USA, Canada, and Germany. Patients were eligible if they had post-surgical clinical or radiographical assessment of the resection site, and TERTp status evaluated by Nov 1, 2024. Multi-modal profiling was used to assess TERTp mutation, focal gene alterations-including CDKN2A/B loss-and copy number alterations. An adjusted WHO grade was calculated for TERTp-mutant meningiomas, incorporating all WHO criteria except TERTp status. Kaplan-Meier curves and multivariable Cox proportional hazards models were used to quantify the effect of TERTp mutation on the endpoints of overall survival and recurrence-free survival across adjusted WHO grade and co-occurring molecular alterations. FINDINGS: 64 (4·3%) of 1492 meningiomas were TERTp-mutant and 1428 (95·7%) were TERTp-wildtype. Of the TERTp-mutant meningiomas, 33 (51·6%) were from female patients and 31 (48·4%) were from male patients, and the overall median age was 67 years (IQR 60-75). Of the wildtype meningiomas, 965 (67·6%) were from female patients and 463 (32·4%) were from male patients, and the overall median age of the patients was 59 years (IQR 48-70). Data on race was inconsistently reported and thus excluded. The TERTp-mutant patients had a 5-year overall survival (49·4% [95% CI 33·7-72·4]) and 5-year recurrence-free survival (27·6% [95% CI 16·8-45·5]) resembling that of patients with WHO grade 3 TERTp-wildtype tumours (5-year overall survival 32·3% [95% CI 17·2-60·5], p=0·28, 5-year recurrence-free survival 14·3% [5·8-35·2], p=0·28). However, the TERTp-mutant group had heterogenous histological grading and was enriched for aggressive molecular features, with 1p loss present in 44 (77·2%) of 57 profiled tumours and CDKN2A/B loss in 24 (41·4%) of the 58 profiled tumours. Adjusting tumour grade revealed a subset of TERTp-mutant meningiomas that were more molecularly and clinically benign. Among TERTp-mutant tumours, CDKN2A/B loss played a defining role in stratifying tumour behaviour. Multivariable analysis confirmed this, with CDKN2A/B loss being significantly associated with shorter overall survival (HR 3·04 [95% CI 1·67-5·52], p=0·00026) and faster time to recurrence (HR 5·22 [95% CI 3·10-8·79], p<0·0001), while TERTp-mutation did not independently affect overall survival (HR 1·00 [95% CI 0·53-1·87], p=0·99) or recurrence-free survival (1·17 [95% CI 0·75-1·83], p=0·49). Sequencing for TERTp-mutation demonstrated clinical impact only among histologically WHO grade 2 meningiomas. INTERPRETATION: The indolent behaviour of certain TERTp-mutant meningiomas suggests that TERTp mutation is not sufficient to assign the most aggressive meningioma grade. Instead, TERT sequencing might offer prognostic utility in identifying high-risk cases among WHO grade 2 meningiomas. FUNDING: National Institutes of Health, National Institute of Neurological Disorders and Stroke, Friedberg Charitable Foundation, Courtney Meningioma Research Fund, Fleming Meningioma Research Fund, and the Gray Family Foundation.

Humans↗

PubMed2026

Cytologic and Surgical Correlation of TERT-Mutated Indeterminate Thyroid Nodules: A Case Series.

IntroductionTelomerase reverse transcriptase (TERT) promoter mutations is a relatively novel mutation that has been linked with thyroid cancers. This study examines the frequency, cytology and histo-morphologic features, and clinical outcomes of TERT-mutated indeterminate thyroid nodules.MethodsA retrospective review of Bethesda III and IV thyroid cytology specimen sent for ThyroSeq® testing (2019-2022) was performed, selecting those with TERT mutations. Demographics, cytologic features, surgical diagnoses, and follow-up data were analyzed.ResultsAmong 567 specimens tested, 12 (2%) harbored TERT mutations; 4 had TERT alone, and 8 had additional mutations. Average age of patients was 69 years (92% > 50 years). Eight had surgical follow-up: 50% were malignant, 25% were benign and 25% were of uncertain malignant potential. Additionally, 62% were oncocytic nodules. Clinical follow-up showed all evaluated patients were alive without recurrences or metastases at last contact.ConclusionIn our cohort, TERT promoter mutations were rare in indeterminate thyroid nodules (2%) and frequently accompanied by additional molecular changes. It is more frequently detected in older patients. Unlike prior reports describing TERT mutations exclusively in malignant thyroid tumors, our findings encompassed a broader histological spectrum, including benign, uncertain malignant potential and malignant lesions.

Humans↗

PubMed2025

Predicting telomerase reverse transcriptase promoter mutation status in glioblastoma by whole-tumor multi-sequence magnetic resonance texture analysis.

OBJECTIVE: This study aimed to determine the feasibility of preoperative multi-sequence magnetic resonance texture analysis (MRTA) for predicting TERT promoter mutation status in IDH-wildtype glioblastoma (IDHwt GB). METHODS: The clinical and imaging data of 111 patients with IDHwt GB at our hospital between November 2018 and June 2023 were retrospectively analyzed as the training set, and those of 23 patients with IDHwt GB between July 2023 and November 2023 were interpreted as the validation set. We used molecular sequencing results to classify the training set into TERT promoter mutation and wildtype groups. Textural features of the whole-tumor volume were extracted, including T2-weighted imaging (T2WI), T2-fluid-attenuated inversion recovery, apparent diffusion coefficient (ADC) map, and contrast-enhanced T1-weighted imaging (CE-T1). All textural features were obtained using open-source pyradiomics. After feature selection, logistic regression was used to build prediction models, and a nomogram was generated. Finally, the model was validated using validation cohort. RESULTS: The CE-T1_Model (AUC 0.704) had a better predictive ability than the T2_Model (AUC 0.684) and ADC_Model (AUC 0.624). The MRI_Combined_Model (CE-T1, T2, and ADC texture features) (AUC 0.780) had a better predictive ability than the Clinical_Model (AUC 0.758). The Combined_Model (CE-T1, T2, ADC texture features, and clinical features) had the best predictive performance (AUC 0.871), with a sensitivity, specificity, and accuracy of 82.60 %, 83.30 %, and 80.18 %, respectively. The AUC, sensitivity, specificity, and accuracy in the validation cohort were 0.775, 86.70 %, 75.00 %, and 69.57 %, respectively. CONCLUSIONS: Whole-tumor multi-sequence MRTA can be used as non-invasive quantitative parameters to assist in the preoperative clinical prediction of TERT promoter mutation status in IDHwt GB.

Humans↗

PubMed2026

Histopathologic, Genomic, and Clinical Characteristics of Primary Cutaneous Melanocytic Tumors With Concomitant NRAS Q61 and IDH1 R132C Mutations.

Cutaneous melanocytic tumors with concomitant NRAS Q61 and IDH1 R132C mutations have been described as intermediate-grade melanocytomas with characteristic biphasic morphology, but the malignant end of this genotype-defined spectrum remains poorly characterized. We assessed histopathologic, immunohistochemical, molecular, and clinical features of 16 primary cutaneous melanocytic tumors harboring both mutations. Following integrated review, 7 tumors were classified as melanocytoma and 9 as melanoma. Melanocytomas showed reproducible biphasic architecture with congenital nevus-like features, a biphasic HMB-45 pattern, low Ki-67, PRAME negativity, retained p16, and minimal copy number variations (CNVs). Melanomas retained partial morphologic overlap in a subset but were distinguished by higher-grade cytology, immunohistochemical features supportive of malignancy, and progression-associated genomic alterations, including TERT promoter mutation (9/9), 9p21/CDKN2A loss (4/7), and higher CNV burden. NRAS and IDH1 variant allele frequencies were strongly concordant (r = 0.83, P < 0.001), supporting their presence in the same dominant clone. Clinically, two patients presented with stage IIIB disease, but no distant metastasis or melanoma-related death occurred during a median melanoma follow-up of 3.9 years (IQR, 2.5-5.1). In exploratory analyses, moderate-to-severe atypia (RR, 6.2; 95% CI, 1.0-38.8; P = .009), Ki-67 ≥10% (RR, 4.4; 95% CI, 1.1-18.4; P = .003), lymphocytic infiltrate (RR, 2.4; 95% CI, 1.1-5.3; P = .03), absence of the typical biphasic pattern (RR, 2.4; 95% CI, 1.1-5.3; P = .03), and complete p16 loss (RR, 2.4; 95% CI, 1.1-5.3; P = .03) were associated with molecular or clinical progression to melanoma, defined as the presence of at least one of the following: TERT promoter mutation, pathogenic CDKN2A mutation, 9p21/CDKN2A loss, ≥3 genome-wide segmental CNVs, or any metastasis. These findings support the existence of NRAS/IDH1 co-mutated melanoma as the malignant counterpart of NRAS/IDH1-mutated melanocytoma within a single genotype-defined spectrum.

IDH1 mutations↗

PubMed2025

Clinical, Morphologic, and Molecular Findings in Neurotrophic Tyrosine Receptor Kinase 3 (NTRK3) Fusion Spitz Neoplasms.

Neurotrophic tyrosine receptor kinase 3 (NTRK3) fusions are a relatively common driver of Spitz neoplasms. This subset of Spitz neoplasms may have smaller cells without the typical abundant glassy eosinophilic cytoplasm seen in most Spitz neoplasms. This can make it difficult to recognize them as belonging to the Spitz family and potentially result in misdiagnosis as melanoma. In this study, we assessed the clinical, morphologic, and genomic features of 60 NTRK3 fusion Spitz neoplasms (13 previously reported and 47 new cases) and performed a comprehensive review of the literature. We identified 5 characteristic morphologic patterns: (1) conventional Spitz nevus (SN) or Spitz tumor (ST), (2) spindle cell nevus of Reed, (3) spindle cell tumor of Reed, (4) dysplastic SN, and (5) exclusively spindle cell variant of SN/ST. The most common fusion partners were MYO5A and ETV6. DNA copy number changes were infrequent (18% of cases), with an average of 1 copy number variant per case. Among 54 cases tested for a TERT promoter mutation, all were negative. One case had a homozygous deletion of 9p21. The majority of cases were diagnosed as SN or Reed nevi (n = 37), rather than ST or Reed tumor (n = 23), and none were diagnosed as Spitz melanoma. Among the 30 patients with outcome data, none experienced recurrence following excision (mean follow-up time was 15 months). NTRK3 fusions can produce morphologic variants of Spitz neoplasms that may be difficult to recognize as belonging to the Spitz family. Familiarity with these morphologic patterns can facilitate identification of the NTRK3 fusion, optimizing classification and distinction from melanoma.

Humans↗

PubMed2026

Distinct molecular profiles of indeterminate and malignant thyroid nodules in patients under 21 years of age.

Although uncommon, thyroid nodules (TN) in pediatric and young adult patients carry higher malignancy risk and often present with a high burden of metastatic disease than adults. The molecular features underlying this distinct clinical behavior remain unclear. We analyzed Afirma Genomic Sequencing Classifier (GSC) data from 283,621 TN, comparing patients <21 and ≥21 years. Cytology (Bethesda), GSC benign (B) vs suspicious (S) calls, and Afirma Xpression Atlas (XA) variant/fusion profiles were evaluated in GSC-S and Bethesda V/VI samples. Genome-wide expression was used to derive pathway signatures and thyroid cancer-related scores: BRAF-RAS score (BRS), ERK, follicular and epithelial-to-mesenchymal transition (FMT, EMT) and thyroid differentiation scores (TDS). Among 2,397 patients <21 (median age 18.9; 81.4% female) and 281,224 adults ≥21 (median age 59.8; 77.1% female), <21 samples showed more Bethesda V/VI cytology (14.5% vs 5.0%; p<0.0001) and a lower GSC-B rate (43.5% vs 68.8%; p<0.0001). In GSC-S samples, total variant detection was higher in <21 (45.3% vs 37.4%), with enriched BRAF p.V600E, TSHR, and DICER1 variants, while HRAS variants were more common in adults (all p<0.01). Gene fusions involving RET, NTRK3 and ALK were enriched in <21 (14.5% vs 5.5%; p<0.0001). TERT promoter mutations were absent in <21 yrs GSC-S and Bethesda V/VI samples (vs 4.2% and 9.3% in adults). GSC-S <21 showed cell-cycle pathway enrichment. RET/NTRK/ALK-positive <21 demonstrated enrichment of angiogenesis and EMT pathways, higher ERK/EMT/FMT scores, and lower BRS/TDS scores vs genotyped-matched adults. These molecular differences provide mechanistic insight into the more invasive phenotype in pediatric and young adult TN.

BRAF↗

PubMed2026

Diagnostic performance of intraoperative in vivo hyperspectral imaging for meningioma grading and molecular alterations: results from a prospective feasibility study.

OBJECTIVE: Hyperspectral imaging (HSI) is an emerging intraoperative, noninvasive, contrast agent-free imaging modality that enables quantitative assessment of tissue composition. The present study aimed to investigate whether HSI-derived tissue parameters correlate with WHO grade and molecular markers of aggressiveness in cranial meningiomas. METHODS: In this prospective study, intraoperative in vivo HSI was performed using the TIVITA tissue system, capturing spectral signatures between 500 and 1000 nm. Quantitative tissue parameters included tissue oxygen saturation (StO2), near-infrared perfusion index, organ hemoglobin index (OHI), and tissue water index (TWI). HSI parameters were correlated with histopathological WHO grade and molecular alterations, including CDKN2A/B deletion, TERT promoter mutation, and 1p/22q loss. Group differences were analyzed using one-way ANOVA, and diagnostic performance was assessed using receiver operating characteristic (ROC) analysis. RESULTS: Forty-six meningiomas were included, comprising WHO grade 1 (n = 35) and WHO grade 2-3 (n = 11) tumors. TWI was significantly higher in WHO grade 2-3 meningiomas compared with WHO grade 1 tumors (mean 0.49 [SD 0.12] vs 0.38 [SD 0.17], p = 0.048). ROC analysis demonstrated an area under the ROC curve (AUC) of 0.71 (95% CI 0.56-0.86, p = 0.036) for TWI in discriminating higher-grade disease. A TWI cutoff ≥ 0.367 identified all WHO grade 2-3 meningiomas with 100% sensitivity and 100% negative predictive value. In a molecular subgroup (n = 15), OHI appeared higher in tumors with homozygous CDKN2A/B deletion than in nondeleted tumors (mean 0.77 [SD 0.04] vs 0.62 [SD 0.10]). However, only 3 CDKN2A/B-deleted cases were available, and these findings should be considered descriptive. ROC analysis yielded an AUC of 0.89 (95% CI 0.71-1.00). An OHI cutoff ≥ 0.712 identified all three CDKN2A/B-deleted tumors (100% sensitivity), with 83.3% specificity and 86.7% accuracy. CONCLUSIONS: The present investigation demonstrated that HSI-derived tissue water and hemoglobin metrics provide biologically meaningful information in meningiomas. Low tissue water content appeared to rule out higher-grade diseases in this first subset cohort, while elevated hemoglobin showed a potential association with CDKN2A/B deletion in a small exploratory subgroup. These findings support the potential of HSI as a real-time noninvasive tool for intraoperative risk stratification and should be evaluated in large-scale studies. German Clinical Trials Register no. DRKS00036771 (www.drks.de).

Humans↗

PubMed2026

Leptomeningeal Dissemination in TERT Promoter-mutant Anaplastic Pleomorphic Xanthoastrocytoma Responding to BRAF-MEK Inhibition: A Case Report.

Pleomorphic xanthoastrocytoma is a rare brain tumor that frequently harbors the oncogenic BRAF V600E mutation. Approximately 28.6%-47% of high-grade pleomorphic xanthoastrocytomas are associated with TERT promoter mutation and leptomeningeal dissemination, for which no established treatment exists and the prognosis remains poor. Combination therapy with BRAF and MEK inhibitors has demonstrated efficacy in BRAF V600E-mutant brain tumors. We report a case of a 22-year-old man with a right temporal lobe tumor initially diagnosed as World Health Organization grade 2 pleomorphic xanthoastrocytoma after gross total resection. Two years later, the tumor recurred and underwent malignant transformation to World Health Organization grade 3 pleomorphic xanthoastrocytoma. At the third resection, pathological and genomic analyses confirmed BRAF V600E mutation together with TERT promoter mutation. Following chemoradiotherapy, spinal leptomeningeal dissemination developed. After spinal irradiation, dabrafenib plus trametinib was initiated, resulting in partial radiological response and symptomatic improvement. Although regrowth occurred 10 months after initiation of targeted therapy, the patient remains alive at the time of writing. Here, we report a case of recurrent anaplastic BRAF V600E-mutant pleomorphic xanthoastrocytoma with leptomeningeal dissemination that showed a transient but clinically meaningful response to combined BRAF-MEK inhibition and spinal radiation therapy. In addition, this case raises the possibility of an association between TERT promoter mutation and leptomeningeal dissemination, although further studies are required to clarify this relationship.

BRAF V600E↗

PubMed2025

High Prevalence of Potential Molecular Therapeutic Targets in Poorly Differentiated Thyroid Carcinoma.

Poorly differentiated thyroid carcinoma (PDTC) is a rare thyroid cancer with aggressive clinical course and peculiar clinical/pathological characteristics but lacking effective therapeutic options, when surgery is not curative. We aimed at the molecular characterization of PDTC with a specific focus on the identification of potential therapeutic targets. A series of PDTC cases was selected from a multi-institutional network. Fifty-nine samples underwent wide targeted DNA and RNA next-generation sequencing (NGS) testing and immunohistochemical analysis for mismatch repair (MMR) proteins. Gene fusion analysis was enriched by 25 additional samples. Prevalence of MMR protein loss was 11.9%. The most prevalent mutations were in NRAS (25%) and TP53 (25%), mutually exclusive. TERT promoter (TERTp) mutations were detected in 19.6% of cases (10/51). NRAS-mutated cases were enriched for mutations in genes belonging to the same pathway. TP53-mutated samples lacked TERTp co-mutations, but were associated with mutations in PTEN and in genes related to MMR system and/or loss of MMR proteins. TERTp mutations were the most prevalent alterations (28%, 7/25) in a third group that lacked NRAS or TP53 mutations. Four cases harbored gene fusions, including two cases harboring the TBL1XR1::PIK3CA fusion that has never been reported in thyroid cancer, so far. In conclusion, PDTC may be genomically segregated in subgroups with specific molecular characteristics. Overall, targetable gene fusions have a prevalence of 9% (4/42). Moreover, 47% of cases are potential candidates for individualized target therapies since they harbor mutations in genes coding for potentially targetable molecules and/or have defects in the MMR system.

Humans↗

PubMed2019

Discovering human transcription factor physical interactions with genetic variants, novel DNA motifs, and repetitive elements using enhanced yeast one-hybrid assays.

Identifying transcription factor (TF) binding to noncoding variants, uncharacterized DNA motifs, and repetitive genomic elements has been technically and computationally challenging. Current experimental methods, such as chromatin immunoprecipitation, generally test one TF at a time, and computational motif algorithms often lead to false-positive and -negative predictions. To address these limitations, we developed an experimental approach based on enhanced yeast one-hybrid assays. The first variation of this approach interrogates the binding of >1000 human TFs to repetitive DNA elements, while the second evaluates TF binding to single nucleotide variants, short insertions and deletions (indels), and novel DNA motifs. Using this approach, we detected the binding of 75 TFs, including several nuclear hormone receptors and ETS factors, to the highly repetitive Alu elements. Further, we identified cancer-associated changes in TF binding, including gain of interactions involving ETS TFs and loss of interactions involving KLF TFs to different mutations in the TERT promoter, and gain of a MYB interaction with an 18-bp indel in the TAL1 superenhancer. Additionally, we identified TFs that bind to three uncharacterized DNA motifs identified in DNase footprinting assays. We anticipate that these enhanced yeast one-hybrid approaches will expand our capabilities to study genetic variation and undercharacterized genomic regions.

Algorithms↗

PubMed2026

Landscape of genetic alterations affecting cancer genes in primary and advanced malignant phyllodes tumours.

BACKGROUND: Malignant phyllodes tumours (MPT) are aggressive breast fibroepithelial neoplasms. Their rarity has limited their genetic characterization, and associations with genetic ancestry and progression drivers remain poorly understood. Prior studies suggest two evolutionary pathways according to MED12 mutational status. We sought to determine the repertoire of somatic genetic alterations in cancer genes in primary versus metastatic/recurrent MPTs, and according to MED12 mutational status and genetic ancestry. MATERIALS AND METHODS: We analysed the paired tumour-normal targeting sequencing data (up to 505 cancer-related genes) of 31 MPTs (primary, n = 20; metastatic/recurrent, n = 11). RESULTS: Metastatic/recurrent MPTs harboured a numerically higher frequency of genetic alterations in CDKN2A/2B (55% vs. 25%). Moreover, analysis of an MPT case with paired primary and metastatic samples revealed a CDKN2A/2B homozygous deletion restricted to the metastatic sample, suggesting a role for CDKN2A/2B in progression. Compared with MED12-wild type MPTs, MED12-mutant MPTs had higher tumour mutation burden (P = 0.002), frequency of TERT promoter (82% vs. 35%; P = 0.02) and RB1 mutations (45% vs. 5%; P = 0.01). Genetic alterations in the PI3K pathway, including PIK3CA and PTEN, were only present in MED12-wild type MPTs, and absent in MED12-mutant cases (15% vs. 0%; P > 0.05). Furthermore, genetic alterations in EGFR were restricted to MPTs from patients of European genetic ancestry and absent in those of Asian ancestry (43% vs. 0%; P > 0.05). CONCLUSIONS: Taken together, the repertoire of genetic alterations in primary and metastatic/recurrent MPTs shows overlap, and CDKN2A/2B homozygous deletions may play a role in progression. Additionally, molecular profiles of MPTs may vary according to genetic ancestry and MED12 mutational status.

Humans↗