TP53 Mutations Research Articles

Characteristics of H3K27M-mutant diffuse gliomas with a non-midline location.

Diffuse midline gliomas (DMG) with H3K27 alterations (H3K27M-DMG) are a highly aggressive form of brain cancer. In rare cases, H3K27 mutations have been observed in diffuse non-midline gliomas (DNMG). It is currently unclear how these tumors should be classified. Herein, we analyze the characteristics of DNMG with H3K27M mutations. We reviewed the clinical, radiological and histological characteristics of all patients with an H3K27M mutated diffuse glioma diagnosed in our institution, between 2016 and 2023, to identify cases with a non-midline location. We then performed a molecular characterization (DNA methylation profiling, whole genome and transcriptome sequencing or targeted sequencing) of patients with an H3K27M-mutant DNMG and reviewed previously reported cases. Among 51 patients (18 children and 33 adults) diagnosed with an H3K27M diffuse glioma, we identified two patients (4%) who had a non-midline location. Including our two patients, 39 patients were reported in the literature with an H3K27M-mutant DNMG. Tumors were most frequently located in the temporal lobe (48%), affected adolescents and adults, and were associated with a poor outcome (median overall survival was 10.3 months (0.1-84)). Median age at diagnosis was 19.1 years. Tumors frequently harbored TP53 mutations (74%), ATRX mutations (71%) and PDGFRA mutations or amplifications (44%). In DNA methylation analysis, H3K27M-mutant DNMG clustered within or close to the reference group of H3K27M-mutant DMG. Compared to their midline counterpart, non-midline gliomas with H3K27M mutations seemed more frequently associated with PDGFRA alterations. DNMG with H3K27M mutations share many similarities with their midline counterpart, suggesting that they correspond to a rare anatomical presentation of these tumors. This is of paramount importance, as they may benefit from new therapeutic approaches such as ONC201.

A common druggable signature of oncogenic c-Myc, mutant KRAS and mutant p53 reveals functional redundancy and competition among oncogenes in cancer

The major driver oncogenes MYC, mutant KRAS, and mutant TP53 often coexist and cooperate to promote human neoplasia, which results in anticancer therapeutic opportunities within their downstream molecular programs. However, little research has been conducted on whether redundancy and competition among oncogenes affect their programs and ability to drive neoplasia. By CRISPR‒Cas9-mediated downregulation we evaluated the downstream proteomics and transcriptomics programs of MYC, mutant KRAS, and mutant TP53 in a panel of cell lines with either one or three of these oncogenes activated, in cancers of the lung, colon and pancreas. Using RNAi screening of the commonly activated molecular programs, we found a signature of three proteins - RUVBL1, HSPA9, and XPO1, which could be efficiently targeted by novel drug combinations in the studied cancer types. Interestingly, the signature was controlled by the oncoproteins in a redundant or competitive manner rather than by cooperation. Each oncoprotein individually upregulated the target genes, while upon oncogene co-expression each target was controlled preferably by a dominant oncoprotein which reduced the influence of the others. This interplay was mediated by redundant routes of target gene activation - as in the case of mutant KRAS signaling to c-Jun/GLI2 transcription factors bypassing c-Myc activation, and by competition - as in the case of mutant p53 and c-Myc competing for binding to target promoters. The global transcriptomics data from the cell lines and patient samples indicate that the redundancy and competition of oncogenic programs are broad phenomena, that may constitute even a majority of the genes dependent on oncoproteins, as shown for mutant p53 in colon and lung cancer cell lines. Nevertheless, we demonstrated that redundant oncogene programs harbor targets for efficient anticancer drug combinations, bypassing the limitations for direct oncoprotein inhibition.

Developing a prognostic signature: identifying differentially expressed genes in cardia and non-cardia gastric cancer for immunity and therapeutic sensitivity analysis.

Gastric cancer (GC) can be anatomically categorized into two subtypes; that is, cardia gastric cancer (CGC) and non-cardia gastric cancer (NCGC), which have distinct molecular mechanisms and prognoses. At present, the majority of pharmacological interventions for GC adhere to non-specific treatment regimens. The stratification of GC based on molecular disparities between CGC and NCGC has important clinical guidance value and could help in the development of precision therapies tailored to individual patient needs. Nevertheless, research in this specialized field remains notably limited. This study aims to investigate the molecular differences between CGC and NCGC and to leverage these differences to develop a prognostic risk scoring model (PRSM). We used patient data from The Cancer Genome Atlas (TCGA) and performed a differentially expressed gene (DEG) analysis between CGC and NCGC. A PRSM was developed from the prognosis-associated DEGs identified through Cox regression analyses and was well validated using Gene Expression Omnibus (GEO) data. A total of 339 DEGs were identified between CGC and NCGC, and four prognosis-associated genes were used to construct the PRSM. Using the risk coefficients and expression levels of signature genes, a median risk score (RS) was calculated to classify patients into high- and low-risk groups. The high-risk group had a significantly worse prognosis than the low-risk group. An in-depth analysis revealed that TP53 mutations were more prevalent in the high-risk group, and MUC16 mutations were more prevalent in the low-risk group. A gene set enrichment analysis (GSEA) and the CIBERSORT algorithm were used to assess the differences in the significantly enriched pathways and immune microenvironment in the high- and low-risk groups, respectively. The inhibitory concentration (IC50) values of the chemotherapy drugs for GC also varied between the two groups. This study elucidated the unique molecular characteristics of GC subtypes based on the anatomical site and provided a preliminary contribution for the development of precision medicine for GC.

Impact of clonal TP53 mutations with loss of heterozygosity on adjuvant chemotherapy and immunotherapy in gastric cancer

BackgroundThis study aimed to reveal the effect of TP53 status on clinical outcomes and underlying mechanism in gastric cancer (GC) patients.MethodsTP53 status was divided into three groups according to genome sequencing, namely clonal mutations with LOH (C-LOH), clonal diploid or subclonal mutations (CD-SC), and wild type (WT). The p53 protein activity was divided into over-expression (OE), Null and WT according to immunohistochemical staining. Four cohorts, including the TCGA, SMC, ZSHS and FUSCC cohort, were analyzed for association between TP53 mutation status and clinical outcomes and the underlying mechanism.ResultsIn TCGA cohort, TP53 CD-SC were associated with superior overall survival compared to TP53 C-LOH cases. GC patients could benefit from ACT only in TP53 CD-SC/ p53 OE and TP53/ p53 WT subgroups, and TP53 C-LOH subgroup demonstrated the worst response to pembrolizumab among three subgroups. Genomic and immunophenotypic deconvolution revealed that TP53 C-LOH, CD-SC and WT differed for genomic and immune-related features.ConclusionsTP53 C-LOH GCs with genomic instability and immune evasion phenotype have poor clinical outcomes in patients treated with ACT or immunotherapy.

Implementing Massive Parallel Sequencing into Biliary Samples Obtained through Endoscopic Retrograde Cholangiopancreatography for Diagnosing Malignant Bile Duct Strictures.

Despite advancements in radiologic, laboratory, and pathological evaluations, differentiating between benign and malignant bile duct strictures remains a diagnostic challenge. Recent developments in massive parallel sequencing (MPS) have introduced new opportunities for early cancer detection and management, but these techniques have not yet been rigorously applied to biliary samples. We prospectively evaluated the Oncomine Comprehensive Assay (OCA) and the Oncomine Pan-Cancer Cell-Free Assay (OPCCFA) using biliary brush cytology and bile fluid obtained via endoscopic retrograde cholangiopancreatography from patients with bile duct strictures. The diagnostic performance of MPS testing was assessed and compared to the pathological findings of biliary brush cytology and primary tissue. Mutations in TP53, BRAF, CTNNB1, SMAD4, and K-/N-RAS identified in biliary brush cytology samples were also detected in the corresponding bile fluid samples from patients with extrahepatic cholangiocarcinoma. These mutations were also identified in the bile fluid samples, but with variant allele frequencies lower than those in the corresponding biliary brush cytology samples. In control patients diagnosed with gallstones, neither the biliary brush cytology samples nor the bile fluid samples showed any pathogenic mutations classified as tier 1 or 2. Our study represents a prospective investigation into the role of MPS-based molecular testing in evaluating bile duct strictures. MPS-based molecular testing shows promise in identifying actionable genomic alterations, potentially enabling the stratification of patients for targeted chemotherapeutic treatments. Future research should focus on integrating OCA and OPCCFA testing, as well as similar MPS-based assays, into existing surveillance and management protocols for patients with bile duct strictures.

Botryoid-type Embryonal Rhabdomyosarcoma: A Comprehensive Clinicopathologic and Molecular Appraisal With Cross-comparison to its Conventional-type Counterpart.

Embryonal rhabdomyosarcoma (ERMS) is the most common subtype of RMS, occurring in soft tissue and visceral sites of young children, and is associated with favorable outcomes. A subset occurs in mucosal-lined luminal structures, displaying a unique grape-like growth termed as "botryoid-type." To further delineate the differences between conventional (cERMS) and botryoid-type (bERMS) RMS, we performed a comparative histologic review and comprehensive molecular profiling of 48 cases (25 bERMS and 23 cERMS). All tumors were subjected to a hybridization capture-based targeted matched tumor-normal DNA NGS assay. The mean age was 17 and 7 years for bERMS and cERMS, respectively. Most bERMS were female with a predilection for the gynecologic tract (75%), while cERMS had a slight male predominance and were preferentially located in abdominopelvic and paratesticular sites (30%, each). All bERMS exhibited an exophytic, bulbous architecture accompanied by a subepithelial "cambium layer." Distinctive germline alterations were detected, with DICER1 (18%) and FH (6%) mutations only in bERMS, and rare TP53, VHL, and APC mutations in cERMS. Similarly, contrasting somatic genomic landscapes were observed, with frequent DICER1 (52%, P**<0.0001) and TP53 (36%, P*<0.05) alterations exclusively in bERMS. Cartilaginous differentiation was only observed in DICER1-mutated bERMS. All patients had longitudinal follow-up. bERMS patients with somatic/germline DICER1 mutations showed significantly improved recurrence-free survival compared with that of DICER1-wild type patients (P*<0.05). Moreover, bERMS showed improved disease-specific survival compared with that of cERMS, with 8% versus 30% (P*<0.05) dead of disease, respectively. In summary, we compare the molecular underpinnings of the largest cohort of bERMS and cERMS with targeted DNA sequencing and long-term follow-up data. Our findings reveal divergent genomic topographies between the 2 groups, with bERMS showing unique germline and somatic abnormalities, including enrichment in DICER1 and TP53 alterations, and a trend towards improved survival.

Real-world Comparison of P53 Immunohistochemistry and TP53 Mutation Analysis Using Next-generation Sequencing.

TP53 mutation in breast cancer (BC) is associated with chemoresistance, endocrine therapy resistance, and late recurrence, resulting in poor prognosis. Nuclear accumulation of p53 in immunohistochemistry (IHC) is a surrogate marker of TP53 mutation. This study analyzed the frequency, type, and distribution of TP53 mutations in BCs and assessed the efficacy of p53 IHC as a surrogate marker of TP53 mutation. We collected data from 112 BC cases, including the results of p53 IHC and next-generation sequencing (NGS). Over-expression of p53 IHC was observed in 36 patients (32.1%), complete absence in 19 patients (17.0%), aberrant cytoplasmic staining in 1 patient (0.9%), and wild-type in 56 (50.0%) patients. The concordance rate between TP53 mutation and p53 IHC was 88.4% in all BCs, 89.9% in luminal BCs, and 86.0% in triple-negative BCs (TNBC). TNBC, abnormal p53 IHC pattern, p53 IHC over-expression, neoadjuvant chemotherapy (NAC) history, TP53 mutation, and high pre-treatment ki-67 labeling index (≥50%) were significantly associated with worse distant metastasis-free survival (DMFS) and overall survival (OS) (p<0.05). Pre-NAC clinical stage III was associated with worse DMFS but not OS. Multivariate analysis showed that NAC history, TNBC, and p53 IHC over-expression were independent predictors of worse DMFS. An abnormal p53 IHC pattern and NAC history were independent predictors of worse OS. P53 IHC is a valid surrogate marker of TP53 mutation in BC. Accumulation of abnormal p53 alone, regardless of TP53 mutation, was associated with worse DMFS and can be used as an easily accessible biomarker to predict chemoresistance.

Incorporation mutational profile might reduce the importance of blast count in prognostication of low-risk myelodysplastic syndromes.

Addition of molecular data to prognostic models has improved risk stratification of myelodysplastic neoplasms (MDS). However, the role of molecular lesions, particularly in the group of low-risk disease (LR-MDS), is uncertain. We evaluated a set of 227 patients with LR-MDS. Overall survival (OS) and probability of leukaemic progression were the main endpoints. RUNX1 was associated with lower OS and SF3B1 with a reduced risk of death (HR: 1.7, 95% CI, 1.1-2.9; p = 0.05; and HR: 0.23, 95% CI 0.1-0.5; p < 0.001; respectively). TP53 and RUNX1 mutations were predictive covariates for the probability of leukaemic progression (p < 0.001). Blast percentage, neither analysed as categorical (<5% vs. 5%-9%; HR: 1.3, 95% CI, 0.7-2.9; p = 0.2) nor as a continuous variable (HR: 1.07, 95% CI, 0.9-1.1; p = 0.07), had impact on survival or probability of progression (sHR: 1.05, 95% CI, 0.9-1.1; p = 0.2). These results retained statistical significance when analysis was restricted to the definition of LR-MDS according to the WHO 2022 and ICC classifications (<5% blasts). Thus, with the incorporation of molecular data, blast percentage happens to lose clinical significance both for survival and probability of progression in the group of patients with LR-MDS.

Prognostic value of anoikis-related genes revealed using multi-omics analysis and machine learning based on lower-grade glioma features and tumor immune microenvironment

BackgroundThe investigation explores the involvement of anoikis-related genes (ARGs) in lower-grade glioma (LGG), seeking to provide fresh insights into the disease's underlying mechanisms and to identify potential targets for therapy. MethodsWe applied unsupervised clustering techniques to categorize LGG patients into distinct molecular subtypes based on ARGs with prognostic significance. Additionally, various machine learning algorithms were employed to pinpoint genes most strongly correlated with patient outcomes, which were then used to develop and assess risk profiles. ResultsOur analysis identified two distinct molecular subtypes of LGG, each with significantly different prognoses. Patients in Cluster 2 had a median survival of 2.036 years, markedly shorter than the 7.994 years observed in Cluster 1 (P < 0.001). We also constructed a six-gene ARG signature that efficiently classified patients into two risk categories, showing median survival durations of 4.084 years for the high-risk group and 10.304 years for the low-risk group (P < 0.001). Significantly, the immune profiles, tumor mutation characteristics, and drug sensitivity varied greatly among these risk groups. The high-risk group was characterized by a “cold” tumor microenvironment (TME), a lower IDH1 mutation rate (61.7 % vs. 91.4 %), a higher TP53 mutation rate (53.7 % vs. 38.9 %), and greater sensitivity to targeted therapies such as QS11 and PF-562271. Furthermore, our nomogram, integrating risk scores with clinicopathological features, demonstrated strong predictive accuracy for clinical outcomes in LGG patients, with an AUC of 0.903 for the first year. The robustness of this prognostic model was further validated through internal cross-validation and across three external cohorts. ConclusionsThe evidence from our research suggests that ARGs could potentially serve as reliable indicators for evaluating immunotherapy effectiveness and forecasting clinical results in patients with LGG.

Aberrant p53 immunostaining patterns in breast carcinoma of no special type strongly correlate with presence and type of TP53 mutations

Recent studies have revealed an association between TP53 mutations and endocrine resistance in hormone receptor-positive, HER2-negative breast cancer (HR + HER2 −BC). Aberrant p53 immunostaining (IHC) patterns may provide a surrogate marker for TP53 mutations. Building upon a ternary algorithm of aberrant staining patterns, this study evaluates the reliability of p53 IHC as screening tool for TP53 mutations in BC (NST). Furthermore, it describes the histopathological and molecular characteristics of TP53-mutated cases, along with the mutational status of PIK3CA. This study comprised 131 early-stage, node-negative BCs with available core biopsies and resection specimens. Cases were categorized as follows: HR + HER2 − (85 cases), HER2 + (21 cases) and triple negative (TN, 25 cases). Aberrant IHC staining patterns for p53 were defined as overexpression (OE), complete absence (CA) and cytoplasmic (CY). In addition, targeted sequencing of TP53 and PIK3CA genes was performed. TP53 mutations were identified in 53 of 126 cases (42.1%). Within HR + HER2 − cases, TP53 mutations were found in 17 of 80 cases (21.3%). IHC accurately predicted TP53 mutation in 96.2% of cases with a specificity of 100%. Additionally, there was a significant agreement between missense mutations and OE, as well as between truncating mutations and CA (κ 73% and 76%). CY was observed in two TN cases with truncating mutations within the nuclear localization signalling domain of p53. TP53-mutated cases exhibited higher grade, greater nuclear pleomorphism and higher Ki-67 proliferation index and were associated with the PIK3CA wild-type status (p < 0.001). p53 IHC may provide a useful screening tool for identifying TP53-mutated BC of NST.

Association between low incidence of TP53 mutations and reduced early relapse rates in Uygur DLBCL.

Diffuse large B-cell lymphoma (DLBCL) demonstrates significant heterogeneity, investigations into the distinctions in clinical and molecular characteristics between Chinese Uygur and Han DLBCL patients remain unexplored. We retrospectively reviewed 279 DLBCL patients (105 Uygur and 174 Han patients), of which 155 patients underwent genetic profiling by NGS. Compared with Han patient, Uygur patients have better clinical prognostic indicators, including a higher proportion of patients with 0-1 extranodal involvement and I/II Ann Arbor staging. Consistently, Uygur patients were significantly associated with lower risk of relapse (P = 0.06), with a one-year relapse rate of 5% vs 17% and two-year relapse rate of 19% vs 36% compared to Han patients. At the molecular level, TP53 (21.3%) was among the top frequently altered gene in the cohort. Notably, the Uygur patients exhibited a significantly lower frequency of TP53 alterations and higher frequency of ASXL3 alterations. Logistic regression analysis showed that the lowered frequency of TP53 and enrichment of ASXL3 in the Uygur patients were independent of other factors. However, only patients with TP53 mutations had higher relapse rate than those with wild type TP53 (one-year, 20% vs 10%; two-year, 51% vs 21%). Our findings highlight the notable contribution of a low TP53 mutation frequency in Uygur patients as a pivotal factor associated with the favorable prognosis of this population.

PIK3CA Mutated Colorectal Cancers Without KRAS, NRAS and BRAF Mutations Possess Common and Potentially Targetable Mutations in Epigenetic Modifiers and DNA Damage Response Genes.

Despite therapeutic advancements, metastatic colorectal cancer is usually fatal, necessitating novel approaches based on the molecular pathogenesis to improve outcomes. Some colorectal cancers have no mutations in the extended RAS panel (KRAS, NRAS, BRAF) genes and represent a special subset, which deserves particular therapeutic considerations. The genomic landscape of colorectal cancers from publicly available genomic series was interrogated, using the cBioportal platform. Colorectal cancer cohorts with cancers devoid of KRAS/NRAS or BRAF mutations were evaluated for the presence of mutations in the catalytic sub-unit alpha of kinase PI3K, encoded by the gene PIK3CA. PIK3CA mutations in the absence of KRAS/NRAS/BRAF mutations were observed in 3.7% to 7.6% of colorectal cancers in the different series examined. Patients with all four genes in wildtype configuration (quadruple wild type) represented 32.2% to 39.9% of cases in the different series examined. Compared with quadruple wild type cancers, triple (KRAS/NRAS/BRAF) wild type/PIK3CA mutated cancers had a higher prevalence of high TMB cases and additional mutations in colorectal cancer associated genes except for mutations in TP53. Mutations in genes encoding for epigenetic modifiers and the DNA damage response (DDR) were also more frequent in triple wild type/PIK3CA mutated cancers. The prognosis of the two groups was comparable. Colorectal cancers with PIK3CA mutations in the absence of KRAS/NRAS/BRAF mutations have frequently mutations in epigenetic modifiers and DDR response genes, which may provide opportunities for targeting. These mutations are present in a smaller subset of quadruple wild type cancers.

Somatic MED12 Mutations in Myometrial Cells.

Over 70% of leiomyoma (LM) harbor MED12 mutations, primarily in exon 2 at c.130-131 (GG). Myometrial cells are the cell origin of leiomyoma, but the MED12 mutation status in non-neoplastic myometrial cells is unknown. In this study, we investigated the mutation burden of MED12 in myometrium. As traditional Sanger or even NGS sequencing may not be able to detect MED12 mutations that are lower than 0.1% in the testing sample, we used duplex deep sequencing analysis (DDS) to overcome this limitation. Tumor-free myometria (confirmed by pathology evaluation) were dissected, and genomic DNA from MED12 exon 2 (test) and TP53 exon 5 (control) were captured by customer-designed probe sets, followed by DDS. Notably, DDS demonstrated that myometrial cells harbored a high frequency of mutations in MED12 exon 2 and predominantly in code c.130-131. In contrast, the baseline mutations in other coding sequences of MED12 exon 2 as well as in the TP53 mutation hotspot, c.477-488 were comparably low in myometrial cells. This is the first report demonstrating a non-random accumulation of MED12 mutations at c.130-131 sites in non-neoplastic myometrial cells which provide molecular evidence of early somatic mutation events in myometrial cells. This early mutation may contribute to the cell origin for uterine LM development in women of reproductive age.

Cell-free DNA from germline TP53 mutation carriers reflect cancer-like fragmentation patterns

Germline pathogenic TP53 variants predispose individuals to a high lifetime risk of developing multiple cancers and are the hallmark feature of Li-Fraumeni syndrome (LFS). Our group has previously shown that LFS patients harbor shorter plasma cell-free DNA fragmentation; independent of cancer status. To understand the functional underpinning of cfDNA fragmentation in LFS, we conducted a fragmentomic analysis of 199 cfDNA samples from 82 TP53 mutation carriers and 30 healthy TP53-wildtype controls. We find that LFS individuals exhibit an increased prevalence of A/T nucleotides at fragment ends, dysregulated nucleosome positioning at p53 binding sites, and loci-specific changes in chromatin accessibility at development-associated transcription factor binding sites and at cancer-associated open chromatin regions. Machine learning classification resulted in robust differentiation between TP53 mutant versus wildtype cfDNA samples (AUC-ROC = 0.710–1.000) and intra-patient longitudinal analysis of ctDNA fragmentation signal enabled early cancer detection. These results suggest that cfDNA fragmentation may be a useful diagnostic tool in LFS patients and provides an important baseline for cancer early detection.

MCL-058 Efficacy and Safety of Ibrutinib Plus Venetoclax in Patients With Mantle Cell Lymphoma (MCL) and TP53 Mutations in the SYMPATICO Study

MCL-058 Efficacy and Safety of Ibrutinib Plus Venetoclax in Patients With Mantle Cell Lymphoma (MCL) and TP53 Mutations in the SYMPATICO Study

TP53 mutations associate with poor response to lenvatinib treatment for advanced thyroid cancer

TP53 mutations associate with poor response to lenvatinib treatment for advanced thyroid cancer

Molecular Analysis of High-Grade Serous Ovarian Carcinoma Exhibiting Low-Grade Serous Carcinoma and Serous Borderline Tumor.

Ovarian cancer is classified as type 1 or 2, representing low- and high-grade serous carcinoma (LGSC and HGSC), respectively. LGSC arises from serous borderline tumor (SBT) in a stepwise manner, while HGSC develops from serous tubal intraepithelial carcinoma (STIC). Rarely, HGSC develops from SBT and LGSC. Herein, we describe the case of a patient with HGSC who presented with SBT and LGSC, and in whom we analyzed the molecular mechanisms of carcinogenesis. We performed primary debulking surgery, resulting in a suboptimal simple total hysterectomy and bilateral salpingo-oophorectomy due to strong adhesions. The diagnosis was stage IIIC HGSC, pT3bcN0cM0, but the tumor contained SBT and LGSC lesions. After surgery, TC (Paclitaxel + Carbopratin) + bevacizumab therapy was administered as adjuvant chemotherapy followed by bevacizumab as maintenance therapy. The tumor was chemo-resistant and caused ileus, and bevacizumab therapy was conducted only twice. Next-Generation Sequencing revealed KRAS (p.G12V) and NF2 (p.W184*) mutations in all lesions. Interestingly, the TP53 mutation was not detected in every lesion, and immunohistochemistry showed those lesions with wild-type p53. MDM2 was amplified in the HGSC lesions. DNA methylation analysis did not show differentially methylated regions. This case suggests that SBT and LGSC may transform into HGSC via p53 dysfunction due to MDM2 amplification.

Minor role of TP53 and TERT promoter mutations in medullary thyroid carcinoma: report of new cases and revision of the literature.

Aims of this study were to investigate the prevalence of TP53 and TERT mutations in Medullary Thyroid carcinoma (MTC) and their role in inducing aggressiveness in positive cases. We performed a literature search in PubMed to identify studies investigating the prevalence of TERT and TP53 mutations in MTC. We also included data on MTC cases (n = 193) obtained at our center and unpublished. The in-silico pathogenicity of the TP53 mutations has been evaluated by predictor tools. We identified a total of 25 and 11 published papers: all together 1280 cases have been investigated for the presence of TP53 mutations and 974 for TERT promoter mutation. Twenty-five out of 1280 (2%) cases had a TP53 mutation while only 3/974 MTC cases (0.3%) have been found to be positive for TERT promoter mutations. Among all, we identified 19 different TP53 mutations that in 12 cases were demonstrated to have an in silico predicted high pathogenic role and a high impact on protein function. Three non-sense and 4 probably not damaging mutations were also reported. The pathogenic role of the TERT promoter mutations has been previously in vitro determined. No correlation between TP53 and/or TERT mutations and aggressiveness of MTC has been demonstrated. The prevalence of TP53 and TERT promoter mutations is very low in MTC. The reported mutations are pathogenic in the majority of cases. Because of their rarity it is not possible to clarify if they play or not a role in the pathogenesis and/or aggressiveness of this specific thyroid tumor.

Final Analysis Data and Exploratory Biomarker Analysis of a Randomized Phase 2 Study of Osimertinib Plus Bevacizumab Versus Osimertinib Monotherapy for Untreated Patients With Nonsquamous NSCLC Harboring EGFR Mutations: The WJOG9717L Study

IntroductionEGFR tyrosine kinase inhibitors have been the standard treatment for patients with NSCLC who have sensitive EGFR mutations. This study revealed final analysis survival data, biomarkers, and resistance mechanisms of osimertinib plus bevacizumab or osimertinib monotherapy in previously untreated patients with advanced EGFR-positive nonsquamous NSCLC. MethodsWe previously reported the primary results of a randomized, open-label, phase 2 study comparing osimertinib plus bevacizumab with osimertinib monotherapy for this population. In this exploratory analysis using tissue and plasma samples, we evaluated gene profiles at baseline and disease progression or the last dose using targeted deep sequencing. ResultsThe median progression-free survival (PFS) by the blinded independent central reviewer was 22.1 months for the osimertinib plus bevacizumab arm and 20.2 months for the osimertinib arm (hazard ratio [HR] = 0.864, 95% confidence interval [CI]: 0.549–1.359). The 3-year overall survival was not different between the two arms (osimertinib plus bevacizumab: 57.1%; osimertinib monotherapy: 65.0%; HR 1.271, 95% CI: 0.727–2.223). A total of 94 patients had assessable plasma samples at baseline, and 40 had assessable pretreatment tissue samples. EGFR mutations (76.6%) and TP53 mutations (44.7%) were detected in plasma samples at baseline. In patients with plasma TP53 mutations (n = 42), the median PFS by blinded independent central reviewer was 19.8 months for the osimertinib plus bevacizumab arm and 20.2 months for the osimertinib arm (HR = 1.107, 95% CI: 0.534–2.297). ConclusionsThere was also no significant difference in the PFS between the two arms, even in patients with TP53 mutations.

Dissecting AI-based mutation prediction in lung adenocarcinoma: A comprehensive real-world study

IntroductionMolecular profiling of lung cancer is essential to identify genetic alterations that predict response to targeted therapy. While deep learning shows promise for predicting oncogenic mutations from whole tissue images, existing studies often face challenges such as limited sample sizes, a focus on earlier stage patients, and insufficient analysis of robustness and generalizability. MethodsThis retrospective study evaluates factors influencing mutation prediction accuracy using the large Heidelberg Lung Adenocarcinoma Cohort (HLCC), a cohort of 2356 late-stage FFPE samples. Validation is performed in the publicly available TCGA-LUAD cohort. ResultsModels trained on the larger HLCC cohort generalized well to the TCGA dataset for mutations in EGFR (AUC 0.76), STK11 (AUC 0.71) and TP53 (AUC 0.75), in line with the hypothesis that larger cohort sizes improve model robustness. Variation in performance due to pre-processing and modeling choices, such as mutation variant calling, affected EGFR prediction accuracy by up to 7 %. DiscussionModel explanations suggest that acinar and papillary growth patterns are critical for the detection of EGFR mutations, whereas solid growth patterns and large nuclei are indicative of TP53 mutations. These findings highlight the importance of specific morphological features in mutation detection and the potential of deep learning models to improve mutation prediction accuracy. ConclusionAlthough deep learning models trained on larger cohorts show improved robustness and generalizability in predicting oncogenic mutations, they cannot replace comprehensive molecular profiling. However, they may support patient pre-selection for clinical trials and deepen the insight in genotype-phenotype relationships.