Types Of Mutations Research Articles

The NF1 gene mutations and co-mutations in lung adenocarcinomas with brain metastasis.

The co-occurrence of lung adenocarcinoma and brain metastasis remains a significant cause of morbidity and mortality despite advancements in cancer treatment. The activity of neurofibromin, the product of Neurofibromatosis Type 1 gene (NF1), is crucial in regulating the RAS/MAPK pathway. The NF1 somatic mutations are significant in conditions such as melanoma, lung cancer, breast cancer, neuroblastoma, and central nervous system tumors. Therefore, this research aims to uncover the profile of NF1 mutations and co-mutations in patients with brain metastases from lung adenocarcinoma, shedding light on their role in the pathophysiology of metastatic lung cancer. In this study, a total of 131 (31 females, 90 males) patients diagnosed with metastatic lung adenocarcinoma who were examined in the Molecular Pathology Laboratory between 2019 and 2022 were retrospectively analyzed. The NF1 somatic mutations and co-mutations were evaluated using the NGS lung panel on the MiniSEQ NGS platform. The average age of the 131 patients (31 females, 90 males) retrospectively examined in the study was 62.05 years. The ages of the cases included in the study followed a normal distribution according to Kolmogorov-Smirnov test (P = 0.200). Lymph node metastasis was detected in 48 patients (36.6%), while distant organ metastasis was observed in 81 patients (61.83%). Metastases were more frequently seen in males. No statistically significant difference was found between metastases and gender (P > 0.05). Distant organ metastasis (n = 26, 19.8%) and NF1 mutations (n = 8/26, 30.77%) were most commonly observed in the brain. The most common NF1 pathogenic variants in brain metastases were c.2325 + 3A > G (p.M1205fs*12) (n = 6/26, 23.07%) and c.1400C > T (p.T4671) (n = 5/26, 19.23%). There was no statistically significant relationship observed between patients' age, gender, brain metastasis, and NF1 mutation types (respectively, P = 0.98, P = 0.63, and P = 0.87). The mutations that showed the most association with NF1 mutations in brain metastases were PTEN and TP53. Somatic NF1 mutations and co-mutations can play a critical driving force in metastatic lung adenocarcinoma and may contribute to treatment resistance. The mutational landscape of somatic NF1 mutations and co-mutations can provide new insights into the pathophysiology of metastatic lung cancer, especially those that have metastasized to the brain.

Targeting Solvent-Front Mutations for Kinase Drug Discovery: From Structural Basis to Design Strategies.

Solvent-front mutations have emerged as a common mechanism leading to acquired resistance to kinase inhibitors, representing a major challenge in the clinic. Several new-generation kinase inhibitors targeting solvent-front mutations have either been approved or advanced to clinical trials. However, there remains a need to discover effective, new-generation inhibitors. In this Perspective, we systematically summarize the general types of solvent-front mutations across the kinome and describe the development of inhibitors targeting some key solvent-front mutations. Additionally, we highlight the challenges and opportunities for the next generation of kinase inhibitors directed toward overcoming solvent-front mutations.

Correction of exon 2, exon 2–9 and exons 8–9 duplications in DMD patient myogenic cells by a single CRISPR/Cas9 system

Duchenne Muscular dystrophy (DMD), a yet-incurable X-linked recessive disorder that results in muscle wasting and loss of ambulation is due to mutations in the dystrophin gene. Exonic duplications of dystrophin gene are a common type of mutations found in DMD patients. In this study, we utilized a single guide RNA CRISPR strategy targeting intronic regions to delete the extra duplicated regions in patient myogenic cells carrying duplication of exon 2, exons 2–9, and exons 8–9 in the DMD gene. Immunostaining on CRISPR-corrected derived myotubes demonstrated the rescue of dystrophin protein. Subsequent RNA sequencing of the DMD cells indicated rescue of genes of dystrophin related pathways. Examination of predicted close-match off-targets evidenced no aberrant gene editing at these loci. Here, we further demonstrate the efficiency of a single guide CRISPR strategy capable of deleting multi-exon duplications in the DMD gene without significant off target effect. Our study contributes valuable insights into the safety and efficacy of using single guide CRISPR strategy as a potential therapeutic approach for DMD patients with duplications of variable size.

Exploring the role of FAT genes in Solanaceae species through genome-wide analysis and genome editing.

Plants produce numerous fatty acid derivatives, and some of these compounds have significant regulatory functions, such as governing effector-induced resistance, systemic resistance, and other defense pathways. This study systematically identified and characterized eight FAT genes (Acyl-acyl carrier protein thioesterases), four in the Solanum lycopersicum and four in the Solanum tuberosum genome. Phylogenetic analysis classified these genes into four distinct groups, exhibiting conserved domain structures across different plant species. Promoter analysis revealed various cis-acting elements, most of which are associated with stress responsiveness and growth and development. Micro-RNA (miRNA) analysis identified specific miRNAs, notably miRNA166, targeting different FAT genes in both species. Utilizing clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated knockout, mutant lines for SlFATB1 and SlFATB3 were successfully generated and exhibited diverse mutation types. Biochemical evaluation of selected mutant lines revealed significant changes in fatty acid composition, with linoleic and linolenic acid content variations. The study also explored the impact of FAT gene knockout on tomato leaf architecture through scanning electron microscopy, providing insights into potential morphological alterations. Knocking out of FAT genes resulted in a significant reduction in both trichome and stoma density. These findings contribute to a comprehensive understanding of FAT genes in Solanaceous species, encompassing genetic, functional, and phenotypic aspects.

Association of mean platelet volume (MPV), MPV/PLATELET (PLT) ratio, and lymphocyte/monocyte ratio (LMR) as poor prognostic factor in EGFR-mutant lung adenocarcinoma treated with EGFR tyrosine kinase inhibitor.

Platelets (PLT) and host systemic inflammatory response (SIR) are known to be effective in the aggregation of cancer cells and the formation of metastasis. There are studies pointing out to the prognostic efficacy of lymphocyte-monocyte ratio (LMR) showing SIR activation and mean platelet volume (MPV) values indicating platelet activation in various cancer types. We predict that easy-to-access hemogram parameters such as MPV, MPV/PLT, and LMR can be guiding in the clinical follow-up period of patients with epidermal growth factor receptor (EGFR) positive mutation and who received EGFR, tyrosine kinase inhibitor (TKI) in the first-line treatment in predicting the progression of the disease, predicting the survival time of the patients, and evaluating the response to treatment. The study is retrospective and included patients with stage III and stage IV pulmonary adenocarcinoma with positive EGFR mutations and for whom TKI was used in the first-line treatment between January 2011 and January 2021. MPV, MPV/PLT, and LMR values of the patients were calculated before treatment. Age, sex, comorbidity, smoking history, TNM stage, metastasis localizations, EGFR mutation types, TKI treatments used in first-line treatment, and MPV, MPV/PLT, and LMR values at the 1st month of treatment were recorded. With Kaplan-Meier, six-month, one-year, three-year, and five-year survival rates, average life expectancy, and 95% confidence intervals for these periods were calculated. Variables that may affect progression and overall survival (OS) were determined by performing univariate and multivariate Cox regression analysis. One hundred and two patients were included in the study. The mean age of the patients was 64.30 ± 12.6 years. Eighty-four patients were in stage IV at the time of diagnosis. The expected mean progression-free survival (PFS) period of the cases was found to be 13.3 months. The mean life expectancy of the cases was found to be 35.1 months. Web-based Cutoff Finder algorithm written in the R program (http://molpath.charite.de/cutoff) was used to determine the ideal cut points for MPV, MPV/PLT, and LMR. The cut-off values were found to be 7.55 fL for MPV, 0.251 for MPV/PLT, and 2.615 for LMR, respectively. In univariate Cox regression analysis, LMR level lower than 2.615 increased the rate of progression 1.747 times (95% confidence interval: 1.129-2.705) and the death rate 2.056 times (95% confidence interval: 1.217-3.475) (p= 0.012, p= 0.007). The mean PFS LMR cut-off value was 10.3 months, and 15.3 months, and mean OS durations were 25.1 months and 40.8 months for the groups with low and high cut-off values respectively (p= 0.011, p= 0.006 log-rank test). According to the results of multivariate Cox regression analysis, MPV/PLT < 0.251, smoking, presence of pleural and adrenal metastases, and gefitinib treatment were independent factors in determining PFS. The independent factors determining OS in multivariate Cox regression analysis were being male, platelet increase, MPV > 7.55, gefitinib treatment, and smoking. MPV, MPV/PLT, and LMR are potential biomarkers that can be used for the clinical follow-up of lung ADC patients receiving EGFR-TKI treatment.

Efficacy of PARP inhibitors in advanced high-grade serous ovarian cancer according to BRCA domain mutations and mutation type.

Preclinical studies have emphasized the potential connection between BRCA specific domains defects and the activity of Poly ADP-ribose polymerase inhibitors (PARPi). Nevertheless, real-world evidence regarding the impact of BRCA domain defects and mutations on PARPi efficacy are limited. The aim of his study was to evaluate the efficacy of PARPi in terms of progression free survival (PFS) according to BRCA domains defects and mutation types. A retrospective analysis was performed among 79 BRCA mutated patients, diagnosed with advanced High-grade serous ovarian carcinoma (HGSOC) who received first- and second-line platinum- based chemotherapy followed by PARPi maintenance treatment. PFS was evaluated according to BRCA1 [Really Interesting Gene (RING), DNA Binding (DBD), Serine Cluster (SCD), BRCA1 C-terminal (BRCT)] and BRCA2 [RAD-51 Domain (RAD-51 BD), DBD] specific domain defects and mutation types [missense (MS), nonsense (NS), frameshift (FS), splicing (S), or large rearrangements (LR)]. After a median follow-up of 51 months, no significant difference in PFS was observed between the BRCA functional domains or mutation types in the BRCA1 and BRCA2 subgroups. Patients with BRCA2 DBD and RAD51-BD defects had the longest (39.8 months) and shortest (24.1 months) median PFS, respectively (p = 0.11). Additionally, patients with BRCA1 DBD defects had the greatest benefit (median PFS = 33.8 months) while those with BRCA1 RING domain mutations experienced the worst outcome (median PFS = 30.9 months (p = 0.43). The efficacy of maintenance treatment with PARPi is independent by BRCA domain defects or mutation types. Patients DBD domain defects experienced numerically longer median PFS compared to those with other BRCA1/2 alterations.

System analysis based on T-cell exhaustion-related genes identifies PTPRT as a promising diagnostic and prognostic biomarker for gastric cancer

Multiple investigations have demonstrated the crucial involvement of T-cell exhaustion (TEX) in anti-tumor immune response and their strong correlation with prognosis. This study aimed at creating a strong signature using TEX for gastric cancer through bioinformatics analysis and experimental validation. We utilized data from The Cancer Genome Atlas (TCGA) databases to retrieve RNA-seq data from patients with stomach adenocarcinoma (STAD). Genes related to TEX were discovered using gene set variance analysis (GSVA) and weighted gene correlation network analysis (WGCNA). Subsequently, prognostic signature based on TEX was developed using LASSO-Cox analysis. Relationship between key genes and immune cells were examined. Finally, biological function of a key TEX-related gene PTPRT in gastric cancer was verified by in vivo experiment. A total of 29 TEX-related biomarkers were screened by WGCNA and random forest. Among them, five core signatures (PTPRT, CAV2, PPIH, PRDM2, and FGF1), further identified by LASSO-Cox, were considered as strong predictors of prognosis for gastric cancer and associated with immune infiltration. PTPRT gene had the largest number of SNPs, with the most mutation types. In vivo experiments revealed that PTPRT overexpression significantly inhibited tumor malignant progression and accelerated apoptosis through stimulating the secretion of killer cytokines such as TNF-α and IFN-γ. In addition, flow cytometry revealed that PTPRT overexpression alleviated TEX by increasing the abundance of CD8+ T cells, with inhibition of cell surface PD-1 and Tim-3. The predictive prognostic value of TEX gene expression levels was evaluated in patients with gastric cancer, providing a new perspective for precision immuno-oncology studies.

Identifying inversions with breakpoints in the Dystrophin gene through long-read sequencing: report of two cases

BackgroundDuchenne Muscular Dystrophy (DMD) is an X-linked disorder caused by mutations in the DMD gene, with large deletions being the most common type of mutation. Inversions involving the DMD gene are a less frequent cause of the disorder, largely because they often evade detection by standard diagnostic methods such as multiplex ligation probe amplification (MLPA) and whole exome sequencing (WES).Case presentation: Our research identified two intrachromosomal inversions involving the dystrophin gene in two unrelated families through Long-read sequencing (LRS). These variants were subsequently confirmed via Sanger sequencing. The first case involved a pericentric inversion extending from DMD intron 47 to Xq27.3. The second case featured a paracentric inversion between DMD intron 42 and Xp21.1, inherited from the mother. In both cases, simple repeat sequences (SRS) were present at the breakpoints of these inversions.ConclusionsOur findings demonstrate that LRS is an effective tool for detecting atypical mutations. The identification of SRS at the breakpoints in DMD patients enhances our understanding of the mechanisms underlying structural variations, thereby facilitating the exploration of potential treatments.

Distinct FLT3 Pathways Gene Expression Profiles in Pediatric De Novo Acute Lymphoblastic and Myeloid Leukemia with FLT3 Mutations: Implications for Targeted Therapy.

Activating FLT3 mutations plays a crucial role in leukemogenesis, but identifying the optimal candidates for FLT3 inhibitor therapy remains controversial. This study aims to explore the impacts of FLT3 mutations in pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) and to compare the mutation profiles between the two types to inspire the targeted application of FLT3 inhibitors. We retrospectively analyzed 243 ALL and 62 AML cases, grouping them into FLT3-mutant and wild-type categories, respectively. We then assessed the associations between FLT3 mutations and the clinical manifestations, genetic characteristics, and prognosis in ALL and AML. Additionally, we compared the distinct features of FLT3 mutations between ALL and AML. In ALL patients, those with FLT3 mutations predominantly exhibited hyperdiploidy (48.6% vs. 14.9%, p < 0.001) and higher FLT3 expression (108.02 [85.11, 142.06] FPKM vs. 23.11 [9.16, 59.14] FPKM, p < 0.001), but lower expression of signaling pathway-related genes such as HRAS, PIK3R3, BAD, MAP2K2, MAPK3, and STAT5A compared to FLT3 wild-type patients. There was no significant difference in prognosis between the two groups. In contrast, AML patients with FLT3 mutations were primarily associated with leucocytosis (82.90 [47.05, 189.76] G/L vs. 20.36 [8.90, 55.39] G/L, p = 0.001), NUP98 rearrangements (30% vs. 4.8%, p = 0.018), elevated FLT3 expression (74.77 [54.31, 109.46] FPKM vs. 34.56 [20.98, 48.28] FPKM, p < 0.001), and upregulated signaling pathway genes including PIK3CB, AKT1, MTOR, BRAF, and MAPK1 relative to FLT3 wild-type, correlating with poor prognosis. Notably, internal tandem duplications were the predominant type of FLT3 mutation in AML (66.7%) with higher inserted base counts, whereas they were almost absent in ALL (6.3%, p < 0.001). In summary, our study demonstrated that the forms and impacts of FLT3 mutations in ALL differed significantly from those in AML. The gene expression profiles of FLT3-related pathways may provide a rationale for using FLT3 inhibitors in AML rather than ALL when FLT3 mutations are present.

EIF1AX mutation in thyroid nodules: a histopathologic analysis of 56 cases in the context of institutional practices.

EIF1AX mutation has been identified as a driver mutation for papillary thyroid carcinoma (PTC) by The Cancer Genome Atlas (TCGA) study. Subsequent studies confirmed this mutation in PTC and Anaplastic Thyroid Carcinoma (ATC) but also reported EIF1AX mutation in Follicular nodular disease (FND) and benign thyroid nodules. In this study, we review thyroid nodules with EIF1AX mutation from two institutions: a tertiary care hospital (YNHH, n = 22) and a major cancer referral center (MSKCC, n = 34) and report the varying histomorphology in the context of additional genetic abnormalities and institutional practices. Pathology diagnoses were reviewed according to the WHO 5th edition and correlated with the type of EIF1AX mutation and additional concurrent molecular alterations, if any. Most cases were splice site type mutations. Cases consisted of 9 FND, 7 follicular (FA) or oncocytic adenomas (OA), 2 non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) and 38 follicular-cell derived thyroid carcinomas. Of 8 cases with isolated EIF1AX mutation, 7 were FND, FA or OA (88%) and one was an oncocytic carcinoma (12%). Of 12 cases with EIF1AX and one additional molecular alteration, 9 (75%) were FND, FA or OA, 2 (17%) were NIFTPs and one (8%) was a poorly differentiated thyroid carcinoma. All 36 cases with EIF1AX mutation and molecular alterations were malignant (100%) and included TP53 and TERT promoter mutations associated with ATC (n = 8) and high-grade follicular cell-derived non-anaplastic carcinoma (HGC, n = 2). Isolated EIF1AX mutation was noted only in thyroid nodules seen at YNHH and were predominantly encountered in benign thyroid nodules including FND. Accumulation of additional genetic abnormalities appears to be progressively associated with malignant tumors.

Distinct phenotypic consequences of cholangiocarcinoma-associated FGFR2 alterations depend on biliary epithelial maturity.

Epithelial cancers disrupt tissue architecture and are often driven by mutations in genes that normally play important roles in epithelial morphogenesis. The intrahepatic biliary system is an epithelial tubular network that forms within the developing liver via the de novo initiation and expansion of apical lumens. Intrahepatic biliary tumors are often driven by different types of mutations in the FGFR2 receptor tyrosine kinase which plays important roles in epithelial morphogenesis in other developmental settings. Using a physiologic and quantitative 3D model we have found that FGFR signaling is important for biliary morphogenesis and that oncogenic FGFR2 mutants disrupt biliary architecture. Importantly, we found that both the trafficking and signaling of normal FGFR2 and the phenotypic consequences of FGFR2 mutants are influenced by the epithelial state of the cell. Unexpectedly, we found that different tumor-driving FGFR2 mutants disrupt biliary morphogenesis in completely different and clinically relevant ways, informing our understanding of morphogenesis and tumorigenesis and highlighting the importance of convergent studies of both.

Genotype–Phenotype Correlations in 83 Korean X-linked Retinoschisis Patients: Impact of Retinoschisin 1 Secretion Profiles on Clinical Phenotypes

To assess the correlation between genotype and phenotype severity in X-linked juvenile retinoschisis (XLRS) by examining clinical and genetic features of a cohort of Korean XLRS patients. Retrospective, observational study. Data from 83 consecutive male patients with molecularly confirmed XLRS were collected retrospectively. Clinical evaluation included best-corrected visual acuity (BCVA), fundus photography, spectral-domain optical coherence tomography (SD-OCT), and full-field electroretinography (ERG). The phenotypic characteristics of a cohort of pediatric Korean XLRS patients, based on mutation types (truncating versus missense) and secretory profile (secretion versus non-secretion), were assessed. One hundred sixty-six eyes of 83 patients were included. The mean age at diagnosis was 6.1 ± 8.8 years (range, 0.5-20.7 years), with a mean follow-up time of 9.2 ± 7.0 years (range, 0.6-24.3 years). The BCVA at first and last examination ranged from light perception to 0.1 logarithm of the minimum angle of resolution (mean ± SD, 0.75 ± 0.59 and 0.82 ± 0.65, respectively). There were no significant differences in the first and last BCVA measurements between the truncating (0.71 ± 0.51 and 0.75 ± 0.44) and missense (0.77 ± 0.59 and 0.84 ± 0.66) variants (P = 0.678 and 0.551, respectively). Additionally, there were no differences in clinical parameters from fundus photography, SD-OCT, and full-field ERG. However, the BCVA at the first and last measurement were better for patients in the secretion group (0.51 ± 0.24 and 0.61 ± 0.30) compared to patients in the non-secretion group (0.65 ± 0.71 and 0.87 ± 0.81). The last BCVA showed a statistically significant difference between the two groups (P = 0.021). In OCT findings, the frequency of ellipsoid zone disruption was higher in patients with non-secretion variants than those with secretion variants (P = 0.030), with no significant differences in other parameters. The secretion profile of RS1 could influence the severity of XLRS phenotypes. Patients with RS1-secreted mutants, particularly with intact octamerization, exhibit more homogeneous phenotypes and better visual acuity than the RS1-non-secreted group. This data provides insights for studying genotype and phenotype correlations in both clinical and research fields.

Phenotype and genotype features of isolated cystic kidney diseases with autosomal recessive type of inheritance in children

The relevance of the problem of hereditary cystic kidney diseases (cystosis) is due to the wide variability of the renal phenotype and the genotype that determines the prognosis, the progression to renal failure as early as in childhood. Purpose. To present the results of the analysis of the correlation of genotype and phenotype, renal function in isolated cystic kidney diseases with an autosomal recessive type of inheritance in children. Material and methods. in 14 children (from 13 families) aged 9 months — 17 years, the features of the clinical phenotype of kidney cysts with autosomal recessive type of inheritance and gene mutation were evaluated according to the results of a molecular genetic study. Results. In 3 (23 %) of 13 families, the family history is burdened by kidney cysts. The characteristic of gene mutation in cystic kidney diseases with autosomal recessive type of inheritance in 13 patients is presented (in 2 tables). Of the 21 identified variants in the genes PKHD1, INVS, NPHP1, TMEM67, 15 (71 %) had known pathogenic significance, 6 (29 %) had previously undescribed variants in data-bases. Variants of the PKHD1 gene were identified in 11 children with the phenotype of polycystic kidney disease with autosomal recessive type of inheritance and liver fibrosis. In the study, variant C.107C&gt;T (Thr36Met) is the most common among children with identified variants of the PKHD1 gene in autosomal recessive polycystic kidney disease in 5 out of 21 (23.8 %), c.664A&gt;G (Ile222Val) in 1 (4.8 %), c.6992T&gt;A (Ile2331Lys) in 1 (4.8 %), c.10444C&gt;T (Arg3482Cys) at 1 (4.8 %). Infantile (n=1) and juvenile (n = 2) nephronophthysis were confirmed in 3 children with homozygous and compound heterozygous pathogenic variants in the INVS, NPHP1, TMEM67 genes. Conclusion. The features of the genotype and phenotype are presented in 14 children with autosomal recessive type of inheritance of isolated kidney cysts in autosomal recessive polycystic kidney disease (n = 11) and nephronophthysis (n = 3), of whom chronic kidney disease was established in 13 children aged 2–17 years: in 4 (30.8 %) C1, in 4 (30.8 %) C2, in 3 (23 %) C3, in 1 (7.7 %) C4, in 1 (7.7 %) C5.

Clinical relevance of subtyping CTNNB1‐mutated hepatocellular adenomas: Different risk patterns according to the mutation type

AbstractBackground and AimsBeta‐catenin‐activated hepatocellular adenomas (b‐HCA) with exon 3 (ex3) non‐S45, ex3 S45 or ex7/8 mutations display different glutamine synthetase (GS)‐immunostaining patterns; the latter two show a GS‐positive/CD34‐negative rim contrasting with diffuse CD34 in the HCA core. Our objective was to determine whether discriminating the three b‐HCA mutation subtypes is clinically relevant.MethodsWe analysed the clinicopathological data of the three b‐HCA subtypes (37 resected cases) and compared it with the corresponding subtypes of beta‐catenin‐activated inflammatory HCA (b‐IHCA, 40 cases).ResultsThe mean age of b‐HCA ex7/8 and ex3 S45 were 25.9 and 27.3 years respectively. Clinical bleeding occurred in 67% and 63%, including five cases of pregnant women; malignant transformation was not observed in these two subtypes. The mean age of the b‐HCA ex3 non‐S45 subtype (41 years) was significantly higher; clinical bleeding occurred in 14% while all cases contained malignancy. Such differences in age and clinical complications were not found in the b‐IHCA subtypes. Additionally, we found abnormal vessels in b‐HCA ex3 S45 and ex7/8, near the GS+/CD34− rim, which was not seen in ex3 non‐S45. These vessels can function as an adjunct to discriminate between the b‐HCA subgroups.ConclusionIn our series, b‐HCA ex7/8 and ex3 S45 patients are significantly younger and have higher clinical bleeding risk than b‐HCA ex3 non‐S45 patients who have a higher malignant risk. Hence, in b‐HCA, due to the differences in clinical complications, it is clinically relevant to identify all three subtypes individually.

Age and Sex Affects the Frequency and Mutation Type of FGFR2 Alterations in Cholangiocarcinoma

PURPOSE FGFR2 alterations are infrequent but currently represent the most common targetable mutation in cholangiocarcinoma. We performed a large-scale genomic analysis to assess associations between FGFR2 and other driver gene alterations in cholangiocarcinoma with patient demographics. METHODS Clinical and molecular data for patients with intrahepatic cholangiocarcinoma were abstracted from the Foundation Medicine (FMI) and Genomics, Evidence, Neoplasia, Information, Exchange (GENIE) genomic databases. The Chi-squared test was used to assess the association between sex and alterations in driver genes. FGFR2 fusion partners were analyzed using descriptive statistics. RESULTS Across both FMI (N = 7,859) and GENIE (N = 1,395) cohorts, FGFR2 rearrangements were more frequent in female than male patients with cholangiocarcinoma (odds ratio, 1.69 and 2.45). By contrast, FGFR2 missense mutations, TP53 mutations, and KRAS mutations were not associated with sex. Stratifying patients by age groups showed that FGFR2 rearrangements were specifically enriched in younger ages (&lt;45 years). Although the most common FGFR2 fusion partners were shared across both sexes, a subset of fusion partners was recurrent and uniquely associated with female or male patients. CONCLUSION FGFR2 rearrangements but not other driver alterations in cholangiocarcinoma are concentrated in young female patients, where the prevalence reached nearly 20% across two large patient cohorts. These results suggest that the molecular basis of FGFR2 rearrangements may be distinct between sexes. These results indicate the importance of genetic testing in cholangiocarcinoma, particularly for younger patients, and suggest that patient recruitment strategies in trials for FGFR2-targeting therapies should seek to reduce barriers to enhance the enrollment of young female patients.

Genetics, Pathophysiology, and Current Challenges in Von Hippel-Lindau Disease Therapeutics.

VHL disease is caused by mutations in the VHL tumor suppressor gene located on chromosome 3. These mutations can be inherited or occur spontaneously. This article details the different types of mutations and their associated clinical features. The underlying cause of VHL disease is the loss of function of the VHL protein (pVHL). This protein normally regulates hypoxia-inducible factors (HIFs), which are involved in cell growth and survival. When pVHL is dysfunctional, HIF levels become elevated, leading to uncontrolled cell growth and tumor formation. VHL disease can affect various organs, including the brain, spinal cord, retina, kidneys, pancreas, and adrenal glands. Symptoms depend on the location and size of the tumors. Diagnosis of VHL disease involves a combination of clinical criteria, imaging studies, and genetic testing. Treatment options for VHL disease depend on the type and location of the tumors. Surgery is the mainstay of treatment, but other options like radiation therapy may also be used. This article highlights the challenges in VHL disease management, including the lack of effective therapies for some tumor types and the need for better methods to monitor disease progression. In conclusion, we emphasize the importance of ongoing research to develop new and improved treatments for VHL disease.

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.

Genotype Distribution and Clinical Characteristics of Thalassemia Patients Needing Transfusion in Yangjiang, Western Guangdong

Plain Language SummaryThis study is a retrospective research that investigates the genotype distribution and iron metabolic imbalance in thalassemia patients requiring blood transfusion. Eighty-four thalassemia patients needing transfusion were enrolled in the study and underwent genotype analysis. Among these patients, 56 were transfusion-dependent and 28 were non-transfusion-dependent. Of the 56 transfusion-dependent patients, 48 were observed for 3 years, and their iron overload status was analyzed in this study. Our research found that among the 84 thalassemia patients needing transfusion, there were six types of α-thalassemia deletions and nine types of β-thalassemia mutations. Among the 56 transfusion-dependent patients, three types of α-thalassemia genotypes and 15 types of β-thalassemia genotypes were identified. Among the 48 transfusion-dependent thalassemia patients observed for 3 years, 40 patients exhibited iron overload with SF levels exceeding 1,000 ng/mL. The recent SF levels were lower than those 3 years ago. Our study found that β-thalassemia is the most common type of transfusion-dependent thalassemia. Standard blood transfusion and iron chelation therapy are necessary for transfusion-dependent thalassemia patients. While some patients show a reduction in SF levels after 3 years of treatment, there are still individuals who exhibit elevated levels necessitating ongoing management.

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.

EGFR mutation based on lung laterality in adenocarcinoma type of non-small cell lung cancer

Targeted therapies have shown promise in improving survival rates for lung adenocarcinoma, a common and deadly malignancy. EGFR-targeting tyrosine kinase inhibitors (TKIs) are particularly effective among these therapies in cases with EGFR mutations. Detecting these mutations before TKI treatment is essential. Various radiological features have been linked to EGFR mutations. However, the relationship between tumor location and mutation types in Indonesian lung adenocarcinoma patients remains unexplored. This study aimed to identify the frequency of EGFR mutation in local lung adenocarcinoma cases based on the tumor location. Clinical data of lung adenocarcinoma patients (n = 272) diagnosed between 2018 and 2022 were retrospectively taken from the Department of Anatomical Pathology, Dr. Sardjito General Hospital, Yogyakarta. The qRT-PCR data of EGFR mutation status was obtained from the Department of Anatomical Pathology, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta. Descriptive analysis was performed using STATA version 14.0. EGFR mutations were found in 60.7% of patients, with 58.2% having exon 19 mutations and 21.2% exhibiting exon 21 L858R mutations. Mutation status was found to be significantly different based on the patient's gender (p = 0.022) and age (p = 0.029) but not with lung laterality (p = 0.093). The proportion of exon 19, exon 21 L858R, and uncommon mutations in the right and left lung adenocarcinoma was similar across all samples. This study found no difference between specific EGFR mutation types and tumor location in lung adenocarcinoma.