Current Trial Report: A Multicenter Phase I/Ib study of Capmatinib Plus Trametinib in Patients With Metastatic Nonsmall Cell Lung Center Harboring MET Exon 14 Skipping Mutations and Other MET-Alterations.

INTRODUCTION: MET tyrosine kinase inhibitor (TKI) therapy is associated with improved outcomes in patients with nonsmall cell lung cancer (NSCLC) harboring a MET alteration, including MET exon 14 (METex14) skipping mutation, MET amplification, or MET fusion. However, primary or acquired resistance to TKI therapy ultimately develops. In preclinical models, hyperactivation of MAPK signaling was shown to promote resistance to MET TKI; resistance was overcome by co-treatment with a MET inhibitor and a MEK inhibitor. This phase I/Ib study offers a potential combination strategy simultaneously targeting MET (with capmatinib) and MEK signaling (with trametinib) to overcome resistance to MET inhibitor monotherapy in METex14 NSCLC. METHODS: In the dose escalation phase, a minimum of 6 and maximum of 18 patients will be enrolled using a conventional 3+3 design with the primary endpoint of identifying a recommended phase 2 dose (RP2D) of capmatinib in combination with trametinib. Once the RP2D is identified, patients will continue to enroll in a dose expansion phase to a total of 15 patients. The primary endpoint of the dose expansion phase is to further characterize the safety profile of the combination. CONCLUSION: This phase I/Ib clinical trial will assess the safety and efficacy of combination capmatinib and trametinib in NSCLC patients whose tumors harbor METex14 skipping mutations, MET amplification, or MET fusion and had developed progressive disease on single agent MET inhibitor therapy.

An ultrasensitive DNA-enhanced amplification method for detecting cfDNA drug-resistant mutations in non-small cell lung cancer with selective FEN-assisted degradation of dominant somatic fragments.

OBJECTIVES: Blood cell-free DNA (cfDNA) can be a new reliable tool for detecting epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) patients. However, the currently reported cfDNA assays have a limited role in detecting drug-resistant mutations due to their deficiencies in sensitivity, stability, or mutation detection rate. METHODS: We developed an Archaeoglobus fulgidus-derived flap endonuclease (Afu FEN)-based DNA-enhanced amplification system of mutated cfDNA by designing a pair of hairpin probes to anneal with wild-type cfDNA to form two 5'-flaps, allowing for the specific cleavage of wild-type cfDNA by Afu FEN. When the dominant wild-type somatic cfDNA fragments were cleaved by structure-recognition-specific Afu FEN, the proportion of mutated cfDNA in the reaction system was greatly enriched. As the amount of mutated cfDNA in the system was further increased by PCR amplification, the mutation status could be easily detected through first-generation sequencing. RESULTS: In a mixture of synthetic wild-type and T790M EGFR DNA fragments, our new assay still could detect T790M mutation at the fg level with remarkably high sensitivity. We also tested its performance in detecting low variant allele frequency (VAF) mutations in clinical samples from NSCLC patients. The plasma cfDNA samples with low VAF (0.1 and 0.5 %) could be easily detected by DNA-enhanced amplification. CONCLUSIONS: This system with enhanced amplification of mutated cfDNA is an effective tool used for the early screening and individualized targeted therapy of NSCLC by providing a rapid, sensitive, and economical way for the detection of drug-resistant mutations in tumors.

1q jumping translocation as a biomarker in myeloid malignancy: frequently mutated genes associated with bad prognosis and low survival.

1q jumping translocation (JT) is rare and its molecular profiles in myeloid malignancies are not well-known. This study evaluated gene mutations in 1q-JT cohorts (0.38%) from hematological malignant specimens that underwent genetic analysis at the Johns Hopkins Hospital (n = 11,908) and the MD Anderson Cancer Center. 1q-JT had frequent mutations in eleven genes, most of which are associated with worse prognosis. BCOR mutations significantly co-occurred with others. Patients tended to have mutations in DNA-repair, spliceosome, and epigenetic modification pathways, though genes utilized within each of these pathways were not randomly distributed. Multi-, albeit overlapping, pathway interruptions tended to manifest in mutations of two gene sets. One gene set consisted of SF3B1 (spliceosome) and TET2 (epigenetic modification), while the other consisted of STAG2 (DNA repair), SRSF2, U2AF (spliceosome), ASXL1, KMT2D (epigenetic modification), BCOR, and GATA2 (transcription factors). An "intermediate" JT-like rearrangement may represent an early sign of occurring 1q-JT. Treatments (hypomethylating agents) and unique structures of the short arms of acrocentric chromosomes may contribute to 1q-JT formation in myeloid malignancies. The median overall survival after identification of a JT was 10 months (95% confidence interval, 5-15 months). Our cohort represents the largest number of myeloid malignancies from multi-centers with before and after the 1q-JT event analyzed to date. Overall, this study identified specific molecular profiles that are associated with 1q-JT in myeloid malignancies. 1q-JT could serve as a poor prognosis biomarker in myeloid malignancies, which could be important in making well-informed clinical decisions and treatment strategies.

Exploring the stress response mechanisms to 2-phenylethanol conferred by Pdr1p mutation in Saccharomyces cerevisiae.

BACKGROUND: The 2-phenylethanol (2-PE) tolerance phenotype is crucial to the production of 2-PE, and Pdr1p mutation can significantly increase the tolerance of 2-PE in Saccharomyces cerevisiae. However, its underlying molecular mechanisms are still unclear, hindering the rational design of superior 2-PE tolerance performance. RESULTS: Here, the physiology and biochemistry of the PDR1_862 and 5D strains were analyzed. At 3.5 g/L 2-PE, the ethanol concentration of PDR1_862 decreased by 21%, and the 2-PE production of PDR1_862 increased by 16% than those of 5D strain. Transcriptome analysis showed that at 2-PE stress, Pdr1p mutation increased the expression of genes involved in the Ehrlich pathway. In addition, Pdr1p mutation attenuated sulfur metabolism and enhanced the one-carbon pool by folate to resist 2-PE stress. These metabolic pathways were closely associated with amino acids metabolism. Furthermore, at 3.5 g/L 2-PE, the free amino acids content of PDR1_862 decreased by 31% than that of 5D strain, among the free amino acids, cysteine was key amino acid for the enhancement of 2-PE stress tolerance conferred by Pdr1p mutation. CONCLUSIONS: The above results indicated that Pdr1p mutation enhanced the Ehrlich pathway to improve 2-PE production of S. cerevisiae, and Pdr1p mutation altered the intracellular amino acids contents, in which cysteine might be a biomarker in response to Pdr1p mutation under 2-PE stress. The findings help to elucidate the molecular mechanisms for 2-PE stress tolerance by Pdr1p mutation in S. cerevisiae, identify key metabolic pathway responsible for 2-PE stress tolerance.

Pseudoendocrine sarcoma: a rare new entity with unique radiologic and pathologic/molecular characteristics.

Pseudoendocrine sarcoma is a rare, recently described intermediate grade sarcoma of uncertain phenotype that most commonly affects the paraspinal location in older patients with a distinctive endocrine/paraganglioma-like morphology and unique CTNNB1 point mutation. While these tumors appear as epithelial or even benign endocrine tumors, these lack markers for such and are highlighted by nuclear expression of beta-catenin. This case is the first among the previously reported only twenty-five cases of this entity, including one original series and a few case reports, to correlate the radiologic imaging with the pathologic features. Furthermore, this case illustrates the oldest-to-date patient with this unique location as a palpable painful chest wall/paraspinal location, with new morphologic observations and, finally, this is only the second case to have this specific CTNNB1 hotspot point mutation for this rare entity.

An Overview on Prevalence and Detection Approaches of BRAF V600E Mutation in Anaplastic Thyroid Carcinoma: A Systematic Review and Meta-Analysis.

Background: BRAF V600E mutation is proved critical in the progression and invasion of thyroid cancer, and as a prognostic biomarker. As anaplastic thyroid cancer (ATC) is a rare and aggressive form of thyroid cancer, this study was conducted to provide a view on prevalence of BRAF V600E as well as the best molecular diagnostic method in ATC patients. Methods: A comprehensive literature search was performed from their inception to Oct 2022 in PubMed, Scopus, Google Scholar, and Web of Science (WoS). The data of the prevalence of ATC were extracted. Moreover, the diagnostic feature of the available diagnostic tools was extracted to measure the sensitivity and specificity. To pool the prevalence data, we used meta-proportion analysis and diagnostic meta-analysis was conducted to determine the specificity and sensitivity of the immunohistochemistry method in detecting BRAF V600E mutation among patients with ATC. Results: Overall, 34 studies were included in this meta-analysis. The incidence of BRAF V600E was shown 33% in the 978 patients. The sensitivity and specificity of IHC in detecting BRAF V600E were detected 78.9% (95%CI: 60.1-97.2), and 69.7% (95%CI: 41.2-98.1), respectively. Conclusion: IHC had an acceptable prognostic profile for detecting BRAF V600E in ATC patients. The diagnosis of BRAF mutation is critical in clinical trials and may be helpful for choosing proper-targeted therapy strategies in ATC patients.

A Novel NR5A1 Mutation in a Thai Boy with 46, XY DSD.

Disorders of sex development (DSD) can be classified as 46,XX DSD, 46,XY DSD, and sex chromosome DSD. Several underlying causes including associated genes have been reported. Steroidogenic factor-1 is encoded by the NR5A1 gene, a crucial regulator of steroidogenesis in the growth of the adrenal and gonadal tissues. It has been discovered to be responsible for 10 to 20% of 46, XY DSD cases. Here, we described a 2-month-old infant who had ambiguous genitalia and 46, XY. Using whole exome sequencing followed by polymerase chain reaction-Sanger sequencing, a novel heterozygous nonsense c.1249C > T (p.Gln417Ter) variant in the NR5A1 gene was identified. It is present in his mother but absent in his father and maternal aunt and uncle. At the age of 7 months, the patient received a monthly intramuscular injection of low-dose testosterone for 3 months in a row. His penile length and diameter increased from 1.8 to 3 cm and from 0.8 to 1.3 cm, respectively. The patient also had normal adrenal reserve function by adrenocorticotropic hormone stimulation test. This study identified a novel causative p.Q417X (c.1249C > T) variant in NR5A1 causing 46,XY DSD in a Thai boy which is inherited from his unaffected mother.

Prediction of Deleterious Single Amino Acid Polymorphisms with a Consensus Holdout Sampler.

Background: Single Amino Acid Polymorphisms (SAPs) or nonsynonymous Single Nucleotide Variants (nsSNVs) are the most common genetic variations. They result from missense mutations where a single base pair substitution changes the genetic code in such a way that the triplet of bases (codon) at a given position is coding a different amino acid. Since genetic mutations sometimes cause genetic diseases, it is important to comprehend and foresee which variations are harmful and which ones are neutral (not causing changes in the phenotype). This can be posed as a classification problem. Methods: Computational methods using machine intelligence are gradually replacing repetitive and exceedingly overpriced mutagenic tests. By and large, uneven quality, deficiencies, and irregularities of nsSNVs datasets debase the convenience of artificial intelligence-based methods. Subsequently, strong and more exact approaches are needed to address these problems. In the present work paper, we show a consensus classifier built on the holdout sampler, which appears strong and precise and outflanks all other popular methods. Results: We produced 100 holdouts to test the structures and diverse classification variables of diverse classifiers during the training phase. The finest performing holdouts were chosen to develop a consensus classifier and tested using a k-fold (1 ≤ k ≤5) cross-validation method. We also examined which protein properties have the biggest impact on the precise prediction of the effects of nsSNVs. Conclusion: Our Consensus Holdout Sampler outflanks other popular algorithms, and gives excellent results, highly accurate with low standard deviation. The advantage of our method emerges from using a tree of holdouts, where diverse LM/AI-based programs are sampled in diverse ways.

Myeloid sarcoma in JAK2-positive myelodysplastic neoplasms with fibrosis: a case report and literature review.

Myeloid sarcoma (MS) occurs in patients with acute myeloid leukemia (AML). In rare cases, MS can represent a form of blast transformation in patients with myeloproliferative neoplasms (MPN), myelodysplastic neoplasms (MDS), or MDS/MPN. The most frequent chromosomal alterations in MS are t(8;21) or inv(16), with other alterations being reported. Cases of MS in Janus kinase 2 (JAK2)-positive MDS with fibrosis are exceedingly rare. Here, we describe such a case. To the best of our knowledge, this is the first report of a JAK2 V617F mutation-positive MDS case occurring concurrently with MS involving the posterior aspect of the left seventh rib. No clear association has been previously demonstrated between the intramedullary AML cytogenetics and extramedullary disease occurrence. Interestingly, samples from the intramedullary MDS and extramedullary mass in this patient presented the same JAK2 V617F mutation. Following a treatment regimen of azacitidine and venetoclax, the patient achieved complete remission. The chest CT scan showed that the seventh posterior rib mass disappeared. This case provides valuable information for the potential future treatment of this disease.

EGFR-mutated lung cancer as a secondary neoplasm in a patient with Li-Fraumeni syndrome: case report.

Background: Li-Fraumeni syndrome (LFS) is a rare hereditary disorder caused by mutations in the tumor protein p53 (TP53). It causes a predisposition for the development of multiple malignancies, primarily including breast cancers, sarcomas, and central nervous system tumors. There are a few cases reported in the literature of patients with LFS presenting with an epidermal growth factor receptor (EGFR) mutated lung cancer. Still, it has been suggested that there may be an association between the TP53 pathogenic variant and lung cancer with EGFR mutation in somatic cells. Case Description: A 47-year-old non-smoker woman with LFS with a history of multiple tumors, including bilateral breast cancer, pecoma, and sarcoma. In one of her computed tomography, a lesion in the lingula of the lung was detected. It was biopsied, which diagnosed lung adenocarcinoma, and genetic studies detected an EGFR exon 19 deletion. She was treated with a left inferior lobectomy, followed by pemetrexed and cisplatin. Conclusions: The association between TP53 and lung cancer with EGFR mutation has been suggested in case reports. Studies in lung cancer cell lines have shown a link between TP53 mutation and EGFR overexpression. Nonetheless, as more cases are reported, further research is needed to comprehend the interrelation between these two pathologies and the risk posed by LFS to the emergence of EGFR-mutated lung cancer.

Synchronous Double Primary Lung Adenocarcinomas With EGFR L858R Point Mutation and MET Exon 14 Skipping Mutation.

Various driver mutations and the corresponding molecular-targeted drugs have been detected and developed in non-small cell lung cancer. There were many cases in which surgical specimens had happened to find double primary cancers. However, to our knowledge, our case was the first report of synchronous double primary lung adenocarcinomas harboring epidermal growth factor receptor (EGFR) L858R and mesenchymal-to-epithelial transition (MET) exon 14 skipping mutations. A 75-year-old Japanese woman with chronic heart and renal failures was referred to our department because of a growing nodule in the right upper lung field on chest X-ray films. Chest computed tomography (CT) detected a nodule in the right S1 and another nodule in the left S1+2. Bronchoscopic biopsy diagnosed the right S1 nodule as moderately differentiated adenocarcinoma. Oncomine Dx Target Test Multi-CDx system of the right S1 adenocarcinoma detected EGFR L858R mutation. The 18F-fluorodeoxyglucose positron emission tomography/CT showed abnormal uptakes both in the right S1 and the left S1+2 nodules, and in the bilateral inferior paratracheal lymph nodes. We made a diagnosis of c-stage IIIA (cT1bN2M0) of adenocarcinoma in the right S1 and suspected another primary lung cancer in the left S1+2. Considering her general conditions, comorbidities and wishes, we started osimertinib. The right S1 cancer achieved partial response (PR), while the left S1+2 nodule and lymph nodes enlarged. Aspiration cytology from the left supraclavicular lymph node showed adenocarcinoma. The FoundationOne® Liquid CDx tumor profiling test detected not only EGFR L858R, but also MET exon 14 skipping mutation. We made a diagnosis of another primary adenocarcinoma from the left S1+2 nodule (cT1bN3M0, c-stage IIIB) with MET mutation, and changed osimertinib to capmatinib. Although the left S1+2 cancer achieved and maintained PR by capmatinib, the right S1 cancer increased, and several new metastases appeared. The subsequent switch from capmatinib to osimertinib could not control cancers. In this case, we tried to switch monotherapies from osimertinib to capmatinib for double primary adenocarcinomas harboring different two driver mutations, according to each cancer progression. The temporal and spatial heterogeneity reinforces the need for primary tissue biopsy if dual primaries are suspected. Temporally distinct liquid biopsies, not standard at present, may be considered.

Association between vitamin D metabolism gene polymorphisms and schizophrenia.

Schizophrenia (SZ) is a multifactorial and neurodegenerative disorder that results from the interaction between genetic and environmental factors. Notably, hundreds of single nucleotide polymorphisms (SNPs) are associated with the susceptibility to SZ. Vitamin D (VD) plays an essential role in regulating several genes important for maintaining brain function and health. To the best of the authors' knowledge, no studies have yet been conducted on the association between the VD pathway and patients with SZ. Therefore, the present study aimed to assess the potential association between eight SNPs in genes related to the VD pathway, including CYP2R1, CYP27B1, CYP24A1 and VDR among patients with SZ. A case-control study was conducted, involving a total of 400 blood samples drawn from 200 patients and 200 healthy controls. Genomic DNA was extracted and variants were genotyped using the tetra-amplification refractory mutation system-polymerase chain reaction method. The present study revealed statistically significant differences between patients with SZ and controls regarding the genotypes and allele distributions of three SNPs [CYP2R1 (rs10741657), CYP27B1 (rs10877012) and CYP24A1 (rs6013897) (P<0.0001)]. The AA genotype of rs10741657 was identified to be associated with SZ (P<0.0001) and the frequency of the A allele was higher in patients with SZ (P<0.0001) compared with the control group. Similarly, the TT genotype of rs10877012 was revealed to be associated with SZ (P<0.0001) and the T allele was more frequent in patients with SZ (P<0.0001) than in the control group. Moreover, the AA genotype of rs6013897 was revealed to be associated with SZ (P<0.0001), although no significant difference was detected between the two groups regarding the A allele (P=0.055). VDR (rs2228570, rs1544410, rs731236 and rs7975232) and CYP27B1 (rs4646536) gene polymorphisms did not exhibit a significant association with SZ. While the studied SNPs revealed promising discriminatory capacity between patients with SZ and controls, the rs10741657 SNP exhibited the most optimal area under the curve value at 0.615. A logistic model was applied considering only the significant SNPs and VD levels, which revealed that rs6013897 (T/A) and VD may have protective effects (0.267, P<0.001; 0.888, P<0.001, respectively). Moreover, a low serum VD level was highly prevalent in patients with SZ compared with the controls. Based on this finding, an association between serum 25(OH)D and SZ could be demonstrated. The present study revealed that CYP2R1 (rs10741657), CYP27B1 (rs10877012) and CYP24A1 (rs6013897) gene SNPs may be associated with SZ susceptibility.

Resistance to Thyroid Hormone Beta Due to THRB Mutation in a Patient Misdiagnosed With TSH-Secreting Pituitary Adenoma.

Elevated concentrations of T3 and T4 concomitant with nonsuppressed TSH are found in both TSH-producing tumors and resistance to thyroid hormone beta (RTHß), posing a diagnostic challenge. We demonstrate here a 54-year-old female who presented with palpitations, goiter, and elevated free T4 with nonsuppressed TSH concentrations (TSH 2.2 mIU/L [normal range, NR 0.27-4.2 mIU/L] and FT4 59.08 pmol/L [NR 12.0-22.0 pmol/L]). Because magnetic resonance imaging revealed a pituitary microadenoma (4 mm), she was diagnosed with TSH-secreting pituitary adenoma and underwent transsphenoidal surgery. Pathological reports showed no tumor cells. Subsequent genetic testing revealed a pathogenic variant in the THRB gene resulting in a His435Arg amino acid substitution in the T3 receptor isoform beta 1 (TRß1), suggestive of RTHß. In vitro and ex vivo studies revealed that the His435Arg mutated TRß1 (TRß1-H435R) completely abolishes the T3-induced transcriptional activation, nuclear receptor corepressor 1 release, steroid receptor coactivator 1 recruitment, and T3-induced thyroid hormone target gene expression, confirming the pathogenicity of this variant. The identification of a pituitary microadenoma in a patient with RTHß led to a misdiagnosis of a TSH-producing tumor and unnecessary surgery. Genetic testing proved pivotal for an accurate diagnosis, suggesting earlier consideration in similar clinical scenarios.

Molecular characteristics of patients with colorectal signet-ring cell carcinoma with different ABO blood groups.

Background: Colorectal signet-ring cell carcinoma (SRCC) is a rare subtype of malignant adenocarcinoma, accounting for approximately 1 % of colorectal cancer (CRC) cases. Its biomarkers and molecular characteristics remain controversial, and there are no specific therapeutic targets or strategies for its clinical treatment. Methods: A retrospective study was conducted between January 2010 and December 2021. 1058 colorectal cancer cases from the Sun Yat-sen University Cancer Center and 489 cases from the Tumor Genome Atlas Project were included in the analysis, of which 64 were SRCC. Data extraction included patient demographics, blood types and risk factors, including clinical variables and genomics (either a 19-gene panel NGS or 1021-gene panel NGS). Univariate analyses were performed to identify factors significantly associated with overall survival. Results: The blood groups of 27 (42.2 %), 18 (28.1 %), 12 (18.8 %), and seven (10.9 %) patients were classified as O, A, B, and AB, respectively. We found that O was a unique blood group characterized by a low frequency of KRAS mutations, a high frequency of heterozygosity at each HLA class I locus, and a high tumor mutational burden (TMB). Patients in blood group A with high-frequency KRAS mutations and those in blood group B with anemia and metabolic abnormalities required targeted treatment. Furthermore, genetic alterations in SRCC differed from those in adenocarcinoma and mucinous adenocarcinoma. Conclusions: Our study revealed genomic changes in SRCC patients across different blood groups, which could advance the understanding and precise treatment of colorectal SRCC.

Extensive Lateral Cervical Desmoid Tumor Dependent on the Levator Scapulae Muscle Involving the Vertebral Artery Treated by Surgical Resection and Intraoperative Navigation: A Case Report and Review of the Literature.

Desmoid tumors are rare, benign, but locally aggressive fibromatoses that pose significant therapeutic challenges, particularly when located in the head and neck region. This report details the case of an extensive cervical desmoid tumor dependent on the levator scapulae muscle and involving the vertebral artery managed through surgical resection and intraoperative navigation. A 45-year-old male presented with a slowly growing cervical mass. Imaging revealed an 83x68x40 mm mass in the right lateral paravertebral space, dependent on the levator scapulae muscle and involving the vertebral artery. Biopsy confirmed a low-grade fusocellular myofibroblastic neoplasm consistent with a desmoid tumor. Given the poor prognosis associated with the symptomatic mass, surgical resection was performed using Brainlab intraoperative navigation (Brainlab, Munich, Germany). The procedure was successful, with preservation of vital structures and no evidence of recurrence postoperatively. Desmoid tumors in the head and neck region, though rare, require precise diagnostic and therapeutic approaches due to their aggressive nature and proximity to critical anatomical structures. The use of intraoperative navigation, in this case, facilitated accurate tumor resection, minimizing damage to surrounding tissues. Pathological analysis revealed a CTNNB1 gene mutation, specifically the S45P variant, which is associated with an increased risk of recurrence. This case highlights the importance of a multidisciplinary approach, incorporating advanced surgical techniques and genetic analysis, in the management of complex desmoid tumors. Intraoperative navigation proved invaluable in achieving successful surgical outcomes, underscoring its potential utility in similar cases. Continued follow-up is essential, given the potential for recurrence associated with desmoid tumors.

Dominant Beta Thalassemia: A Very Rare Cause of Thalassemia in a Mediterranean Country.

Beta thalassemia is one of the monogenic disorders characterized by decreased production of ß-globin chains and various types of mutations have been reported to cause thalassemia phenotype. On the other hand, rare mutations also affect and diversify the disease spectrum. Herein, we present an anemic patient from Turkey diagnosed with dominant ß thalassemia due to a heterozygous mutation in exon 3 of the HBB gene.

Inborn errors of immunity and its clinical significance in children with lymphoma in China: a single-center study

Abstract Objective: To investigate the incidence, clinical and genetic characteristics of pediatric lymphoma patients of China with inborn errors of immunity (IEI)-related gene mutations, which have not been fully studied. Method: From Jan. 2020 to Mar. 2023, IEI-related genetic mutations were retrospectively explored in 108 children with lymphomas admitted to Beijing Children's Hospital by NGS. Genetic rule and clinical characteristics as well as treatment outcomes were compared between patients with or without IEI-related gene mutations. Results: A total of 17 patients (15.7 %) harbored IEI-associated mutations, including 4 cases with X-linked lymphoproliferative syndrome (XLP), 3 cases had mutations in tumor necrosis factor receptor superfamily 13B (TNFRSF13B), 2 cases with Activated p110 syndrome (APDS). Patients with IEI all had alteration of immunocompetence with decreased levels of immunoglobulin and lymphocyte subsets. Recurrent infection existed in 41.2 % of patients. The 18-month event-free survival (EFS) and the overall response rate (ORR) of patients with IEI are significantly lower than those without IEI (33.86% vs. 73.26 %, p = 0.011; 52.94% vs. 87.91 %, p = 0.002, respectively). In addition, patients with IEI had a higher progression disease (PD) rate of 23.5 % than those without IEI of 4.4% (p = 0.006). Conclusion: The present study demonstrated that IEI-associated lymphomas were much more common than originally appreciated in pediatric lymphomas, and those were insensitive to treatment and more likely to progress or relapse. The genomic analysis and a thorough review of the medical history of IEI can be used to distinguish them from pediatric lymphomas without IEI, which are beneficial for the early diagnosis and direct intervention.

Mutation of mpv17 results in loss of iridophores due to mitochondrial dysfunction in tilapia.

Mpv17 (mitochondrial inner membrane protein MPV17) deficiency causes severe mitochondrial DNA depletion syndrome in mammals and loss of pigmentation of iridophores and a significant decrease of melanophores in zebrafish. The reasons for this are still unclear. In this study, we established an mpv17 homozygous mutant line in Nile tilapia. The developing mutants are transparent due to loss of iridophores and aggregation of pigment granules in the melanophores and disappearance of the vertical pigment bars on the side of the fish. Transcriptome analysis using skin of fish at 30 dpf (days post fertilization) revealed that the genes related to purine (especially pnp4a) and melanin synthesis were significantly downregulated. However, administration of guanine diets failed to rescue the phenotype of the mutants. In addition, no obvious apoptosis signals were observed in the iris of the mutants by TUNEL staining. Significant downregulation of genes related to iridophore differentiation was detected by qPCR. Insufficient ATP, as revealed by ATP assay, α-MSH treatment and adcy5 mutational analysis, might account for the defects of melanophores in mpv17 mutants. Several tissues displayed less mtDNA and decreased ATP levels. Taken together, these results indicated that mutation of mpv17 led to mitochondrial dTMP deficiency, followed by impaired mtDNA content and mitochondrial function, which in turn, led to loss of iridophores and a transparent body color in tilapia.

The cytidine deaminase APOBEC3C has unique sequence and genome feature preferences.

APOBEC proteins are cytidine deaminases that restrict the replication of viruses and transposable elements. Several members of the APOBEC3 family, APOBEC3A, APOBEC3B, and APOBEC3H-I, can access the nucleus and cause what is thought to be indiscriminate deamination of the genome, resulting in mutagenesis and genome instability. Although APOBEC3C is also present in the nucleus, the full scope of its deamination target preferences is unknown. By expressing human APOBEC3C in a yeast model system, I have defined the APOBEC3C mutation signature, as well as the preferred genome features of APOBEC3C targets. The APOBEC3C mutation signature is distinct from those of the known cancer genome mutators APOBEC3A and APOBEC3B. APOBEC3C produces DNA strand-coordinated mutation clusters, and APOBEC3C mutations are enriched near the transcription start sites of active genes. Surprisingly, APOBEC3C lacks the bias for the lagging strand of DNA replication that is seen for APOBEC3A and APOBEC3B. The unique preferences of APOBEC3C constitute a mutation profile that will be useful in defining sites of APOBEC3C mutagenesis in human genomes.

Eosinophilic Cells in Ovarian Borderline Serous Tumors as a Predictor of BRAF Mutation.

According to recent reports, ovarian serous borderline tumor (SBT) harboring the BRAF V600E mutation is associated with a lower risk of progression to low-grade serous carcinoma. Preliminary observations suggest that there may be an association between eosinophilic cells (ECs) and the above-mentioned mutation, so this study aimed to evaluate interobserver reproducibility for assessing ECs. Forty-two samples of SBTs were analyzed for ECs with abundant eosinophilic cytoplasm. Immunohistochemical staining and genetic pro-filing were performed in all cases to verify the BRAF V600E mutation. A BRAF V600E mutation was found in 19 of 42 (45%) cases. Inter-observer reproducibility in the assessment of ECs was substantial (κ = 0.7). The sensitivity and specificity for predicting the mutation were 79% and 91%, respectively. Patients with BRAF-mutated SBTs were significantly younger than those without mutation (p = 0.005). SBTs with BRAF mutation were less likely to be accompanied by non-invasive implants than wild-type SBT: 12% (2/17) versus 33% (6/18). Seven cases were excluded due to incomplete cytoreductive surgery. Nevertheless, Fisher's exact test showed no significant differences between the two groups (p = 0.228). Overall, this study strengthens the idea that ECs in ovarian SBTs may represent a mutation with prognostic significance, which can serve as a primary screening test for BRAF V600E mutation in this pathologic entity.