Variant Patterns Research Articles

A Cadaveric Study to Define the Variant Patterns of Median Nerve Formation.

The median nerve is one of the important nerves of the upper limb which supplies the muscles of the front of the forearm,muscles of the hand, and skin of the hand. Many works of literature mentioned its formation by the fusion of two roots, the medial root from the medial cord and the lateral root from the lateral cord. But multiple variations in the median nerve formation have clinical importance from surgical and anesthetic points of view. For the study purpose, we dissected 68 axillae of 34 formalin-fixed cadavers. Out of 68 axillae, two (2.9%) showed median nerve formation by a single root, 19 (27.9%) showed median nerve formation by three roots, and three (4.4%) showed median nerve formation by four roots. A normal pattern of median nerve formation by fusion of two roots was seen in 44 (64.7%)axilla. The knowledge of variant patterns of median nerve formation will be helpful to surgeons and anesthetists while performing surgical or anesthetic procedures in the axilla to avoid any injury to the median nerve.

Case Report: human early embryonic arrest in a consanguineous Chinese family caused by a novel missense variant of PADI6.

Peptidyl arginine deiminase 6 (PADI6) is a member of the subcortical maternal complex, and PADI6 biallelic mutations have been reported to be cause female infertility via abnormalities in embryonic development. This study examined a consanguineous Chinese family in which two sisters had infertility caused by early embryonic arrest. Whole exome sequencing was performed on the affected sisters and their parents to identify the potential causative mutated genes. A novel missense variant in PADI6 (NM_207421:exon16:c.G1864A:p.V622M) was identified as the pathogenic cause of female infertility caused by early embryonic arrest. Subsequent experiments confirmed the segregation pattern of this PADI6 variant with a recessive mode of inheritance. This variant has not been reported in public databases. Furthermore, in silico analysis predicted that the missense variant was detrimental to the function of PADI6, and the mutated site was highly conserved among several species. In conclusion, our study identified a novel mutation in PADI6, further expanding the spectrum of mutations of this gene.

Cadaveric Study to Define the Anatomy of the Medial Patellofemoral Ligament (MPFL) and Its Variant Patterns.

The medial patellofemoral ligament (MPFL) is one of the major soft tissue stabilizers on the medial side of the knee joint, extending from the medial condyle of the femur to the medial aspect of the patella. Different kinds of literature described different sizes and different origins and insertions of MPFL. Injury of MPFL causes patellar instability and dislocation.We reported the anatomy and morphology of MPFL and its implications in the repair of MPFL. The aim of the study was also to look at the variant forms of the MPFL. Methodology: A total of 40 lower limbs fixed in formalin were dissected to study the MPFL of the knee. After reflecting the deep fascia and retinaculum on the medial side of the knee joint the MPFL was exposed. For better learning the lower medial part of vastus medialis was reflected, so that the part of MPFL undercover was exposed. Different forms of MPFL were seen like two straps 12.5%, broad rectangle 20%, and triangular shaped 67.5% MPFL.The origin of MPFL was found between the adductor tubercle and medial epicondyle of the femur and insertion was seen extending from the proximal medial half of the patella to the tendinous aponeurosis of vastus medialis obliquus (VMO) and vastus intermedius muscle (VIM). This is the first study that described three variant patterns of MPFL in accordance with their morphological appearance. This knowledge will be helpful to the surgeons for easy identification and repair of the MPFL.

Mechanisms underlying phenotypic variation in neurogenetic disorders.

Neurological diseases associated with pathogenic variants in a specific gene, or even with a specific pathogenic variant, can show profound phenotypic variation with regard to symptom presentation, age at onset and disease course. Highlighting examples from a range of neurogenetic disorders, this Review explores emerging mechanisms that are involved in this variability, including environmental, genetic and epigenetic factors that influence the expressivity and penetrance of pathogenic variants. Environmental factors, some of which can potentially be modified to prevent disease, include trauma, stress and metabolic changes. Dynamic patterns of pathogenic variants might explain some of the phenotypic variations, for example, in the case of disorders caused by DNA repeat expansions such as Huntington disease (HD). An important role for modifier genes has also been identified in some neurogenetic disorders, including HD, spinocerebellar ataxia and X-linked dystonia-parkinsonism. In other disorders, such as spastic paraplegia, the basis for most of the phenotypic variability remains unclear. Epigenetic factors have been implicated in disorders such as SGCE-related myoclonus-dystonia and HD. Knowledge of the mechanisms underlying phenotypic variation is already starting to influence management strategies and clinical trials for neurogenetic disorders.

Lessons drawn from Shanghai for controlling highly transmissible SARS-CoV-2 variants: insights from a modelling study

BackgroundThe continuous emergence of novel SARS-CoV-2 variants with markedly increased transmissibility presents major challenges to the zero-COVID policy in China. It is critical to adjust aspects of the policy about non-pharmaceutical interventions (NPIs) by searching for and implementing more effective ways. We use a mathematical model to mimic the epidemic pattern of the Omicron variant in Shanghai to quantitatively show the control challenges and investigate the feasibility of different control patterns in avoiding other epidemic waves.MethodsWe initially construct a dynamic model with a core step-by-step release strategy to reveal its role in controlling the spread of COVID-19, including the city-based pattern and the district-based pattern. We used the least squares method and real reported case data to fit the model for Shanghai and its 16 districts, respectively. Optimal control theory was utilized to explore the quantitative and optimal solutions of the time-varying control strength (i.e., contact rate) to suppress the highly transmissible SARS-CoV-2 variants.ResultsThe necessary period for reaching the zero-COVID goal can be nearly 4 months, and the final epidemic size was 629,625 (95%CI: [608,049, 651,201]). By adopting the city-based pattern, 7 out of 16 strategies released the NPIs more or earlier than the baseline and ensured a zero-resurgence risk at the average cost of 10 to 129 more cases in June. By adopting the district-based pattern, a regional linked release can allow resumption of social activity to ~ 100% in the boundary-region group about 14 days earlier and allow people to flow between different districts without causing infection resurgence. Optimal solutions of the contact rate were obtained with various testing intensities, and higher diagnosis rate correlated with higher optimal contact rate while the number of daily reported cases remained almost unchanged.ConclusionsShanghai could have been bolder and more flexible in unleashing social activity than they did. The boundary-region group should be relaxed earlier and more attention should be paid to the centre-region group. With a more intensive testing strategy, people could return to normal life as much as possible but still ensure the epidemic was maintained at a relatively low level.

Distribution pattern of haemoglobin variants, ABO and Rhesus blood groups among undergraduate students of EBSU, Abakaliki, Ebonyi State, southeast Nigeria

Distribution pattern of haemoglobin variants, ABO and Rhesus blood groups among undergraduate students of EBSU, Abakaliki, Ebonyi State, southeast Nigeria

Clinical relevance of somatic mosaic variants detected from exome sequencing data

Several recent reports have implicated somatic mosaic variants as phenocopies of germline defects of inborn errors of immunity (IEI). Somatic variants can also result from clonal hematopoiesis (CH), which has been associated with increased risk of hematological malignancies and cardiovascular disorders. The extent of clinical relevance of somatic variants remain uncertain.We developed a workflow to detect and interpret somatic mosaic variants from exome data obtained from blood-extracted DNA of 2841 patients, a subset of whom had a genetic diagnoses in genes implicated in IEI. These somatic variants had variant allele fraction (VAF) between 0.05 and 0.31 and were called using LoFreq2, an algorithm that detects variants with low VAF that may be missed by standard germline variant calling pipelines. We highlight three examples of characterization of this somatic variant data from 2841 exomes.1) We identified 39 somatic variants as potential clinical diagnoses in our cohort. These variants were previously associated with disorders overlapping with the clinical features of the respective patients. Ten of these variants were not detected by a standard pipeline for calling germline variants.2) We detected 16 predicted loss of function and missense somatic variants in 12 published IEI genes that were consistent with disease pathogenesis. The clinical relevance of these findings is under investigation.3) Clustering analysis of somatic variants in genes known to be recurrently mutated in CH identified groups of patients harboring distinct patterns of somatic variants. For example, patients with germline defects in GATA2 were enriched in predicted loss of function variants in a subset of genes implicated in CH namely ASXL1, STAG2, and DNMT3A. These results were independently replicated in a formal case control analysis. We plan to extend this analysis to cohorts with germline defects in other IEI genes. Here we report a pipeline for calling and interpreting somatic variants that resulted in clinical diagnoses and allowed characterization of clonal hematopoiesis. Further investigation of the identified somatic variants will contribute to new diagnoses and methods for prognostication and potentially uncover new genes underlying inborn errors of immunity.

Immunohistochemical Pattern of Histone H2A Variant Expression in an Experimental Model of Ischemia-Reperfusion-Induced Acute Kidney Injury.

Ischemia-reperfusion injury (IRI) is a frequent cause of AKI, resulting in vasoconstriction, cellular dysfunction, inflammation and the induction of oxidative stress. DNA damage, including physical DNA strand breaks, is also a potential consequence of renal IRI. The histone H2A variants, primary H2AX and H2AZ participate in DNA damage response pathways to promote genome stability. The aim of this study was to evaluate the immunohistochemical pattern of histone H2A variants' (H2AX, γH2AX(S139), H2AXY142ph and H2AZ) expression in an experimental model of ischemia-reperfusion-induced acute kidney injury in spontaneously hypertensive rats. Comparing the immunohistochemical nuclear expression of γH2AX(S139) and H2AXY142ph in AKI, we observed that there is an inverse ratio of these two histone H2AX variants. If we follow different regions from the subcapsular structures to the medulla, there is an increasing extent gradient in the nuclear expression of H2AXY142ph, accompanied by a decreasing nuclear expression of γH2AX. In addition, we observed that different structures dominated when γH2AX and H2AXY142ph expression levels were compared. γH2AX was expressed only in the proximal tubule, with the exception of when they were dilated. In the medulla, H2AXY142ph is predominantly expressed in the loop of Henle and the collecting ducts. Our results show moderate sporadic nuclear H2AZ expression mainly in the cells of the distal tubules and the collecting ducts that were surrounded by dilated tubules with PAS (periodic acid-Schiff stain)-positive casts. These findings may indicate the degree of DNA damage, followed by postischemic AKI, with potential clinical and prognostic implications regarding this condition.

Retrospective Study of Normal Variations in Vertebral Artery on Computed Tomography Angiography With Special Emphasis on Relevant Embryology.

Background The vertebral arteries (VA) nourish the posterior cerebral circulation. Planning neck and cervical interventions like drilling and instrumentation, which involves VA manipulation, require an in-depth acquaintance with the normal and variant patterns encountered in the origin and course of the VA. Embryological events involved in forming these variant patterns can be correlated to their prior disposition in the lower vertebrate's understanding which becomes crucial while planning cervical interventions. Study design This is a single-center, retrospective study. Materials and methods The study involved 70 patients of both sexes and was done from September 2021 to February 2022 in the Department of Radiodiagnosis and Imaging at North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences (NEIGRIHMS), Meghalaya, India. The CT angiographies were studied for variations of VA under V1 - from origin to entrance into the foramen transversarium (FT), V2 - part inside FT, V3 - from its exit from FT till it pierces the cranial dura mater, and V4 - intracranial part. Further, VA was observed for its origin, dominance, level of entry in FT, and any associated anomalies. Results The VA was found mostly to be codominant. There was an opposite directional relationship between the basilar artery curvature and the dominance of VA. The association of ischemic events with hypoplastic VA was more on the left side (66.67%). Left VA originated from the aorta in 4.3% of subjects. One case presented a dual origin of VA. The abnormal origin of the LVA from the aorta showed a higher rate of abnormal entry into FT which was also found to be statistically significant. Conclusion Our study identifies and documents the anatomical variations present in VA specific to the population of northeast India by CT angiography and thus provides a much-needed reference for the healthcare professionals working in the field of Head and Neck interventions by providing opportunities further to understand these patterns for better diagnostic and therapeutic outcomes.

Capture of TAD reorganization endows variant patterns of gene transcription

Capture of TAD reorganization endows variant patterns of gene transcription

Hepatocytes undergo punctuated expansion dynamics from a periportal stem cell niche in normal human liver

While normal human liver is thought to be generally quiescent, clonal hepatocyte expansions have been observed, though neither their cellular source nor their expansion dynamics have been determined. Knowing the hepatocyte cell of origin, and their subsequent dynamics and trajectory within the human liver will provide an important basis to understand disease-associated dysregulation. Herein, we use invivo lineage tracing and methylation sequence analysis to demonstrate normal human hepatocyte ancestry. We exploit next-generation mitochondrial sequencing to determine hepatocyte clonal expansion dynamics across spatially distinct areas of laser-captured, microdissected, clones, in tandem with computational modelling in morphologically normal human liver. Hepatocyte clones and rare SOX9+ hepatocyte progenitors commonly associate with portal tracts and we present evidence that clones can lineage-trace with cholangiocytes, indicating the presence of a bipotential common ancestor at this niche. Within clones, we demonstrate methylation CpG sequence diversity patterns indicative of periportal not pericentral ancestral origins, indicating a portal to central vein expansion trajectory. Using spatial analysis of mitochondrial DNA variants by next-generation sequencing coupled with mathematical modelling and Bayesian inference across the portal-central axis, we demonstrate that patterns of mitochondrial DNA variants reveal large numbers of spatially restricted mutations in conjunction with limited numbers of clonal mutations. These datasets support the existence of a periportal progenitor niche and indicate that clonal patches exhibit punctuated but slow growth, then quiesce, likely due to acute environmental stimuli. These findings crucially contribute to our understanding of hepatocyte dynamics in the normal human liver. The liver is mainly composed of hepatocytes, but we know little regarding the source of these cells or how they multiply over time within the disease-free human liver. In this study, we determine a source of new hepatocytes by combining many different lab-based methods and computational predictions to show that hepatocytes share a common cell of origin with bile ducts. Both our experimental and computational data also demonstrate hepatocyte clones are likely to expand in slow waves across the liver in a specific trajectory, but often lie dormant for many years. These data show for the first time the expansion dynamics of hepatocytes in normal liver and their cell of origin enabling the accurate measurment of changes to their dynamics that may lead to liver disease. These findings are important for researchers determining cancer risk in human liver.

The interaction between MC4R gene variant (rs17782313) and dominant dietary patterns on depression in obese and overweight women: a cross sectional study

BackgroundPrevious studies have shown that the minor allele (C allele) for melanocortin 4 receptor (MC4R) rs17782313 may be associated with depressed mood. Moreover, dietary patterns have potentially adverse effects on depression. This study investigates the interactions between the MC4R gene variant (rs17782313) and dietary patterns on depression among Iranian obese and overweight women.MethodsA total of 289 Iranian overweight and obese women, aged 18–50 years, were enrolled in this cross-sectional study. Biochemical, anthropometric, and body composition indices were assessed in all participants. Moreover, MC4R rs17782313, by the restriction fragment length polymorphism (PCR-RFLP) method, and depression, using the 21-item Depression Anxiety Stress Scales (DASS) questionnaire, were assessed. Food intakes were assessed by completing a 147-item semi-quantitative food frequency questionnaire (FFQ).ResultsBy the use of factor analysis, 2 major dietary patterns were extracted: healthy dietary pattern (HDP) and unhealthy dietary pattern (UDP). Binary logistic analysis showed that individuals with minor allele risk (CC) with high adherence to the unhealthy pattern increased odds for depression (OR: 8.77, 95%CI: -0.86-18.40, P: 0.07), after controlling for confounders. Also, a logical inverse relationship was observed between CT genotype and HDP on depression in the crude and adjusted models (OR: -0.56, 95% CI: -3.69-2.57, P: 0.72) (OR: -4.17, 95% CI: -9.28-0.94, P: 0.11), although this interaction was not statistically significant.ConclusionAccording to the above findings, adherence to unhealthy food intake pattern increases odds of depression in MC4R risk allele (C allele) carriers. To confirm these findings, more studies are needed in the form of clinical trials and prospective studies with higher sample sizes.

Multi-Polymorphism Analysis Reveals Joint Effects in Males With Chronic Central Serous Chorioretinopathy.

Central serous chorioretinopathy (CSCR) is a leading cause of central vision impairment in the working-age population with male predilection. Knowledge about the genetic basis of CSCR and its male predilection remained limited. This study aimed to evaluate the association patterns of multiple gene variants in chronic CSCR (cCSCR) in Chinese patients. This case-control genetic association study included 531 patients with cCSCR and 2383 controls from two independent Chinese cohorts. Nine single-nucleotide polymorphisms (SNPs) of six genes, namely CFH, NR3C2, GATA5, VIPR2, TNFRSF10A, and ARMS2, were genotyped in all subjects. The main outcome measures were the association of individual single-nucleotide polymorphism (SNP) with cCSCR, the sex-stratification effects of individual SNP, and joint effects of different SNPs on cCSCR. Association results in the two cohorts were consistent with low heterogeneities. In the combined analysis, SNPs CFH rs800292 (odds ratio [OR] = 1.25, P = 0.0020), CFH rs1329428 (OR = 1.23, P = 0.0037), and TNFRSF10A rs13278062 (OR = 1.43, P = 0.0014) were significantly associated with cCSCR. In stratification analysis by sex, 3SNPs in CFH, rs3753394, rs800292, and rs1329428, were associated with cCSCR in male patients, but not in female patients. Joint analysis revealed that subjects homozygous for the risk alleles of CFH rs800292 and TNFRSF10A rs13278062 had over 4-fold of increased risk of cCSCR when compared with subjects homozygous for the non-risk alleles (OR = 4.06, P = 2.30 × 10-5). This study revealed main and joint effects of SNPs in CFH and TNFRSF10A on cCSCR, and suggested CFH as a potential genetic factor underlying the male predilection of cCSCR. Further replication in other study populations is needed.

Leri–Weill Dyschondrosteosis Caused by a Leaky Homozygous SHOX Splice-Site Variant

SHOX deficiency is a common genetic cause of short stature of variable degree. SHOX haploinsufficiency causes Leri-Weill dyschondrosteosis (LWD) as well as nonspecific short stature. SHOX haploinsufficiency is known to result from heterozygous loss-of-function variants with pseudo-autosomal dominant inheritance, while biallelic SHOX loss-of-function variants cause the more severe skeletal dysplasia, Langer mesomelic dyschondrosteosis (LMD). Here we report for the first time the pseudo-autosomal recessive inheritance of LWD in two siblings caused by a novel homozygous non-canonical, leaky splice-site variant in intron 3 of SHOX: c.544+5G>C. Transcript analyses in patient-derived fibroblasts showed homozygous patients to produce approximately equal amounts of normally spliced mRNA and mRNA with the abnormal retention of intron 3 and containing a premature stop codon (p.Val183Glyfs*31). The aberrant transcript was shown to undergo nonsense-mediated mRNA decay, and thus resulting in SHOX haploinsufficiency in the homozygous patient. Six healthy relatives who are of normal height are heterozygous for this variant and fibroblasts from a heterozygote for the c.544+5G>C variant produced wild-type transcript amounts comparable to healthy control. The unique situation reported here highlights the fact that the dosage of SHOX determines the clinical phenotype rather than the Mendelian inheritance pattern of SHOX variants. This study extends the molecular and inheritance spectrum of SHOX deficiency disorder and highlights the importance of functional testing of SHOX variants of unknown significance in order to allow appropriate counseling and precision medicine for each family individual.

Abstract 5585: Tissue based next generation sequence is more accurate than ctDNA to detected pathogenic variants in MTAP wild type tumors

Abstract Next generation sequencing (NGS) of circulating tumor DNA (ctDNA) prevents invasive biopsies and captures tumor heterogeneity. In a prior report by Zhang et al (Nat Commun 2021), certain actionable mutations were more prevalent in ctDNA than tissue-based databases (e.g., EGFR 48% versus 25.2%). Our group investigated if discrepancies in patterns of pathogenic variants between liquid biopsy and tissue specimens in a subtype of metastatic urothelial carcinoma (MTAP deleted) can inform the best approach of utilizing tissue or blood. MTAP (methyl-adenosine phosphorylase) is an enzyme involved in salvage purine biosynthesis and its deletion confers sensitivity to pemetrexed and taxanes, but resistance to immune checkpoint inhibitors. The MTAP gene is deleted in 25% of urothelial carcinomas. We report herein the pattern of pathogenic variants from ctDNA in 17 patients with metastatic urothelial carcinoma, 10 with MTAP-deletion and 17 with MTAP wild-type. Among 10 patients with MTAP-deleted urothelial carcinoma with collected ctDNA, 3 had no detected pathogenic variant. The most common pathogenic variants in 7 patients were TP53 (4/7, 57%), TERT (4/7, 57%), ERBB2 (2/7, 28%); PIK3CA (2/7, 28%), and NFE2L2 (2/7, 28%). The mutations found in paired ctDNA and tissue based NGS were TP53 in 26.6 % (4/15), TERT in 21.0 % (4/19), ERBB2 in 66.6 % (2/3), PIK3CA in 50 % (2/4), and NFE2L2 in 100% (1/1) of patients. Three of the 10 patients with collected ctDNA had ELF3 frameshift loss-of- function alterations on tissue not found on ctDNA. Among 54 patients with MTAP wild-type urothelial carcinoma, 26 had collected ctDNA. Among these 26 patients, 9 had no detected pathogenic variants. Among the 17 patients with pathogenic variants, the most common mutations were TP53 (76%, 13/17), TERT (47%, 8/17), ERBB2 (24%, 4/17), RB1 (24%, 4/17), and BRCA1 or BRCA2 (24%, 4/17). Three of these 17 patients had no or insufficient tissue for NGS. The mutations found in paired ctDNA and tissue based NGS were TP53 in 100% (14/14), TERT in 64% (9/14), ERBB2 in 43% (6/14), RB1 in 29% (5/14), and BRCA1 or BRCA2 in 36% (5/14) of patients. MTAP wild-type patients had a higher frequency of TERT alterations (p=0.012), but not ERBB2, (p=0.453) than patients with MTAP-deleted type tumors. Ongoing evaluation of timing and location of pathogenic variants will inform where (primary tumor, metastatic site) and when (after chemotherapy, immune checkpoint inhibitors, antibody drug conjugates) to biopsy patients on progression after cancer therapies. Citation Format: Andre Luiz De Souza. Tissue based next generation sequence is more accurate than ctDNA to detected pathogenic variants in MTAP wild type tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5585.

Upper Limb Nerve Variations May Alter Clinical Diagnosis: A Scoping Review

Upper limb nerve variations may be related to the absence of a nerve, an interconnection between two nerves or a variant course. The purpose of this review is to screen the existing literature on upper limb nerve variations that may alter the neurologic diagnostic process. A scoping review was performed following PRISMA for Scoping Reviews guidelines. Initially, 1331 articles were identified by searching Pubmed and Web of Science until the 22nd of October 2022. After screening, reading, and additional searching 50 articles were included in this review. Variations were divided into two categories: 1) variations causing a different innervation pattern involving sensory, motor, or both types of fibers, and 2) variations causing or related to compression syndromes. Two-thirds of the included articles were cadaver studies. Nine articles were diagnostic studies on symptomatic or healthy individuals involving medical imaging and/or surgery. Nerve variations that may cause a different innervation pattern concern most frequently their interconnection. The connection between the median and musculocutaneous nerve in the upper limb and the connection between the median and ulnar nerve in the forearm (Martin-Gruber) or hand (Riche-Cannieu) may be present in half of the population. Injury to these connections may cause compound peripheral neuropathies a result of variant sensory and motor branching patterns. Muscular, vascular, or combined anomalies in the forearm were reported as causes of entrapment neuropathies. These nerve variations may mimic classical entrapment syndromes such as carpal tunnel syndrome or compression at ulnar canal (Guyon's canal). Knowledge of frequent nerve variations in the arm may be important during the diagnostic process and examination. Variant innervation patterns may explain non-classical clinical signs and/or symptoms during provocative tests. Classical nerve compression syndromes in the arm may warrant for differential diagnosis, especially in the case of persistent or recurrent symptoms.

Distinct gene expression patterns of SOX2 and SOX2OT variants in different types of brain tumours

Numerous investigations have been recently published on the dysregulated expression of long-noncoding RNAs (lncRNAs) in various cancer types, emphasizing that abnormal lncRNA expression is a major contributor to tumourigenesis. A broad spectrum of lncRNAs is expressed in the central nervous system, where these RNAs seem to play key roles in brain development and function. In addition to expressing SOX2, a master regulator of pluripotency that lies within its third intron, lncRNA SOX2OT has a proposed role in regulating neural development. Based on our previous studies, alternative splicing of SOX2OT generates two alternatively spliced variants (SOX2OT-S1 and SOX2OT-S2). The present study investigated the expression patterns of SOX2OT variants and SOX2 in three principal types of brain tumours (gliomas, meningiomas and pituitary adenomas) and in four brain tumour cell lines (U87-MG, 1321N1, A172 and DAOY). Total RNAwas extracted from 34 human brain tumour specimens, and the expression profile of target genes was measured using a real-time reverse transcription PCR approach. Our data revealed distinct expression patterns for SOX2OT variants and SOX2 in the brain tumour samples, indicating their potential involvement in brain tumourigenesis. Moreover, our results highlighted the potential usefulness of SOX2OT-S1, SOX2OT-S2, and SOX2 in molecular diagnosis and brain tumour classification.

Lineages and Sublineages of Human Papillomavirus Type 16 in Cervical Samples of Iranian Women

Aim: This study was designed to analyze intratypic variations of human papillomavirus type 16 (HPV16) and to assess the risk of these variants for progression to cervical cancer. Materials & Methods: HPV16 variants of 58 women were determined by PCR-directed sequencing. Results: The most frequent lineage was D (67.2%) followed by A (32.8%). Lineage A was found predominantly in normal (62.5%) and cervical intraepithelial neoplasia-1 (CIN-1) (83.3%), while lineage D was the most prevalent variant in cervical cancer (100%). Conclusion: The present study revealed a distinct pattern of HPV16 variants in Iran. Based on our data, the predominant HPV16 lineage was D and there was a significant association between lineage D variants and cervical cancer.

Clonal hematopoiesis driven by chromosome 1q/MDM4 trisomy defines a canonical route toward leukemia in Fanconi anemia.

Fanconi anemia (FA) patients experience chromosome instability, yielding hematopoietic stem/progenitor cell (HSPC) exhaustion and predisposition to poor-prognosis myeloid leukemia. Based on a longitudinal cohort of 335 patients, we performed clinical, genomic, and functional studies in 62 patients with clonal evolution. We found a unique pattern of somatic structural variants and mutations that shares features of BRCA-related cancers, the FA-hallmark being unbalanced, microhomology-mediated translocations driving copy-number alterations. Half the patients developed chromosome 1q gain, driving clonal hematopoiesis through MDM4 trisomy downmodulating p53 signaling later followed by secondary acute myeloid lukemia genomic alterations. Functionally, MDM4 triplication conferred greater fitness to murine and human primary FA HSPCs, rescued inflammation-mediated bone marrow failure, and drove clonal dominance in FA mouse models, while targeting MDM4 impaired leukemia cells invitro and invivo. Our results identify a linear route toward secondary leukemogenesis whereby early MDM4-driven downregulation of basal p53 activation plays a pivotal role, opening monitoring and therapeutic prospects.

Patterns of Somatic Variants in Colorectal Adenoma and Carcinoma Tissue and Matched Plasma Samples from the Hungarian Oncogenome Program.

Analysis of circulating cell-free DNA (cfDNA) of colorectal adenoma (AD) and cancer (CRC) patients provides a minimally invasive approach that is able to explore genetic alterations. It is unknown whether there are specific genetic variants that could explain the high prevalence of CRC in Hungary. Whole-exome sequencing (WES) was performed on colon tissues (27 AD, 51 CRC) and matched cfDNAs (17 AD, 33 CRC); furthermore, targeted panel sequencing was performed on a subset of cfDNA samples. The most frequently mutated genes were APC, KRAS, and FBN3 in AD, while APC, TP53, TTN, and KRAS were the most frequently mutated in CRC tissue. Variants in KRAS codons 12 (AD: 8/27, CRC: 11/51 (0.216)) and 13 (CRC: 3/51 (0.06)) were the most frequent in our sample set, with G12V (5/27) dominance in ADs and G12D (5/51 (0.098)) in CRCs. In terms of the cfDNA WES results, tumor somatic variants were found in 6/33 of CRC cases. Panel sequencing revealed somatic variants in 8 out of the 12 enrolled patients, identifying 12/20 tumor somatic variants falling on its targeted regions, while WES recovered only 20% in the respective regions in cfDNA of the same patients. In liquid biopsy analyses, WES is less efficient compared to the targeted panel sequencing with a higher coverage depth that can hold a relevant clinical potential to be applied in everyday practice in the future.