Chromosome 9p21 Research Articles

Low-level mosaic GCK mutations in children with diazoxide-unresponsive congenital hyperinsulinism.

Some children with diazoxide-unresponsive congenital hyperinsulinism (HI) lack any detectable disease-causing mutation in peripheral blood DNA. To examine whether somatic post-zygotic mutations of known HI genes are responsible for disease in children with diazoxide-unresponsive HI requiring surgery with histology not classified as focal or Localized Islet Nuclear Enlargement (LINE), and without detectable mutations by standard genetic testing of peripheral blood DNA. Next-generation sequencing (NGS) was performed on specimens of pancreas from 10 children with diazoxide-unresponsive HI. Four unique GCK mutations were identified at low levels of mosaicism ranging from 4.4-10.1% in pancreatic DNA from five of these 10 children. The GCK mutations were not detectable in peripheral blood DNA by NGS in three cases from which peripheral blood DNA was available for testing. All four GCK mutations have been previously published as activating HI mutations. The histology was consistent with diffuse-HI in four of the five cases with mosaic GCK mutations. In one of these, hypomethylation of IC2 on chromosome 11p was identified in pancreatic and peripheral blood DNA. Histology of the fifth case revealed minor islet abnormalities suggestive of Beckwith Wiedemann Spectrum (BWSp) although molecular analysis for 11pUPD was negative in pancreas. These results indicate that post-zygotic somatic GCK mutations are responsible for some cases of non-focal diazoxide-unresponsive hyperinsulinism.

Sarcomatoid Urothelial Carcinoma Arising in Autosomal Dominant Polycystic Kidney Disease: A Case Report and Literature Review.

Autosomal dominant polycystic kidney disease (ADPKD) may be associated with various epithelial malignancies. The most reported ones are papillary renal cell carcinoma (RCC) and clear cell RCC. Only one noninvasive urothelial carcinoma arising in the renal pelvis has been previously reported in the setting of ADPKD in the English literature. A 52-year-old patient with ADPKD and a history of renal transplant presented with a poorly differentiated sarcomatoid neoplasm in his native left polycystic kidney. A recognizable urothelial or renal cell carcinoma differentiation was not identified in the resected neoplasm microscopically. The initial diagnosis for this specimen was challenging on morphology and immunohistochemistry, but targeted next-generation sequencing provided molecular evidence in support of urothelial origin, indicating a hotspot mutation -124 C > T in the TERT promoter (C228 T) and loss of heterozygosity on chromosomes 9p and 8p. This tumor is unique because, to our knowledge, this is the first report of upper tract sarcomatoid urothelial carcinoma in a patient with ADPKD.

7238 A rare cause of primary ovarian failure in an adolescent due to a genetic mutation in mitochondrial poly-A-polymerase (mTPAP) mRNA

Abstract Disclosure: J. Epstein: None. S. Veera: None. J. Pappas: None. B.C. Shah: None. Primary ovarian insufficiency (POI) is a dysfunction or loss of ovarian follicles with associated amenorrhea. While most causes are idiopathic, approximately 15% of POI cases are due to single gene or chromosomal abnormalities, such as X chromosome abnormalities. Many of these nuclear genes encode for proteins that function within the mitochondria. Mitochondrial disorders affect tissues with high energy demand, such as the neurological, skeletal, cardiac, and endocrine systems. Furthermore, mature ovaries have a relatively higher concentration of mitochondria, which play a role in cellular respiration along with steroidogenesis. Mutations that disrupt these pathways can therefore lead to ovarian dysfunction. We present a case of a 17-year-old female with concern for primary amenorrhea. She underwent pubarche at age 12 years and thelarche at 14 years, with slowed progression. Height Z score was -1.61 and weight Z score was -0.41. Lab work at presentation was significant for LH 18.6 IU/L (N 2.4-12.6 IU/L), FSH 43.9 IU/L (N 1.1-9.6 IU/L), low estradiol <2.5 pg/mL (N 30-100 pg/mL), low total testosterone 8.3 ng/dL (N 15-31 ng/dL), unremarkable HbA1C, cortisol, thyroid levels, and a 46 XX karyotype. Pelvic ultrasound showed small ovarian volumes with a 1.9 cc right ovary, 1.5 cc left ovary consistent with lack of hormonal stimulation, and uterus length of 4.9 cm (N > 4 cm) consistent with early hormonal stimulation. She was started on transdermal estrogen replacement. Past medical history included stable pericardial effusion, episodes of supraventricular tachycardia, pre-cataracts, speech delays, mild learning disabilities, spastic diplegia, progressive gait abnormalities, ligamentous laxity, and recurrent patellar dislocations requiring multiple orthopedic limb surgeries. Family history was significant for parental consanguinity as first cousins. As the etiology of the POI remained unknown, genetic testing was completed. Whole exome sequencing (WES) revealed a homozygous pathogenic variant in the MTPAP gene: p.(Leu495Arg) (CTG>CGG): c.1484 T>G in exon 9 on chromosome 10p11.23. MTPAP, also known as SPAX4, TENT6, or PAPD1, is a nuclear-encoded polymerase involved in synthesizing the 3’ poly(A) tail of mitochondrial transcripts as well as in mRNA degradation. She was diagnosed with autosomal recessive MTPAP-related neurodevelopmental and movement disorder. Monogenic disorders affecting mitochondrial function are rare causes of POI. A high index of suspicion should be raised when a constellation of neurological, musculoskeletal, and cardiac problems co-exist. WES can be a very useful tool for uncovering rare genetic disorders. Further studies are needed to clarify details of organ specific mitochondrial dysfunction and possible therapeutics in individuals affected with MTPAP-related neurodevelopmental and movement disorders. Presentation: 6/1/2024

Ancient viral DNA in the human genome linked to neurodegenerative diseases

BackgroundHuman endogenous retroviruses (HERVs) are sequences in the human genome that originated from infections with ancient retroviruses during our evolution. Previous studies have linked HERVs to neurodegenerative diseases, but defining their role in aetiology has been challenging. Here, we used a retrotranscriptome-wide association study (rTWAS) approach to assess the relationships between genetic risk for neurodegenerative diseases and HERV expression in the brain, calculated with genomic precision. MethodsWe analysed genetic association statistics pertaining to Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and Parkinson’s disease, using HERV expression models calculated from 792 cortical samples. Robust risk factors were considered those that survived multiple testing correction in the primary analysis, which were also significant in conditional and joint analyses, and that had a posterior inclusion probability above 0.5 in fine-mapping analyses. ResultsThe primary analysis identified 12 HERV expression signatures associated with neurodegenerative disease susceptibility. We found one HERV expression signature robustly associated with amyotrophic lateral sclerosis on chromosome 12q14 (MER61_12q14.2) and one robustly associated with multiple sclerosis on chromosome 1p36 (ERVLE_1p36.32a). A co-expression analysis suggested that these HERVs are involved in homophilic cell adhesion via plasma membrane adhesion molecules. ConclusionsWe found HERV expression profiles robustly associated with amyotrophic lateral sclerosis and multiple sclerosis susceptibility, highlighting novel risk mechanisms underlying neurodegenerative disease, and offering potential new targets for therapeutic intervention.

Microsatellite Instability and Loss of Heterozygosity as Prognostic Markers in Oral Squamous Cell Carcinoma: Molecular Mechanisms, Detection Techniques, and Therapeutic Strategies.

The aim of this study was to conduct a systematic review of research investigating the potential role of microsatellite instability (MSI) and loss of heterozygosity (LOH) in oral squamous cell carcinoma (OSCC), with a focus on molecular mechanisms, detection methods, and therapeutic approaches. Search for articles involved the PubMed and Scopus. Previous retrospective and prospective studies identified variations between oral cancers that exhibit microsatellite stability and LOH. In this search, 294 articles were initially retrieved. Of these, 70 were excluded due to duplication, 106 were identified as ineligible by automated tools, and 24 were excluded as they were published in languages other than English. An additional 94 articles were excluded, 32 of which focused on head and neck cancers broadly, and 8 could not be accessed due to withdrawal. Ultimately, a systematic review was conducted based on 54 selected articles. Among the chromosomes analyzed for MSI and LOH, the highest frequency of LOH was observed on chromosome 9p. The MSI subtype is particularly susceptible to immunotherapeutic methods, such as the use of anti-PD-L1 and anti-CTLA4 antibodies, owing to its strong immunogenicity and ubiquitous expression of immune checkpoint ligands. Given the distinct characteristics and clinical behavior of oral cancer with MSI compared to microsatellite stable disease, it is advisable to incorporate MSI testing into the diagnostic process for all stages of tumor development. This ensured that each patient had received precise and effective treatment.

GENETIC MAPPING OF THREE LARGE CONSANGUINEOUS KASHMIRI FAMILIES WITH AUTOSOMAL RECESSIVE POLYDACTYLY SCREENED FOR FIVE PREVALENT GENES

Background: Polydactyly, a congenital hand defect characterized by extra digits, is more complicated than simple duplication, delicately weaving aberrant anatomical components with hypoplasia, uneven joint shapes, and unusual tendon and ligament placements. The dominant theory attributes its genesis to a group of five genes: GLI1 (chromosome 12q13.3), ZNF141 (chromosome 4p16.3), IQCE (chromosome 7p22.2), KIAA0825 (chromosome 5q15), and FAM92A (chromosome 8q22.1). The objective of this study is to identify the most prevalent genes responsible for polydactyly in the population of Azad Jammu and Kashmir. Method: The microsatellite markers used for PCR amplification and subsequently testing linkage to known genes are presented below. Represent electropherograms of ethidium bromide-stained 8% non-denaturing polyacrylamide gels (PAGEs) obtained by genotyping microsatellite markers linked on chromosome 8q22.1, 5q15, 12q13.3, 4p16.3, and 7p22.3 in family A, B, C. Genetic positions (in centiMorgan) for these marker loci were obtained from Rutgers combined linkage-physical map of the human genome. Results: Screening of most prevalent genes that include GLI1 (chromosome 12q13.3), ZNF141 (chromosome 4p16.3), IQCE (Chromosome 7p22.2), KIAA0825 (chromosome 5q15) and FAM92A (8q22.1) showed heterozygosity on every locus. Already known disease loci were further narrowed down with highly polymorphic markers which failed to find any linkage. Conclusion: The previously reported genotypic-phenotypic relation was not revealed in these 3 families signifying the probable involvement of unexplored genetic segments in intricate pathogenesis of this condition, emphasizing the need for further exploration beyond the established genetic association. Pak J Physiol 2024;20(3):44–8, DOI: https://doi.org/10.69656/pjp.v20i3.1611

Upregulation of Apoptosis Related Genes in Clinically Normal Tongue Contralateral to Squamous Cell Carcinoma of the Oral Tongue, an Effort to Maintain Tissue Homeostasis

PurposeThe field cancerization concept indicates the presence of pre-cancerous changes in clinically normal tissue surrounding the tumor. In squamous cell carcinoma of the oral tongue (SCCOT) which is infrequently linked to human papillomavirus infection, we have previously reported that clinically normal tongue contralateral to tumor (NTCT) is molecularly abnormal. Here, combining our transcriptomic and genomic data, we aimed to investigate the contribution of molecular changes in NTCT to cancer development.MethodsMicroarray gene expression data of 14 healthy controls, 23 NTCT and 29 SCCOT samples were investigated to characterize transcriptional profiles in NTCT. Whole exome sequencing and RNA-sequencing data of paired NTCT and tumor samples from 15 SCCOT patients were used to study correlation between copy number variation and differential gene expression.ResultsUsing supervised multivariate partial least squares discriminant analysis, a total of 61 mRNAs that distinguish NTCT from healthy tongue were selected. Functional enrichment analysis of the 22 upregulated genes showed increased “positive regulation of nitrogen compound metabolic process” in NTCT. All 12 genes involved in this process have roles in apoptosis (anti- and/or pro-apoptotic). Compared to healthy controls, Zinc Finger Protein 395 (ZNF395), a pro-apoptotic tumor suppressor located on chromosome 8p, was the only gene showing increased mRNA level in NTCT whereas decreased in SCCOT. Given the frequent loss of chromosome 8p in SCCOT, the impact of ZNF395 copy number variation on gene expression was further examined, revealing a positive correlation between copy number and mRNA level (correlation coefficient = 0.572, p < 0.001).ConclusionNTCT is susceptible to malignant transformation, where tissue homeostasis is maintained at least partly through regulation of apoptosis. Loss of the pro-apoptotic gene ZNF395 could thus initiate cancer development.

MTAP protein status is highly concordant with CDKN2A fluorescent in situ hybridization and allows stratification of the luminal subtype in muscle-invasive bladder cancer.

Loss of heterozygosity in chromosome 9p21, common in urothelial carcinoma (UC), typically involves deletion of CDKN2A and MTAP genes. MTAP loss is emerging as a promising therapeutic target and predictive biomarker in UC. This single-centrre retrospective study examined the incidence of CDKN2A deletions and MTAP loss in muscle-invasive bladder cancer (MIBC) and metastatic urothelial carcinoma (mUC), investigating their correlations with clinical, pathological, and genomic features, as well as patient outcomes. Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) were performed on 302 MIBC specimens and 63 biopsy-proven metachronous urothelial metastases to assess CDKN2A deletions and MTAP protein expression. CDKN2A homozygous deletion (HD), identified in 30.3% of MIBCs, and MTAP loss, found in 28.8% of MIBCs, were both significantly associated with the luminal-URO subtype, FGFR3 mutations, and normal/wildtype p53 IHC (P < 0.05). Loss of MTAP expression was significantly correlated with CDKN2A HD, with 84.0% sensitivity, 92.3% negative predictive value (NPV), 96.3% specificity, and 91.9% positive predictive value (PPV). MTAP expression was 100% concordant between primary tumours and nodal metastases. Patients with MTAP loss had a higher incidence of visceral metastases (50%) compared to bone/soft tissue (35.7%) and nodes (14.3%). Mean progression-free survival and overall survival were shorter for patients with MTAP loss, although not statistically significant. Our findings highlight CDKN2A HD and MTAP loss as prevalent genetic alterations in MIBC and mUC, particularly within the luminal-URO subtype and FGFR3-mutated, p53-normal/wildtype tumours. MTAP IHC can serve as a surrogate marker for 9p21.3 HD, highlighting its clinical relevance and potential as a therapeutic target and predictive biomarker in MIBC.

Monozygotic triplets with juvenile-onset autoimmunity and 18p microdeletion involving PTPRM.

Abnormal gene dosage from copy number variants has been associated with susceptibility to autoimmune disease. This includes 18p deletion syndrome, a chromosomal disorder with an estimated prevalence of 1 in 50,000 characterized by intellectual disability, facial dysmorphology, and brain abnormalities. The underlying causes for autoimmune manifestations associated with 18p deletions, however, remain unknown. Our objective was to investigate a distinctive case involving monozygotic triplets concordant for developmental delay, white matter abnormalities, and autoimmunity, specifically juvenile-onset Graves' thyroiditis. By chromosomal microarray analysis and whole genome sequencing, we found the triplets to carry a de novo interstitial 5.9Mb deletion of chromosome 18p11.31p11.21 spanning 19 protein-coding genes. We conducted a literature review to pinpoint genes affected by the deletion that could be associated with immune dysregulation and identified PTPRM as a potential candidate. Through dephosphorylation, PTPRM serves as a negative regulator of STAT3, a key factor in the generation of Th17 cells and the onset of specific autoimmune manifestations. We hypothesized that PTPRM hemizygosity results in increased STAT3 activation. We therefore performed assays investigating PTPRM expression, STAT3 phosphorylation, Th1/Th2/Th17 cell fractions, Treg cells, and overall immunophenotype, and in support of the hypothesis, our investigations showed an increase in cells with phosphorylated STAT3 and higher levels of Th17 cells in the triplets. We propose that PTPRM hemizygosity can serve as a contributing factor to autoimmune susceptibility in 18p deletion syndrome. If confirmed in unrelated 18p/PTPRM deletion patients, this susceptibility could potentially be treated by targeted inhibition of IL-17.

Further Delineation of the Proximal 16p11.2 Microdeletion Syndrome: Novel Findings Among 22 New Individuals.

The recurrent chromosome 16p11.2 BP4-BP5 microdeletion (MIM #611913) predisposes to a neurodevelopmental disorder with variable associated congenital anomalies and susceptibility to early-onset obesity. We identified 22 new individuals with proximal 16p11.2 deletions through retrospective data analysis at our institution and performed phenotyping through in-depth chart review. Our cohort exhibited a spectrum of neurodevelopmental abnormalities largely consistent with other publications, however they also were found to have a higher rate than expected of congenital anomalies, some of which have not yet been reported in association with 16p11.2 microdeletions to our knowledge. This series contributes to the body of data on this population, which we anticipate will continue to evolve along with increased uptake of genetic testing.

Neural EGFL like 1 as a novel gene for Trabecular Bone Score in older adults: The Bushehr Elderly Health (BEH) program.

Neural EGFL like 1 (NELL-1), is a secreted glycoprotein and stimulates osteogenic cell differentiation and bone mineralization. This study aimed to explore the relationship between NELL-1 and Trabecular Bone Score (TBS) as a novel tool for the evaluation of osteoporosis in an elderly population-based cohort study in Iran. A single-locus analysis was performed on TBS using data from 2,071 participants in the Bushehr Elderly Health (BEH) Program. The study investigated 376 independent single nucleotide polymorphisms (SNPs) within the NELL-1 on chromosome 11p15.1. The association between SNPs and the mean TBS L1 to L4 was analyzed through an additive model. Significant variants in the additive model (PFDR<0.05) were further examined within dominant, recessive, over-dominant, and co-dominant models. Multiple linear regression was employed to assess the relationship between the genetic risk score (GRS) derived from significant SNPs and TBS. Three SNPs within the NELL-1 showed a statistically significant association with TBS after adjusting for age and sex. The associations for rs1901945 (β = 0.013, PFDR = 0.0007), rs1584851 (β = -0.011, PFDR = 0.0003), and rs58028601 (β = 0.011, PFDR = 0.0003) were significant in the additive model. Additionally, significant results were observed for rs1901945 and rs58028601 in the dominant model (P<0.05). The GRS showed a statistically significant relationship with TBS, considering adjustments for age, sex, Body Mass Index, type 2 diabetes, and smoking (β = 0.077, P = 1.7×10-5). This study highlights the association of NELL-1 with TBS, underscoring its potential as a candidate for further research and personalized medicine concerning the impact of this gene on bone quality.

De novo and inherited micro-CNV at 16p13.11 in 21 Chinese patients with defective cardiac left-right patterning.

Copy number changes at Chromosomal 16p13.11 have been implicated in a variety of human diseases including congenital cardiac abnormalities. The clinical correlation of copy number variants (CNVs) in this region with developmental abnormalities remains controversial as most of the patients inherit the duplication from an unaffected parent. We performed CNV analysis on 164 patients with defective left-right (LR) patterning based on whole genome-exome sequencing (WG-ES) followed by multiplex ligation-dependent probe amplification (MLPA) validation. Most cases were accompanied with complex congenital heart disease (CHD). CNVs at 16p13.11 were identified in a total of 21 cases, accounting for 12.80% (21/164) evaluated cases. We observed a marked overrepresentation of chromosome 16p13.11 duplications in cases when compared with healthy controls according to literature reports (15/164, 9.14% versus 0.09% in controls). Notably, in two independent family trios, de novo 16p13.11 micro-duplications were identified in two patients with laterality defects and CHD. Moreover, 16p13.11 micro-duplication was segregated with the disease in a family trio containing 2 affected individuals. Notably, five coding genes, NOMO1, PKD1P3, NPIPA1, PDXDC1, and NTAN1, were potentially affected by micro-CNV at 16p13.11 in these patients. Our study provides new family-trio based evidences to support 16p13.11 micro-duplications predispose individuals to defective cardiac left-right patterning and laterality disorder.

Identification of genomic alteration and prognosis using pathomics-based artificial intelligence in oral leukoplakia and head and neck squamous cell carcinoma: A multicenter experimental study.

Loss of chromosome 9p is an important biomarker in the malignant transformation of oral leukoplakia (OLK) to head and neck squamous cell carcinoma (HNSCC), and is associated with the prognosis of HNSCC patients. However, various challenges have prevented 9p loss from being assessed in clinical practice. The objective of this study was to develop a pathomics-based artificial intelligence (AI) model for the rapid and cost-effective prediction of 9p loss (9PLP). 333 OLK cases were retrospectively collected with hematoxylin and eosin (H&E)-stained whole slide images and genomic alteration data from multicenter cohorts to develop the genomic alteration prediction AI model. They were divided into a training dataset (n=217), a validation dataset (n=93), and an external testing dataset (n=23). The latest Transformer method and XGBoost algorithm were combined to develop the 9PLP model. The AI model was further applied and validated in two multicenter HNSCC datasets (n=42, n=365, respectively). Moreover, the combination of 9PLP with clinicopathological parameters was used to develop a nomogram model for assessing HNSCC patient prognosis. 9PLP could predict chromosome 9p loss rapidly and effectively using both OLK and HNSCC images, with the area under the curve achieving 0.890 and 0.825, respectively. Furthermore, the predictive model showed high accuracy in HNSCC patient prognosis assessment (the area under the curve was 0.739 for 1-year prediction, 0.705 for 3-year prediction, and 0.691 for 5-year prediction). To the best of our knowledge, this study developed the first genomic alteration prediction deep learning model in OLK and HNSCC. This novel AI model could predict 9p loss and assess patient prognosis by identifying pathomics features in H&E-stained images with good performance. In the future, the 9PLP model may potentially contribute to better clinical management of OLK and HNSCC.

Chromosome 16p11.2 microdeletion syndrome with microcephaly and Dandy-Walker malformation spectrum: expanding the known phenotype

BackgroundChromosome 16p11.2 deletions and duplications were found to be the second most common copy number variation (CNV) reported in cases with clinical presentation suggestive of chromosomal syndromes. Chromosome 16p11.2 deletion syndrome shows remarkable phenotypic heterogeneity with a wide variability of presentation extending from normal development and cognition to severe phenotypes. The clinical spectrum ranges from neurocognitive and global developmental delay (GDD), intellectual disability, and language defects (dysarthria /apraxia) to neuropsychiatric and autism spectrum disorders. Other presentations include dysmorphic features, congenital malformations, insulin resistance, and a tendency for obesity. Our study aims to narrow the gap of knowledge in Saudi Arabia and the Middle Eastern and Northern African (MENA) region about genetic disorders, particularly CNV-associated disorders. Despite their rarity, genetic studies in the MENA region revealed high potential with remarkable genetic and phenotypic novelty.ResultsWe identified a heterozygous de novo recurrent proximal chromosome 16p11.2 microdeletion by microarray (arr[GRCh38]16p11.2(29555974_30166595)x1) [(arr[GRCh37]16p11.2(29567295_30177916)x1)] and confirmed by whole exome sequencing (arr[GRCh37]16p11.2(29635211_30199850)x1). We report a Saudi girl with severe motor and cognitive disability, myoclonic epilepsy, deafness, and visual impairment carrying the above-described deletion. Our study broadens the known phenotypic spectrum associated with recurrent proximal 16p11.2 microdeletion syndrome to include developmental dysplasia of the hip, optic atrophy, and a flat retina. Notably, the patient exhibited a rare combination of microcephaly, features consistent with the Dandy-Walker spectrum, and a thin corpus callosum (TCC), which are extremely infrequent presentations in patients with the 16p11.2 microdeletion. Additionally, the patient displayed areas of skin and hair hypopigmentation, attributed to a homozygous hypomorphic allele in the TYR gene.ConclusionThis report expands on the clinical phenotype associated with proximal 16p11.2 microdeletion syndrome, highlighting the potential of genetic research in Saudi Arabia and the MENA region. It underscores the importance of similar future studies.

700P Detection of circulating tumor DNA and chromosome 3p25.3 gain in relapsed/refractory germ cell tumors and impact of salvage high-dose chemotherapy: Results from the Italian Germ Cell Cancer Group 04 study

700P Detection of circulating tumor DNA and chromosome 3p25.3 gain in relapsed/refractory germ cell tumors and impact of salvage high-dose chemotherapy: Results from the Italian Germ Cell Cancer Group 04 study

A Review on Anaplastic Lymphoma Kinase (ALK) Rearrangements and Mutations: Implications for Gastric Carcinogenesis and Target Therapy.

Gastric adenocarcinoma is a complex disease with diverse genetic modifications, including Anaplastic Lymphoma Kinase (ALK) gene changes. The ALK gene is located on chromosome 2p23 and encodes a receptor tyrosine kinase that plays a crucial role in embryonic development and cellular differentiation. ALK alterations can result from gene fusion, mutation, amplification, or overexpression in gastric adenocarcinoma. Fusion occurs when the ALK gene fuses with another gene, resulting in a chimeric protein with constitutive kinase activity and promoting oncogenesis. ALK mutations are less common but can also result in the activation of ALK signaling pathways. Targeted therapies for ALK variations in gastric adenocarcinoma have been developed, including ALK inhibitors that have shown promising results in pre-clinical studies. Future studies are needed to elucidate the ALK role in gastric cancer and to identify predictive biomarkers to improve patient selection for targeted therapy. Overall, ALK alterations are a relevant biomarker for gastric adenocarcinoma treatment and targeted therapies for ALK may improve patients' overall survival.

Loss of copy numbers of retrotransposons (HERVK) on chromosome 7p11.2 impacts EGFR (Epidermal Growth Factor Receptor)-induced phenotypes for platinum sensitivity and long-term survival in ovarian cancer-A study from the OVCAD consortium.

We analyzed variations in the epidermal growth factor receptor (EGFR) gene and 5'-upstream region to identify potential molecular predictors of treatment response in primary epithelial ovarian cancer. Tumor tissues collected during debulking surgery from the prospective multicenter OVCAD study were investigated. Copy number variations in the human endogenous retrovirus sequence human endogenous retrovirus K9 (HERVK9) and EGFR Exons 7 and 9, as well as repeat length and loss of heterozygosity of polymorphic CA-SSR I and relative EGFR mRNA expression were determined quantitatively. At least one EGFR variation was observed in 94% of the patients. Among the 30 combinations of variations discovered, enhanced platinum sensitivity (n = 151) was found dominantly with HERVK9 haploidy and Exon 7 tetraploidy, overrepresented among patients with survival ≥120 months (24/29, p = .0212). EGFR overexpression (≥80 percentile) was significantly less likely in the responders (17% vs. 32%, p = .044). Multivariate Cox regression analysis, including age, FIGO stage, and grade, indicated that the patients' subgroup was prognostically significant for CA-SSR I repeat length <18 CA for both alleles (HR 0.276, 95% confidence interval 0.109-0.655, p = .001). Although EGFR variations occur in ovarian cancer, the mRNA levels remain low compared to other EGFR-mutated cancers. Notably, the inherited length of the CA-SSR I repeat, HERVK9 haploidy, and Exon 7 tetraploidy conferred three times higher odds ratio to survive for more than 10 years under therapy. This may add value in guiding therapies if determined during follow-up in circulating tumor cells or circulating tumor DNA and offers HERVK9 as a potential therapeutic target.

Fgf17: A regulator of the mid/hind brain boundary in mammals

The Fibroblast growth factor (FGFs) family consists of at least 22 members that exert their function by binding and activating fibroblast growth factor receptors (FGFRs). The Fgf8/FgfD subfamily member, Fgf17, is located on human chromosome 8p21.3 and mouse chromosome 14 D2. In humans, FGF17 can be alternatively spliced to produce two isoforms (FGF17a and b) whereas three isoforms are present in mice (Fgf17a, b, and c), however, only Fgf17a and Fgf17b produce functional proteins. Fgf17 is a secreted protein with a cleavable N-terminal signal peptide and contains two binding domains, namely a conserved core region and a heparin binding site. Fgf17 mRNA is expressed in a wide range of different tissues during development, including the rostral patterning centre, midbrain-hindbrain boundary, tailbud mesoderm, olfactory placode, mammary glands, and smooth muscle precursors of major arteries. Given its broad expression pattern during development, it is surprising that adult Fgf17−/− mice displayed a rather mild phenotype; such that mutants only exhibited morphological changes in the frontal cortex and mid/hind brain boundary and changes in certain social behaviours. In humans, FGF17 mutations are implicated in several diseases, including Congenital Hypogonadotropic Hypogonadism and Kallmann Syndrome. FGF17 mutations contribute to CHH/KS in 1.1% of affected individuals, often presenting in conjunction with mutations in other FGF pathway genes like FGFR1 and FLRT3. FGF17 mutations were also identified in patients diagnosed with Dandy-Walker malformation and Pituitary Stalk Interruption Syndrome, however, it remains unclear how FGF17 is implicated in these diseases. Altered FGF17 expression has been observed in several cancers, including prostate cancer, hematopoietic cancers (acute myeloid leukemia and acute lymphoblastic leukemia), glioblastomas, perineural invasion in cervical cancer, and renal cell carcinomas. Furthermore, FGF17 has demonstrated neuroprotective effects, particularly during ischemic stroke, and has been shown to improve cognitive function in ageing mice.

CIMPACT-NOW Update 8: Clarifications on molecular risk parameters and recommendations for WHO grading of meningiomas.

Meningiomas are the most frequent primary intracranial tumors. Hence, they constitute a major share of diagnostic specimens in neuropathology practice. The 2021 WHO Classification of Central Nervous System Tumors ("CNS5") has introduced the first molecular grading parameters for meningioma with oncogenic variants in the TERT promoter and homozygous deletion of CDKN2A/B as markers for CNS WHO grade 3. However, after publication of the new classification volume, clarifications were requested, not only on novel but also on long-standing questions in meningioma grading that were beyond the scope of the WHO "blue book". In addition, more recent research into possible new molecular grading parameters could not yet be implemented in the 2021 classification but constitute a compelling body of literature. Hence, the cIMPACT-NOW Steering Committee convened a working group to provide such clarification and assess the evidence of possible novel molecular criteria. As a result, this cIMPACT-NOW update provides guidance for more standardized morphological evaluation and interpretation, most prominently pertaining to brain invasion, identifies scenarios in which advanced molecular testing is recommended, proposes to assign CNS WHO grade 2 for cases with CNS WHO grade 1 morphology but chromosomal arm 1p deletion in combination with 22q deletion and/or NF2 oncogenic variants, and discusses areas in which the current evidence is not yet sufficient to result in new recommendations.

Spatial Distribution of Meningiomas: A Magnetic Resonance Image Atlas.

The size and anatomic location of meningiomas have been shown to correlate with distinct clinical manifestations, histopathological subtypes, and surgical risk. However, meningioma anatomic origin sites can be obscured in large tumors and those crossing compartments. We therefore sought to apply unbiased lesion mapping to localize intracranial meningioma distributions and their association with biology and grade. MRI scans, World Health Organization (WHO) grade, and a molecularly Integrated Grade (IG) derived from cytogenetics were analyzed from adult patients with intracranial meningiomas. Semi-automated tumor segmentation was performed on T1-weighted contrast-enhanced MRI. We used the voxel-based lesion mapping technique to generate a meningioma atlas, mapping spatial frequency and correlating with tumor grades. Of 881 patients with meningioma (median age: 57 years, 68.8% female), 589 were WHO grade 1 (66.8%), 265 WHO grade 2 (30.1%), and 27 WHO grade 3 (3.1%) with a median tumor volume of 14.6 cm3. After molecular reclassification, 585 were IG-1 (66.4%), 160 IG-2 (18.2%), and 136 IG-3 (15.4%). Benign tumors were concentrated in and around the midline anterior skull base while malignant meningiomas were enriched in the falcine/parasagittal region and the sphenoid wing, similar to the distribution when stratified by chromosome 1p loss. Meningiomas exhibited sharper spatial clustering when stratified by the molecular IG than by WHO grade. WHO grade 2 meningiomas divided equally across IG 1-3, with corresponding partition of spatial distribution in the midline anterior skull base (in WHO grade 2, IG-1) and falcine/parasagittal and sphenoid regions (WHO grade 2, IG-3). Meningioma volumes significantly varied across age, sex, and WHO/IG grades. We demonstrate the utility of voxel-based lesion mapping for intracranial tumors, characterizing distinct meningioma distribution patterns across histopathological and molecularly defined grades. Molecular grading associated with sharper tumor spatial clusters, supporting a phenotype-genotype association in meningiomas.