Chromosome 22q11 Research Articles

Impact of Aneuploidy and Chromosome 9p Loss on Tumor Immune Microenvironment and Immune Checkpoint Inhibitor Efficacy in NSCLC

IntroductionAlthough gene-level copy number alterations have been studied as a potential biomarker of immunotherapy efficacy in NSCLC, the impact of aneuploidy burden and chromosomal arm-level events on immune checkpoint inhibitor (ICI) efficacy in NSCLC is uncertain. MethodsPatients who received programmed cell death protein 1 or programmed death-ligand 1 (PD-L1) inhibitor at two academic centers were included. Across all 22 chromosomes analyzed, an arm was considered altered if at least 70% of its territory was either gained or deleted. Among nonsquamous NSCLCs which underwent targeted next-generation sequencing, we retrospectively quantified aneuploidy using the adjusted fraction of chromosomal arm alterations (FAA), defined as the number of altered chromosome arms divided by the number of chromosome arms assessed, adjusted for tumor purity. ResultsAmong 2293 nonsquamous NSCLCs identified, the median FAA increased with more advanced cancer stage and decreased with higher PD-L1 tumor proportion score (TPS) levels (median FAA in TPS < 1%: 0.09, TPS 1%–49%: 0.08, TPS ≥ 50%: 0.05, p < 0.0001). There was a very weak correlation between FAA and tumor mutational burden when taken as continuous variables (R: 0.07, p = 0.0005). A total of 765 advanced nonsquamous NSCLCs with available FAA values were treated with ICIs. With decreasing FAA tertiles, there was a progressive improvement in objective response rate (ORR 15.1% in upper tertile versus 23.2% in middle tertile versus 28.4% in lowest tertile, p = 0.001), median progression-free survival (mPFS 2.5 versus 3.3 versus 4.1 mo, p < 0.0001), and median overall survival (mOS 12.5 versus 13.9 versus 16.4 mo, p = 0.006), respectively. In the arm-level enrichment analysis, chromosome 9p loss (OR = 0.22, Q = 0.0002) and chromosome 1q gain (OR = 0.43, Q = 0.002) were significantly enriched in ICI nonresponders after false discovery rate adjustment. Compared with NSCLCs without chromosome 9p loss (n = 452), those with 9p loss (n = 154) had a lower ORR (28.1% versus 7.8%, p < 0.0001), a shorter mPFS (4.1 versus 2.3 mo, p < 0.0001), and a shorter mOS (18.0 versus 9.6 mo, p < 0.0001) to immunotherapy. In addition, among NSCLCs with high PD-L1 expression (TPS ≥ 50%), chromosome 9p loss was associated with lower ORR (43% versus 6%, p < 0.0001), shorter mPFS (6.4 versus 2.6 mo, p = 0.0006), and shorter mOS (30.2 versus 14.3 mo, p = 0.0008) to immunotherapy compared with NSCLCs without 9p loss. In multivariable analysis, adjusting for key variables including FAA, chromosome 9p loss, but not 1q gain, retained a significant impact on ORR (hazard ratio [HR] = 0.25, p < 0.001), mPFS (HR = 1.49, p = 0.001), and mOS (HR = 1.47, p = 0.003). Multiplexed immunofluorescence and computational deconvolution of RNA sequencing data revealed that tumors with either high FAA levels or chromosome 9p loss had significantly fewer tumor-associated cytotoxic immune cells. ConclusionsNonsquamous NSCLCs with high aneuploidy and chromosome 9p loss have a distinct tumor immune microenvironment and less favorable outcomes to ICIs.

The Oncogenic Role of Cyclin-Dependent Kinase Inhibitor 2C in Lower-Grade Glioma.

Lower-grade gliomas (LGGs) are slow-growing, indolent tumors that usually affect younger patients and present a therapeutic challenge due to the heterogeneity of their clinical presentation. Dysregulation of cell cycle regulatory factors is implicated in the progression of many tumors, and drugs that target cell cycle machinery have shown efficacy as promising therapeutic approaches. To date, however, no comprehensive study has examined how cell cycle-related genes affect LGG outcomes. The cancer genome atlas (TCGA) data were used as the training set for differential analysis of gene expression and patient outcomes; the Chinese glioma genome atlas (CGGA) was used for validation. Levels of one candidate protein, cyclin-dependent kinase inhibitor 2C (CDKN2C), and its relationship to clinical prognosis were determined using a tissue microarray containing 34 LGG tumors. A nomogram was constructed to model the putative role of candidate factors in LGG. Cell type proportion analysis was performed to evaluate immune cell infiltration in LGG. Various genes encoding cell cycle regulatory factors showed increased expression in LGG and were significantly related to isocitrate dehydrogenase and chromosome arms 1p and 19q mutation status. CDKN2C expression independently predicted the outcome of LGG patients. High M2 macrophage values along with elevated CDKN2C expression were associated with poorer prognosis in LGG patients. CDKN2C plays an oncogenic role in LGG, which is associated with M2 macrophages.

Whole exome sequencing of low grade serous ovarian carcinoma identifies genomic events associated with clinical outcome

ObjectivesLow-grade serous ovarian carcinoma (LGSOC) is a distinct, rare, ovarian cancer type characterised by younger patient age and intrinsic chemoresistance. Understanding the molecular landscape is crucial for optimising targeted therapy. MethodsGenomic data from whole exome sequencing of tumour tissue was analysed in a LGSOC cohort with detailed clinical annotation. Results63 cases were analysed and three subgroups identified based on single nucleotide variants: canonical MAPK mutant (cMAPKm: 52%, KRAS/BRAF/NRAS), MAPK-associated gene mutation (MAPK-assoc: 27%) and MAPK wild-type (MAPKwt: 21%). NOTCH pathway disruption occurred across all subgroups. Tumour mutational burden (TMB), mutational signatures and recurrent copy number (CN) changes varied across the cohort with co-occurrence of chromosome 1p loss and 1q gain (CN Chr1pq) a recurrent feature. Low TMB and CN Chr1pq were associated with inferior disease-specific survival (HR 6.43; p < 0.001 and HR 3.29, p = 0.011 respectively). Stepwise genomic classification in relation to outcome resulted in four groups (TMB low; CN Chr1pq; MAPKwt/MAPKassoc; cMAPKm). 5 year disease-specific survival was 46%, 55%, 79% and 100% respectively for these groups. The two most favourable genomic subgroups were enriched for the SBS10b mutational signature, particularly the cMAPKm subgroup. ConclusionsLGSOC comprises multiple genomic subgroups with distinct clinical and molecular features. Chr1pq CN arm disruption and TMB represent promising methods to identify individuals with poorer prognosis. Further investigation of the molecular basis for these observations is required. MAPKwt cases represent around a fifth of patients. NOTCH inhibitors represent a candidate therapeutic strategy worthy of exploration across these cases.

Chromosome 22q11.2 Deletion Syndrome: A Comprehensive Review of Molecular Genetics in the Context of Multidisciplinary Clinical Approach.

The 22q11.2 deletion syndrome is a multisystemic disorder characterized by a marked variability of phenotypic features, making the diagnosis challenging for clinicians. The wide spectrum of clinical manifestations includes congenital heart defects-most frequently conotruncal cardiac anomalies-thymic hypoplasia and predominating cellular immune deficiency, laryngeal developmental defects, midline anomalies with cleft palate and velar insufficiency, structural airway defects, facial dysmorphism, parathyroid and thyroid gland hormonal dysfunctions, speech delay, developmental delay, and neurocognitive and psychiatric disorders. Significant progress has been made in understanding the complex molecular genetic etiology of 22q11.2 deletion syndrome underpinning the heterogeneity of clinical manifestations. The deletion is caused by chromosomal rearrangements in meiosis and is mediated by non-allelic homologous recombination events between low copy repeats or segmental duplications in the 22q11.2 region. A range of genetic modifiers and environmental factors, as well as the impact of hemizygosity on the remaining allele, contribute to the intricate genotype-phenotype relationships. This comprehensive review has been aimed at highlighting the molecular genetic background of 22q11.2 deletion syndrome in correlation with a clinical multidisciplinary approach.

Hypocalcemia and pulseless electric activity revealing chromosome 22q11.2 deletion syndrome in the midst of a conglomerate of potential etiologic factors

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

A Girl Presented with Learning Difficulty and Poor School Performance: A case report

DiGeorge Syndrome (DGS) which is also known as chromosome 22q11.2 deletion syndrome is a primary immunodeficiency caused by the deletion of chromosome 22. Its main features include dysmorphia, hypoparathyroidism, hypocalcemia, hypoplasia or aplasia of the thymus, cardiac anomalies, renal anomalies, and behavioral/ psychiatric issues. This incurable syndrome could be treated for its complications to increase the quality of life. With the advancement of technology, DGS can now be identified in childhood itself where FISH is the main diagnostic method used. A case report of a 7 year-old girl who visited the learning difficulty, poor memorization,poor school performance and socialization problems is presented here. On the evaluation of his case, DiGeorge Syndrome was confirmed. Bangladesh J Medicine 2023; 34(2): 147-150

Burden of disease of spinal muscular atrophy linked to chromosome 5q (5q-SMA) in Colombia

ABSTRACT Objective This article estimates the disease burden of 5q-SMA in Colombia by using the disability-adjusted life years (DALYs) metric. Methods Epidemiological data were obtained from local databases and medical literature and were adjusted in the DisMod II tool. DALYs were obtained by adding years of life lost due to premature death (YLL) and years lived with disability (YLD). Results The modeled prevalence of 5q-SMA in Colombia was 0.74 per 100,000 population. The fatality rate for all types was 14.1%. The disease burden of 5q-SMA was estimated at 4,421 DALYs (8.6 DALYs/100,000), corresponding to 4,214 (95.3%) YLLs and 207 (4.7%) YLDs. Most of the DALYs were accounted in the 2–17 age group. Of the total burden, 78% correspond to SMA type 1, 18% to type 2, and 4% to type 3. Conclusions Although 5q-SMA is a rare disease, it is linked to a significant disease burden due to premature mortality and severe sequelae. The estimates shown in this article are important inputs to inform public policy decisions on how to ensure adequate health service provision for patients with 5q-SMA.

Aggressive Lymphoplasmacytic Neoplasm With an Unusual In-frame Deletion of MYD88 Associated With TRAF3 and TP53 Mutations and Complex Karyotype.

Lymphoplasmacytic lymphoma often needs to be differentiated from other B-cell lymphomas with plasmacytic differentiation, especially marginal zone cell lymphoma. Molecular detection of MYD88 p.L265P hotspot mutation supports the diagnosis of lymphoplasmacytic lymphoma since it is seen in about 90% of such lymphoma, which is much higher than other B-cell lymphomas. MYD88 p.L265P is a gain-of-function mutation that enhances the activity of the NF-κB signaling pathway and therefore drives lymphomagenesis. Other mutations in MYD88 are rarely reported. This study aims to report an unusual MYD88 in-frame deletion in an aggressive lymphoplasmacytic neoplasm. This is an IgM-positive, CD5- and CD10-negative mature B-cell lymphoma with prominent plasmacytic differentiation and aggressive features. The clinical and pathologic findings were most consistent with lymphoplasmacytic lymphoma. Next-generation sequencing identified an unusual MYD88 in-frame deletion in the absence of the hotpot p.L265P mutation. Other concurrent pathogenic mutations also include truncating mutations of TRAF3, which is a negative regulator of the NF-κB signaling pathway, and a missense mutation of TP53. Karyotype analysis showed complex karyotypes, including chromosome 6q deletion. By searching literature and online cancer databases, we identified only 8 other mature B-cell lymphomas with MYD88 in-frame deletions, but none of them was diagnosed with lymphoplasmacytic lymphoma. Recognizing such in-frame deletions is necessary to help understand the mutational spectrum of MYD88 in B-cell lymphomas. It remains to be further investigated whether such MYD88 in-frame deletions are also overrepresented in lymphoplasmacytic lymphoma among other B-cell lymphomas.

Biallelic ELOC-Inactivated Renal Cell Carcinoma: Molecular Features Supporting Classification as a Distinct Entity

Approximately 70% of clear cell renal cell carcinoma (ccRCC) is characterized by the biallelic inactivation of von Hippel-Lindau (VHL) on chromosome 3p. ELOC-mutated (Elongin C-mutated) renal cell carcinoma containing biallelic ELOC inactivations with chromosome 8q deletions is considered a novel subtype of renal cancer possessing a morphologic overlap with ccRCC, renal cell carcinoma (RCC) with fibromyomatous stroma exhibiting Tuberous Sclerosis Complex (TSC)/mammalian Target of Rapamycin (mTOR) mutations, and clear cell papillary tumor. However, the frequency and consequences of ELOC alterations in wild-type VHL and mutated VHL RCC are unclear. In this study, we characterize 123 renal tumors with clear cell morphology and known VHL mutation status to assess the morphologic and molecular consequences of ELOC inactivation. Using OncoScan and whole-exome sequencing, we identify 18 ELOC-deleted RCCs, 3 of which contain ELOC mutations resulting in the biallelic inactivation of ELOC. Biallelic ELOC and biallelic VHL aberrations were mutually exclusive; however, 2 ELOC-mutated RCCs showed monoallelic VHL alterations. Furthermore, no mutations in TSC1, TSC2, or mTOR were identified in ELOC-mutated RCC with biallelic ELOC inactivation. Using High Ambiguity Driven biomolecular DOCKing, we report a novel ELOC variant containing a duplication event disrupting ELOC-VHL interaction alongside the frequently seen Y79C alteration. Using hyper reaction monitoring mass spectrometry, we show RCCs with biallelic ELOC alterations have significantly reduced ELOC expression but similar carbonic anhydrase 9 and vascular endothelial growth factor A expression compared with classical ccRCC with biallelic VHL inactivation. The absence of biallelic VHL and TSC1, TSC2, or mTOR inactivation in RCC with biallelic ELOC inactivation (ELOC mutation in combination with ELOC deletions on chromosome 8q) supports the notion of a novel, molecularly defined tumor entity.

The selective RyR2 inhibitor ent-verticilide suppresses atrial fibrillation susceptibility caused by Pitx2 deficiency

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major cause of stroke and morbidity. The strongest genetic risk factors for AF in humans are variants on chromosome 4q25, near the paired-like homeobox transcription factor 2 gene PITX2. Although mice deficient in Pitx2 (Pitx2+/−) have increased AF susceptibility, the mechanism remains controversial. Recent evidence has implicated hyperactivation of the cardiac ryanodine receptor (RyR2) in Pitx2 deficiency, which may be associated with AF susceptibility. We investigated pacing-induced AF susceptibility and spontaneous Ca2+ release events in Pitx2 haploinsufficient (+/−) mice and isolated atrial myocytes to test the hypothesis that hyperactivity of RyR2 increases susceptibility to AF, which can be prevented by a potent and selective RyR2 channel inhibitor, ent-verticilide. Compared with littermate wild-type Pitx2+/+, the frequency of Ca2+ sparks and spontaneous Ca2+ release events increased in permeabilized and intact atrial myocytes from Pitx2+/− mice. Atrial burst pacing consistently increased the incidence and duration of AF in Pitx2+/− mice. The RyR2 inhibitor ent-verticilide significantly reduced the frequency of spontaneous Ca2+ release in intact atrial myocytes and attenuated AF susceptibility with reduced AF incidence and duration. Our data demonstrate that RyR2 hyperactivity enhances SR Ca2+ leak and AF inducibility in Pitx2+/− mice via abnormal Ca2+ handling. Therapeutic targeting of hyperactive RyR2 in AF using ent-verticilide may be a viable mechanism-based approach to treat atrial arrhythmias caused by Pitx2 deficiency.

Genetic Screening of Targeted Region on the Chromosome 22q11.2 in Patients with Microtia and Congenital Heart Defect.

Microtia is a congenital malformation characterized by a small, abnormally shaped auricle (pinna) ranging in severity. Congenital heart defect (CHD) is one of the comorbid anomalies with microtia. However, the genetic basis of the co-existence of microtia and CHD remains unclear. Copy number variations (CNVs) of 22q11.2 contribute significantly to microtia and CHD, respectively, thus suggesting a possible shared genetic cause embedded in this genomic region. In this study, 19 sporadic patients with microtia and CHD, as well as a nuclear family, were enrolled for genetic screening of single nucleotide variations (SNVs) and CNVs in 22q11.2 by target capture sequencing. We detected a total of 105 potential deleterious variations, which were enriched in ear- or heart-development-related genes, including TBX1 and DGCR8. The gene burden analysis also suggested that these genes carry more deleterious mutations in the patients, as well as several other genes associated with cardiac development, such as CLTCL1. Additionally, a microduplication harboring SUSD2 was validated in an independent cohort. This study provides new insights into the underlying mechanisms for the comorbidity of microtia and CHD focusing on chromosome 22q11.2, and suggests that a combination of genetic variations, including SNVs and CNVs, may play a crucial role instead of single gene mutation.

Impact of bortezomib-based versus lenalidomide maintenance therapy on outcomes of patients with high-risk multiple myeloma.

Lenalidomide maintenance after autologous stem cell transplant (ASCT) in multiple myeloma (MM) results in superior progression-free survival and overall survival. However, patients with high-risk multiple myeloma (HRMM) do not derive the same survival benefit from lenalidomide maintenance compared with standard-risk patients. The authors sought to determine the outcomes of bortezomib-based maintenance compared with lenalidomide maintenance in patients with HRMM undergoing ASCT. In total, the authors identified 503 patients with HRMM who were undergoing ASCT within 12months of diagnosis from January 2013 to December 2018 after receiving triplet novel-agent induction in the Center for International Blood and Marrow Transplant Research database. HRMM was defined as deletion 17p, t(14;16), t(4;14), t(14;20), or chromosome 1q gain. Three hundred fifty-seven patients (67%) received lenalidomide alone, and 146 (33%) received bortezomib-based maintenance (with bortezomib alone in 58%). Patients in the bortezomib-based maintenance group were more likely to harbor two or more high-risk abnormalities and International Staging System stage III disease (30% vs. 22%; p=.01) compared with the lenalidomide group (24% vs. 15%; p<.01). Patients who were receiving lenalidomide maintenance had superior progression-free survival at 2years compared with those who were receiving either bortezomib monotherapy or combination therapy (75% vs. 63%; p=.009). Overall survival at 2years was also superior in the lenalidomide group (93% vs. 84%; p=.001). No superior outcomes were observed in patients with HRMM who received bortezomib monotherapy or (to a lesser extent) in those who received bortezomib in combination as maintenance compared with lenalidomide alone. Until prospective data from randomized clinical trials are available, post-transplant therapy should be tailored to each patient with consideration for treating patients in clinical trials that target novel therapeutic strategies for HRMM, and lenalidomide should remain a cornerstone of treatment.

Abstract 5003: Repurposing passenger amplifications for specific therapeutic targeting of solid cancers

Abstract Current cancer therapies focus on targeting driver alterations responsible for tumorigenesis - either oncogenic point mutations or oncogenic driver events within large somatic copy number alterations (SCNAs). However, these alterations are often not actionable or are only present in a small subset of patients. Thus, new therapeutic targets are urgently needed. Apart from oncogenic drivers, SCNAs usually also comprise neutral bystander genes without an active role in neoplastic transformation. We hypothesized that passenger events, specifically in amplified regions, could be therapeutically exploited by providing actionable molecules on the cell surface. Using publicly available multi-omics data, we screened cell surface protein-coding genes for their genomic status and expression levels in liver cancer. This screen identified MPZL1 (Myelin protein zero-like 1), a gene amplified in 75% of hepatocellular carcinomas, accompanied by high mRNA expression in tumors compared to normal livers. MPZL1 is located on chromosome 1q, one of the most commonly amplified regions across several solid cancer types, and codes for a glycosylated cell surface receptor. We further validated MPZL1 protein expression in a wide range of human cancer entities (n=2038 samples) and normal tissues (n=163 samples) by immunohistochemistry and assigned expression scores analogous to the clinically implemented HER2-score. A high percentage of tumors showed scores 2 or 3 (e.g. 48% of HCCs or 89% of TNBCs), whereas healthy tissues were mostly negative or just faintly positive (scores 0 or 1). Moreover, in order to target MPZL1-expressing cells, we generated a highly specific monoclonal antibody directed to the extracellular domain of human MPZL1 protein and thoroughly characterized its binding capacity. Next, the scFv sequence of this antibody was used to generate a CAR (chimeric antigen receptor) construct targeting MPZL1. Luciferase-based cytotoxic assays showed that T cells transduced with this construct can kill various MPZL1-high human cancer cell lines in vitro (liver, breast and lung malignant cell lines, among others), whereas they fail to kill respective isogenic cell lines harboring knockout of MPZL1. Upon antigen-specific exposure, MPZL1-28ζ CAR-T cells underwent antigen-dependent proliferation and showed increased cytokine production (IFNγ, TNFα, IL-2, GZMB), further confirming their specificity. In summary, our findings reveal MPZL1 as a new target for treatment of 1q-amplified cancers and implement a novel immunotherapeutic strategy based on MPZL1-28ζ CAR-T cells. Furthermore, our work provides a proof of concept that passenger events within large chromosomal amplifications can serve as potent therapeutic targets and thus opens a new avenue for innovative approaches in anti-cancer drug development. Citation Format: Sonia Jiménez Vázquez, Christos Patsis, Luise Butthof, Joan Crous Masó, Hendrik Wiethoff, Matthias Gaida, Thomas Longerich, Rosella Pellegrino, Ilse Hofmann, Judith Feucht, Darjus Felix Tschaharganeh. Repurposing passenger amplifications for specific therapeutic targeting of solid cancers. [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 5003.

Abstract 955: Proteogenomic insights suggest druggable pathways in endometrial cancer

Abstract Endometrial carcinoma (EC) is the most common gynecologic cancer diagnosed in developed countries, with incidence on the rise globally. Over the past decade, EC outcomes have worsened in the United States, despite the fact that early stage, well-differentiated cancers are often cured by simple hysterectomy. Work by the Cancer Genome Atlas Consortium (TCGA) and others has stratified EC patients by four genomically-defined subtypes: POLE ultramutated, microsatellite instability high (MSI-H) hypermutated, copy-number low (CNV-L), and copy-number high (CNV-H). These subtypes not only correlate with clinical outcome but also, in specific instances, response to targeted agents such as immune checkpoint inhibitors (ICI). By integrating genomic and proteomic data, our recent study with the Clinical Proteomic Tumor Analysis Consortium (CPTAC) built upon findings from the TCGA, specifically identifying immunologic subtypes which differentiate tumors based on their overall mutation burdens and antigen processing machinery (APM) profiles. Despite this progress, effective treatments for advanced stage, metastatic and/or recurrent disease are often lacking. Thus, a better understanding of how EC subtypes can be efficiently identified and targeted to improve their outcomes is urgently needed. Here, we present the results of a comprehensive proteogenomic analysis of a new prospectively curated set of 138 EC tumors and 20 specimens enriched for normal endometrium. We also evaluated the utility of a novel machine learning algorithm for parsing clinically-relevant genomic features based solely on images from Hematoxylin and Eosin (H&amp;E) stained cross-sections. Our integrative multi-omic analyses examined the diverse dimensions of molecular pathways to better describe diagnostic and therapeutic targets. From our targeted proteomic assay, we describe a model that uses two peptides to accurately predict tumor APM status. Using gene expression and clinical data, we observed an association between lower Myc activity and Metformin usage in our patients with diabetes. Linking genomics, proteomics, and phospho-proteomics, we uncovered an upregulation of AKT-pT308 in tumors with PIK3R1 in-frame indels. Multi-omic clustering revealed a subset of CNV-L tumors enriched for ß-catenin hotspot mutations, which have elevated Wnt signaling due to impaired ß-catenin degradation signals. Lastly, we observe a subset of MSI-H tumors with a gain of chromosome 1q that show lowered immune infiltration. Analysis of this independent cohort, incorporating published EC tumor and cell line cohorts, has not only confirmed findings from our recent exploratory study but also provided new biological insights relevant to potential therapeutic strategies. These findings can be further investigated to guide patient stratification for improved precision treatment of EC. Citation Format: Lizabeth Katsnelson, Yongchao Dou, Marina A. Gritsenko, Matthew L. Anderson, Karin D. Rodland, Bing Zhang, Tao Liu, David Fenyö, the Clinical Proteomic Tumor Analysis Consortium. Proteogenomic insights suggest druggable pathways in endometrial cancer [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 955.

Clinical and genetic characteristics of 9 rare cases with coexistence of dual genetic diagnoses

Objective: To analyze the clinical and genetic characteristics of pediatric patients with dual genetic diagnoses (DGD). Methods: Clinical and genetic data of pediatric patients with DGD from January 2021 to February 2022 in Peking University First Hospital were collected and analyzed retrospectively. Results: Among the 9 children, 6 were boys and 3 were girls. The age of last visit or follow-up was 5.0 (2.7,6.8) years. The main clinical manifestations included motor retardation, mental retardation, multiple malformations, and skeletal deformity. Cases 1-4 were all all boys, showed myopathic gait, poor running and jumping, and significantly increased level of serum creatine kinase. Disease-causing variations in Duchenne muscular dystrophy (DMD) gene were confirmed by genetic testing. The 4 children were diagnosed with DMD or Becker muscular dystrophy combined with a second genetic disease, including hypertrophic osteoarthropathy, spinal muscular atrophy, fragile X syndrome, and cerebral cavernous malformations type 3, respectively. Cases 5-9 were clinically and genetically diagnosed as COL9A1 gene-related multiple epiphyseal dysplasia type 6 combined with NF1 gene-related neurofibromatosis type 1, COL6A3 gene-related Bethlem myopathy with WNT1 gene-related osteogenesis imperfecta type XV, Turner syndrome (45, X0/46, XX chimera) with TH gene-related Segawa syndrome, Chromosome 22q11.2 microduplication syndrome with DYNC1H1 gene-related autosomal dominant lower extremity-predominant spinal muscular atrophy-1, and ANKRD11 gene-related KBG syndrome combined with IRF2BPL gene-related neurodevelopmental disorder with regression, abnormal movement, language loss and epilepsy. DMD was the most common, and there were 6 autosomal dominant diseases caused by de novo heterozygous pathogenic variations. Conclusions: Pediatric patients with coexistence of double genetic diagnoses show complex phenotypes. When the clinical manifestations and progression are not fully consistent with the diagnosed rare genetic disease, a second rare genetic disease should be considered, and autosomal dominant diseases caused by de novo heterozygous pathogenic variation should be paid attention to. Trio-based whole-exome sequencing combining a variety of molecular genetic tests would be helpful for precise diagnosis.

Evolutionary characterization of lung adenocarcinoma morphology in TRACERx.

Lung adenocarcinomas (LUADs) display a broad histological spectrum from low-grade lepidic tumors through to mid-grade acinar and papillary and high-grade solid, cribriform and micropapillary tumors. How morphology reflects tumor evolution and disease progression is poorly understood. Whole-exome sequencing data generated from 805 primary tumor regions and 121 paired metastatic samples across 248 LUADs from the TRACERx 421 cohort, together with RNA-sequencing data from 463 primary tumor regions, were integrated with detailed whole-tumor and regional histopathological analysis. Tumors with predominantly high-grade patterns showed increased chromosomal complexity, with higher burden of loss of heterozygosity and subclonal somatic copy number alterations. Individual regions in predominantly high-grade pattern tumors exhibited higher proliferation and lower clonal diversity, potentially reflecting large recent subclonal expansions. Co-occurrence of truncal loss of chromosomes 3p and 3q was enriched in predominantly low-/mid-grade tumors, while purely undifferentiated solid-pattern tumors had a higher frequency of truncal arm or focal 3q gains and SMARCA4 gene alterations compared with mixed-pattern tumors with a solid component, suggesting distinct evolutionary trajectories. Clonal evolution analysis revealed that tumors tend to evolve toward higher-grade patterns. The presence of micropapillary pattern and 'tumor spread through air spaces' were associated with intrathoracic recurrence, in contrast to the presence of solid/cribriform patterns, necrosis and preoperative circulating tumor DNA detection, which were associated with extra-thoracic recurrence. These data provide insights into the relationship between LUAD morphology, the underlying evolutionary genomic landscape, and clinical and anatomical relapse risk.

MP17-16 COMPARING INTRADUCTAL CARCINOMA OF THE PROSTATE TO GRADE AND STAGE: A COPY NUMBER ALTERATION CHARACTERIZATION STUDY

You have accessJournal of UrologyCME1 Apr 2023MP17-16 COMPARING INTRADUCTAL CARCINOMA OF THE PROSTATE TO GRADE AND STAGE: A COPY NUMBER ALTERATION CHARACTERIZATION STUDY Helen Pantazopoulos, Afnan Al-Saleh, Mame Kany Diop, David Boucher Roy, Roy Nitulescu, Roula Albadine, and Dominique Trudel Helen PantazopoulosHelen Pantazopoulos More articles by this author , Afnan Al-SalehAfnan Al-Saleh More articles by this author , Mame Kany DiopMame Kany Diop More articles by this author , David Boucher RoyDavid Boucher Roy More articles by this author , Roy NitulescuRoy Nitulescu More articles by this author , Roula AlbadineRoula Albadine More articles by this author , and Dominique TrudelDominique Trudel More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003237.16AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Prostate cancer (PCa) is the most diagnosed cancer in North American men varying greatly at clinical presentation from indolent to aggressive tumors. An aggressive subtype of PCa is intraductal carcinoma of the prostate (IDC-P), identified in ∼20% of men with PCa. While accurate stratification of these high-risk patients is a clinical necessity, the question arose whether IDC-P could be related to the grade or not. We hypothesized that through the genomic characterization of IDC-P, we could explore the link between IDC-P, grade, and or stage. The objective of this study was to characterize the copy number alterations (CNAs) of IDC-P to aid in the characterization of these high-risk men, while exploring whether IDC-P should be integrated into the grade or stage of PCa. METHODS: We selected 462 radical prostatectomy specimens obtained through The Cancer Genome Atlas (TCGA). Specifically, 38 patients were excluded from the original TCGA cohort (n=500) due to stage T4 and incomplete genomic data. We further characterized the TCGA cohort by identifying the IDC-P status (present or not identified) for each patient through the online available tissue. For each patient, IDC-P status was evaluated alongside the CNAs of 488 genes involved in androgen receptor signaling and or carcinogenesis. RESULTS: Out of 462 patients, 41% (191/462) were IDC-P present, and these patients were mostly of high grade (53.9%) and advanced pT3b stage (38.7%). Overall, 38 genes were significantly associated to IDC-P growth, of which, 37 genes were novel and not unique to IDC-P or documented in PCa. Specifically, 10 genes were associated to chromosome 10q deletions, including the well-recognized PTEN, while 28 genes were associated to chromosome 8q amplifications. Of the IDC-P present men identified, 36% (69/191) of these men had multiple deletions and 16% (31/191) of these men had multiple amplifications. CONCLUSIONS: We found significant deletions in 10 genes and amplifications in 28 genes in IDC-P. Importantly, high-risk men with IDC-P have numerous deletions and amplifications in the identified 38 genes. We have identified novel genes, except for PTEN. Indeed, more than 2/3 of these genes are amplified on 8q and their expression could be targeted as biomarkers of IDC-P. We are exploring the presence of these anomalies in PCa and their relation to Grade group (especially cribriform pattern) and or stage. Together, these findings will genomically characterize IDC-P and allow for improved precision in the stratification of these high-risk patients. Source of Funding: Institut du Cancer de Montréal © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e219 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Helen Pantazopoulos More articles by this author Afnan Al-Saleh More articles by this author Mame Kany Diop More articles by this author David Boucher Roy More articles by this author Roy Nitulescu More articles by this author Roula Albadine More articles by this author Dominique Trudel More articles by this author Expand All Advertisement PDF downloadLoading ...

PD17-05 GENOMIC FEATURES OF RENAL CELL CARCINOMA DEVELOPED DURING END-STAGE RENAL DISEASE AND DIALYSIS

You have accessJournal of UrologyCME1 Apr 2023PD17-05 GENOMIC FEATURES OF RENAL CELL CARCINOMA DEVELOPED DURING END-STAGE RENAL DISEASE AND DIALYSIS Shigekatsu Maekawa, Todd Johnson, Masashi Fujita, Ryo Takata, Daiki Ikarashi, Tomohiko Matsuura, Renpei Kato, Mitsugu Kanehira, Jun Sugimura, Takaya Abe, Hikewaki Nakagawa, and Wataru Obara Shigekatsu MaekawaShigekatsu Maekawa More articles by this author , Todd JohnsonTodd Johnson More articles by this author , Masashi FujitaMasashi Fujita More articles by this author , Ryo TakataRyo Takata More articles by this author , Daiki IkarashiDaiki Ikarashi More articles by this author , Tomohiko MatsuuraTomohiko Matsuura More articles by this author , Renpei KatoRenpei Kato More articles by this author , Mitsugu KanehiraMitsugu Kanehira More articles by this author , Jun SugimuraJun Sugimura More articles by this author , Takaya AbeTakaya Abe More articles by this author , Hikewaki NakagawaHikewaki Nakagawa More articles by this author , and Wataru ObaraWataru Obara More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003272.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Patients with end-stage renal disease (ESRD) or receiving dialysis have a much higher risk for renal cell carcinoma (RCC), but carcinogenic mechanisms and genomic features remain little explored and undefined. This study’s goal was to identify the genomic features of ESRD RCC and characterize them for associations with tumor histology and dialysis exposure. In this study, we obtained 33 RCCs, with various histological subtypes, that developed in ESRD patients receiving dialysis and performed whole-genome sequencing and transcriptome analyses. METHODS: Frozen kidney samples were obtained from 48 patients who were undergoing dialysis treatment and developed RCC at Iwate Medical University Hospital. Among them, we selected 38 subjects for study from whom matched tumor and adjacent non-tumor tissue samples could be obtained and from which DNA (n=38) or RNA (n=26) could be isolated. We performed whole genome sequencing of genomic DNA using MGIEasy FS DNA Library Prep Set and short read sequencer DNBSEQ-G400. mRNA Sample were sequenced using HiSeq. Driver events, copy-number alteration (CNA) analysis, and mutational signature profiling was performed using an analysis pipeline that integrated data from germline and somatic SNVs, Indels, and structural variants as well as CNAs, while transcriptome data was analyzed for differentially expressed genes and through gene set enrichment analysis. RESULTS: ESRD related clear cell RCCs' driver genes and mutations mirrored those in sporadic ccRCCs. Longer dialysis periods significantly correlated with a rare mutational signature SBS23, whose etiology is unknown, and increased mitochondrial copy number. All ACD (acquired cystic disease)-RCCs, which developed specifically in ESRD patients, showed chromosome 16q amplification. Gene expression analysis suggests similarity between certain ACD-RCCs and papillary RCCs and in TCGA papillary RCCs with chromosome 16 gain identified enrichment for genes related to DNA repair, as well as pathways related to reactive oxygen species, oxidative phosphorylation, and targets of Myc. CONCLUSIONS: This analysis suggests that ESRD or dialysis could induce types of cellular stress that impact some specific types of genomic damage leading to oncogenesis. Source of Funding: none © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e497 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Shigekatsu Maekawa More articles by this author Todd Johnson More articles by this author Masashi Fujita More articles by this author Ryo Takata More articles by this author Daiki Ikarashi More articles by this author Tomohiko Matsuura More articles by this author Renpei Kato More articles by this author Mitsugu Kanehira More articles by this author Jun Sugimura More articles by this author Takaya Abe More articles by this author Hikewaki Nakagawa More articles by this author Wataru Obara More articles by this author Expand All Advertisement PDF downloadLoading ...

KaryoCreate: A CRISPR-based technology to study chromosome-specific aneuploidy by targeting human centromeres

Aneuploidy, the presence of chromosome gains or losses, is a hallmark of cancer. Here, we describe KaryoCreate (karyotype CRISPR-engineered aneuploidy technology), a system that enables the generation of chromosome-specific aneuploidies by co-expression of an sgRNA targeting chromosome-specific CENPA-binding ɑ-satellite repeats together with dCas9 fused to mutant KNL1. We design unique and highly specific sgRNAs for 19 of the 24 chromosomes. Expression of these constructs leads to missegregation and induction of gains or losses of the targeted chromosome in cellular progeny, with an average efficiency of 8% for gains and 12% for losses (up to 20%) validated across 10 chromosomes. Using KaryoCreate in colon epithelial cells, we show that chromosome 18q loss, frequent in gastrointestinal cancers, promotes resistance to TGF-β, likely due to synergistic hemizygous deletion of multiple genes. Altogether, we describe an innovative technology to create and study chromosome missegregation and aneuploidy in the context of cancer and beyond.

Unique Considerations in the Treatment of Psychosis in DiGeorge Syndrome: A Case Report

AbstractIntroductionDiGeorge Syndrome is a microdeletion of chromosome 22q11.2 and is most commonly de novo. Manifestations of DiGeorge are wide-spread including cardiac malformations, palatal abnormalities, intellectual disability, hypocalcemia, dysmorphic facial features, and psychiatric disorders (psychotic disorders, Autism, ADHD, etc). This case report highlights difficulties with diagnosis and treatment of psychosis in DiGeorge. This 29 yo male with history of DiGeorge and associated cardiac anomalies presented to the outpatient clinic with prior diagnoses of schizoaffective disorder, bipolar disorder, DMDD, autism, and ADHD. Patient denied all symptoms, though mother noted hallucinations for 5–6 years. He was previously on aripiprazole and divalproex and developed a resting tremor. With family history of Parkinson’s disease (PD), increased risk of PD in DiGeorge, and no improvement in tremor with dose reduction of aripiprazole or discontinuation of divalproex, neurology diagnosed PD, which was later negated when tremor resolved with complete discontinuation of aripiprazole. In our clinic we slowly increased divalproex and olanzapine, though parent concern of sedation limited higher doses. Patient had moderate improvement in symptoms per parents, but after several months on moderate-dose olanzapine, he developed a tremor. Sensitivity to extrapyramidal symptoms limits medication selection. Furthermore, QT prolongation in a population with cardiac abnormalities poses a unique risk. Given complexity and poor response, we researched pathogenesis and treatment of psychosis in DiGeorge.MethodsWe reviewed literature on PubMed with keywords including “DiGeorge,” “treatment,” “psychosis.” Specifically, we looked at articles addressing treatment response, efficacy, side effects, novel treatments, and the pathogenesis as it relates to treatment.ResultsLiterature indicates that psychotic symptoms are more treatment resistant compared to psychotic disorders not associated with DiGeorge and there is little consensus on which antipsychotics are more effective. The 22q11.2 deletion contains the gene segment for catechol-O-methyltransferase (COMT) and the resulting COMT deficiency leads to excess catecholamines. The presence of the low activity COMT variant on the remaining allele is associated with possibly more severe psychiatric symptoms. Metyrosine may be a potential medication in the treatment of psychosis in DiGeorge by interfering with dopamine synthesis. Overall there is sparse research on treatment of psychosis in DiGeorge and a lack of firm recommendations.ConclusionThis case study exemplifies the need for further research on DiGeorge Syndrome and treatment of psychosis. Treatment is complicated by cardiac abnormalities, comorbid neuropsychiatric conditions confounding diagnosis, and little research on treatments that target the unique pathogenesis. Research is inconsistent concerning recommendations and novel treatments are primarily anecdotal.FundingNo Funding