Chromosome 22q11 Research Articles

DNA methylation dysregulation patterns in the 1p36 region instability.

In the monosomy 1p36 deletion syndrome, the role of DNA methylation in the genomic stability of the 1p36 region remains elusive. We hypothesize that changes in the methylation pattern at the 1p36 breakpoint hotspot region influenced the chromosomal breakage leading to terminal deletions. From the monosomy 1p36 material collection, four cases with 4.0 to 5.5Mb terminal deletions and their parents were investigated. DNA samples were assessed by targeted bisulfite sequencing (NimbleGen SeqCap Epi) to examine DNA methylation status in the 1p36 hotspot region at single-base resolution as compared to the chromosomal hotspot regions, 9p22, 18q21.1, and 22q11.2. Additionally, in in silico assessment, the mean GC content of various classes of repeats in the genome and especially in the breakpoint regions was evaluated. A complex landscape of DNA methylation in the 1p36 breakpoint hotspot region was found. Changes in DNA methylation level in the vicinity of the breakpoint in the child's DNA when compared to parents' and control DNA were observed, with a shift from 15.1 to 70.8% spanning the breakpoint region. In the main classes of evaluated repeats, higher mean GC contents in the 1p36 breakpoint region (47.06%), 22q11.2 (48.47%), and 18q21.1 (44.21%) were found, compared to the rest of the genome (40.78%). The 9p22 region showed a lower GC content (39.42%) compared to the rest of the genome. Both dysregulation of DNA methylation and high GC content were found to be specific for the 1p36 breakpoint hotspot region suggesting that methylation abnormalities could contribute to aberrations at 1p36.

Impact of bortezomib on 1q21+ in multiple myeloma: A meta-analysis of treatment outcomes and prognostic implications.

The gain of chromosomal region 1q21 is a significant risk factor in multiple myeloma (MM) and is associated with poor prognosis. The introduction of bortezomib has notably improved outcomes for patients with MM. However, recent studies have reported conflicting results regarding the efficacy of bortezomib in mitigating the adverse effects of 1q21 aberration in these patients. To address this, in the present study, a meta-analysis was conducted based on 6 studies encompassing 1,575 patients with MM. The prognosis of patients with 1q21+ who underwent treatment with a bortezomib-based regimen was evaluated in terms of complete response (CR), overall survival (OS) and progression-free survival (PFS) rates. The results demonstrated that patients with 1q21 aberration were more likely to achieve CR than those without 1q21+ under bortezomib-based treatment [odds ratio, 0.64; 95% confidence interval (CI), 0.49-0.83; P=0.0008]. However, 1q21+ remained a high-risk factor in patients with MM even after bortezomib treatment [PFS: hazard ratio (HR), 1.72; 95% CI, 1.53-1.93; P<0.00001; and OS: HR, 1.95; 95% CI, 1.58-2.42; P<0.00001]. In conclusion, although bortezomib improved the likelihood of achieving CR in patients with 1q21+, this genetic aberration continues to be considered a high-risk factor in patients with MM treated with a bortezomib-based regimen.

SHARPIN is a novel gene of colorectal cancer that promotes tumor growth potentially via inhibition of p53 expression.

Colorectal cancer (CRC) is widely prevalent and represents a significant contributor to global cancer‑related mortality. There remains a pressing demand for advancements in CRC treatment modalities. The E3 ubiquitin ligase is a critical enzyme involved in modulating protein expression levels via posttranslational ubiquitin‑mediated proteolysis, and it is reportedly involved in the progression of various cancers, making it a target of recent interest in anticancer therapy. In the present study, using comprehensive expression analysis involving spatial transcriptomic analysis with single‑cell RNA sequencing in clinical CRC datasets, the ubiquitin‑associated protein Shank‑associated RH domain interactor (SHARPIN) was identified, located on amplified chromosome 8q, which could promote CRC progression. SHARPIN was found to be upregulated in tumor cells, with elevated expression observed in tumor tissues. This heightened expression of SHARPIN was positively associated with lymphatic invasion and served as an independent predictor of a poor prognosis in patients with CRC. In vitro and in vivo analyses using SHARPIN‑overexpressing or ‑knockout CRC cells revealed that SHARPIN overexpression upregulated MDM2, resulting in the downregulation of p53, while SHARPIN silencing or knockout downregulated MDM2, leading to p53 upregulation, which affects cell cycle progression, tumor cell apoptosis and tumor growth in CRC. Furthermore, SHARPIN was found to be overexpressed in several cancer types, exerting significant effects on survival outcomes. In conclusion, SHARPIN represents a newly identified novel gene with the potential to promote tumor growth following apoptosis inhibition and cell cycle progression in part by inhibiting p53 expression via MDM2 upregulation; therefore, SHARPIN represents a potential therapeutic target for CRC.

Phenotype of patients with late diagnosis of 22q11 deletion: a review and retrospective study.

Chromosome 22q11.2 deletion syndrome (22q11DS) is the most common microdeletion syndrome, typically presenting in neonates with congenital cardiac anomalies, hypocalcaemia and thymic hypoplasia. Some patients are diagnosed later in adolescence and adulthood, with less known about the clinical phenotype of these patients. To summarise key clinical features in cases of 22q11DS diagnosed during adolescence and adulthood. This is a retrospective cohort study of 22q11DS patients diagnosed after 13 years of age over 2010-2021, with a literature review of published cases highlighting other late diagnoses. The study was performed in a large multicentre tertiary health network in Melbourne, Australia. Patients diagnosed with 22q11DS after the age of 13 years were included in the study. Main outcome measures were key clinical features in cases of late diagnosis of 22q11DS. A literature search yielded 53 published case reports and one cohort study for review (62 subjects). Additionally, 10 cases of late diagnosis of 22q11DS were identified through a retrospective electronic medical chart review. Findings suggest that intellectual disability and learning difficulties, hypocalcaemia with hypoparathyroidism and facial dysmorphism remain key features in patients with a late diagnosis of 22q11DS, with hypocalcaemia being the most common presentation leading to diagnosis. Patients diagnosed in adulthood may lack classical clinical features of congenital cardiac anomalies and thymic hypoplasia. Immunological consequences of 22q11DS are also an important late-onset consideration. Atypical features may include basal ganglia calcification. Chromosome 22q11DS has diverse clinical features and a highly variable phenotype, likely contributing to underdiagnosis and later diagnoses.

A case of esophageal squamous cell carcinoma with epidermization showing a unique morphology.

An 80-year-old woman with a history of endoscopic balloon dilation for esophageal stricture caused by accidental ingestion of caustic soda during infancy presented with dysphagia. Upper gastrointestinal endoscopy revealed a 10-cm-long, highly white, elevated lesion with a feathered appearance. This lesion was determined to be the cause of dysphagia and was completely resected via endoscopic submucosal dissection. Histopathological examination revealed a thick keratin layer on the surface of the stratified squamous epithelium, with a prominent granular layer underneath and some areas showing nuclear atypia. The lesion was diagnosed as a well-differentiated squamous cell carcinoma, pT1a-LPM, derived from epidermoid metaplasia. Cancer genome analysis revealed mutations in TP53 as well as amplification of MYC, FGFR1, chromosome 7, and chromosome 20q. This case suggests that epidermoid metaplasia caused by chronic irritation from an esophageal stricture may have been exacerbated by the dilation procedure.

Epilepsy in Angelman syndrome and the most common electroencephalographic findings

Angelman syndrome is a genetic disorder characterised by severe mental retardation, subtle dysmorphic facial features, a characteristic behavioural phenotype, seizures and abnormalities in video electroencephalograms (video EEG). Angelman syndrome may be associated with genetic mechanisms involving the region of chromosome 15q11-13. Up to 90% of cases have epileptic seizures, usually in the early years of life. Videoelectroencephalography patterns with some typical characteristics associated with Angelman syndrome have been reported, although these are not specific to it, and as such it is also useful for early diagnosis, especially in the first months or years of life. To characterise the videoelectroencephalography findings of 17 patients diagnosed with Angelman syndrome, and compare them with previously published studies. We conducted a retrospective observational study of 34 video EEGs performed on 17 patients diagnosed with Angelman syndrome at the clinical neurophysiology service of the Puerta de Hierro University Hospital in Madrid between 2019 and 2022. The primary objective was to characterise the videoelectroencephalographic findings and compare them with previously published studies. As secondary objectives, we analysed the patterns proposed by Dan and Boyd, and other demographic, genetic and clinical data. Video EEG supported the clinical suspicion in our study, as baseline brain activity was altered in all the patients. We identified a pattern similar to those defined by Dan and Boyd in 88% of the cases, and the type III pattern was the most common in our series. These findings confirm that video EEG is highly sensitive for the diagnosis of Angelman syndrome, and very useful as a diagnostic biomarker in the early stages of life.

Malignant Rhabdoid Tumor masquerading as Neuroblastoma: A rare Case-report

Abstract Introduction/Objective Malignant rhabdoid tumors (MRT) predominantly impact infants and young children, typically occurring around the age of 15 months. While they can emerge from soft tissues throughout the body, but commonly initiate in the kidneys. Neuroblastoma-like characteristics are seldom observed within the varied phenotypes of malignant rhabdoid tumors. Here, we present an exceptionally rare and distinctive subtype of malignant rhabdoid tumor exhibiting features akin to neuroblastoma localized within the unusal parapharyngeal space. Methods/Case Report A 2-month-old female presented to the ED with an enlarging right cervical neck mass. The mother reported a one-week history of upper respiratory tract symptoms and noticed an enlarging mass of her right neck. CT reported a “parapharyngeal abscess with airway compression”. The patient was started on Augmentin with no significant improvement. Repeat CT with contrast demonstrated an enlarging rim-enhancing 3 cm mass involving the right parapharyngeal space, trachea, and right carotid arteries. Laryngoscopy and incisional biopsy of right neck lymph nodes demonstrated a high-grade malignancy with prominent nucleoli, high N/C ratio and scant cytoplasm. The tumor tested positive for CD 99, synaptophysin, and neurofilament, leading to the initial diagnosis of neuroblastoma. However, molecular analysis uncovered the loss of INI-1 on 22q11.2, prompting a reevaluation and a final diagnosis of MRT with neuroblastoma-like characteristics was made. Results (if a Case Study enter NA) NA Conclusion A range of tumors displaying distinct “rhabdoid” cytological features are collectively termed as malignant rhabdoid tumors (MRTs). Conventional immunohistochemistry (IHC) staining for CD99, synaptophysin, neurofilament, and myogenin might suggest neuroblastoma, Ewing sarcoma, or rhabdomyosarcoma. However, the absence of INI-1 expression provides a definitive diagnosis. INI-1 loss, a purported tumor suppressor gene located on chromosome 22q11.2, solidifies the tumor’s classification as malignant rhabdoid tumor (MRT). Additionally, a positive neurofilament stain in MRT is crucial for diagnostic and therapeutic assessments. This differentiation is vital, given the dismal prognosis of MRT with a 5-year survival rate of less than 10%.

Event-free survival in neuroblastoma with MYCN amplification and deletion of 1p or 11q may be associated with altered immune status

BackgroundNeuroblastoma exhibits substantial heterogeneity, which is intricately linked to various genetic alterations. We aimed to explore immune status in the peripheral blood and prognosis of patients with neuroblastoma with different genetic characteristics.MethodsWe enrolled 31 patients with neuroblastoma and collected samples to detect three genetic characteristics. Peripheral blood samples were tested for immune cells and cytokines by fluorescent microspheres conjugated with antibodies and flow cytometry. Event-free survival (EFS) was analyzed using the Kaplan‒Meier method.ResultsTwenty-two patients had genetic aberrations, including MYCN amplification in 6 patients, chromosome 1p deletion in 9 patients, and chromosome 11q deletion in 14 patients. Two genetic alterations were present in seven patients. The EFS was worse in patients with MYCN amplification or 1p deletion than in the corresponding group, whereas 11q deletion was a prognostic factor only in patients with unamplified MYCN. Changes in immune status revealed a decrease in the proportion of T cells in blood, and an increase in regulatory T cells and immunosuppression-related cytokines such as interleukin (IL)-10. The EFS of the IL-10 high-level group was lower than that of the low-level group. Patients with concomitant genetic alterations and a high level of IL-10 had worse EFS than other patients.ConclusionsPatients with neuroblastoma characterized by these genetic characteristics often have suppressed T cell response and an overabundance of immunosuppressive cells and cytokines in the peripheral blood. This imbalance is significantly associated with poor EFS. Moreover, if these patients show an elevated levels of immunosuppressive cytokines such as IL-10, the prognosis will be worse.

A Clinico-Genetic Score Incorporating Disease-Free Intervals and Chromosome 8q Copy Numbers: A Novel Prognostic Marker for Recurrence and Survival Following Liver Resection in Patients with Liver Metastases of Uveal Melanoma

Surgical treatment of liver metastases of uveal melanoma (LMUM) could be proposed for selected patients. This retrospective study examined the prognostic significance of the genetic profiles of liver metastases after LMUM resection. A total of 86 patients treated with resection for LMUM, who underwent genetic analysis of liver metastasis, were included. A multivariable Cox model identified the independent predictors of recurrence-free survival (RFS) and overall survival (OS). The disease-free interval (DFI) and a chromosome 8q surgain (&gt;3 copies) were independent predictors and categorized patients into three risk groups with distinct postoperative prognoses. For the low-, intermediate-, and high-risk scores of recurrence, the median RFS values were 15 months (95% CI: 10–22), 6 months (95% CI: 4–11), and 4 months (95% CI: 2–7), and the median OS values were 86 months (95% CI: 55-NR), 25 months (95% CI: 17–48), and 19 months (95% CI: 12–22), respectively. The predictive accuracy of this scoring system was demonstrated by a mean area under the curve (AUC(t)) of 0.77 (95% CI: 0.65–0.90) for RFS and 0.81 (95% CI: 0.70–0.92) for OS. This novel score, based on a DFI of ≤24 months combined with a chromosome 8q surgain, identifies patients at a high risk of early recurrence and could help clinicians to propose perioperative treatment.

The role of 1q abnormalities in multiple myeloma: Genomic insights, clinical implications, and therapeutic challenges

Chromosome 1q copy number variations, collectively termed +1q, are 1 of the most common cytogenetic abnormalities in multiple myeloma. 1q abnormalities are associated with overexpression of a high-risk gene signature promoting cell proliferation, apoptosis resistance, genomic instability, and treatment resistance, and acquisition or expansion of +1q subclones mediate disease development and relapse. While there remains significant controversy as to whether the presence of +1q is itself an independent driver of poor prognosis or is simply a marker of other high-risk features, +1q has recently been incorporated into multiple prognostic scoring models as a new high-risk cytogenetic abnormality. In this review, we present possible underlying genetic mechanisms of high-risk disease in +1q myeloma, implications for subclonal development, its role in modifying the tumor microenvironment, current evidence for clinical significance in newly-diagnosed and relapsed patients, and current controversies in +1q classification and prognostication.

From diagnosis to postoperative challenges: a comprehensive case report on 2q37 deletion syndrome with CHD.

Chromosomal 2q37 deletion syndrome, marked by developmental delays, distinctive facial features, and a spectrum of congenital anomalies, presents significant challenges in the cardiac management of affected individuals. This paper details the case of an 8-month-old male with 2q37 deletion syndrome, manifesting atrial and ventricular septal defects, patent ductus arteriosus, and right ventricular outflow tract stenosis, leading to a demanding postoperative course. Despite an initially stable post-surgery phase, the onset of junctional ectopic tachycardia necessitated prolonged veno-arterial extracorporeal membrane oxygenation support, highlighting the syndrome's potential for intricate postoperative courses. The complexities encountered in this case, including extended renal replacement therapy and delayed thoracic closure, underscore the syndrome's multisystem impact and the critical need for tailored, multidisciplinary care approaches. This report contributes to the growing body of knowledge on the cardiac implications of 2q37 deletion syndrome, emphasising the importance of individualised surgical strategies and the ongoing exploration of genotype-phenotype correlations in this rare genetic disorder.

Clinicogenetic characterization and response to disease-modifying therapies in spinal muscular atrophy: real-world experience from a reference center in Southern Brazil

ObjectiveSpinal Muscular Atrophy linked to chromosome 5q (SMA) is an autosomal recessive neurodegenerative disease characterized by progressive proximal muscle atrophy and weakness. This study addresses the scarcity of research on novel disease-modifying therapies for SMA in Latin America by reporting a real-world experience in Southern Brazil. MethodologyThis is a single-center historical cohort that included all patients diagnosed with spinal muscular atrophy at a Regional Reference Service for rare diseases. ResultsEighty-one patients were included, of whom 7 died during follow-up. Of the remaining 74 patients, 5.4 % were classified as pre-symptomatic, 24.3 % with SMA type 1, 28.4 % with type 2, 36.5 % with type 3, and 5.4 % with type 4. The mean follow-up time ranged from 1.8 years for pre-symptomatic cases to 8.7 years for SMA types 2 and 3. Approximately 42 % of these patients received specific disease-modifying therapy, of these, 96.8 % received Nusinersen, with 19.4 % transitioning to gene therapy using Onasemnogene Abeparvovec, and 6.4 % starting Risdiplam. Most patients with SMA type 1 were on disease-modifying treatment, whereas only slightly over a third of patients with type 2 and about 10 % of type 3 were receiving such treatments. Among treated patients, 80 % demonstrated improvement in motor performance during the follow-up, with a lesser therapeutic response being associated with late initiation of treatment and low motor function scores at baseline. ConclusionThis real-world study reinforces the effectiveness of disease-modifying therapies for SMA in Brazil within the context of low- and middle-income countries, which is greater the earlier and the better the patient's functional status.

Abstract C154: Clinical, genomic, and socioeconomic factors underlying low survival rates from colorectal cancer in African American patients

Abstract Background: Colorectal cancer (CRC) patients of African ancestry (AFR) have higher incidence, higher mortality, and shorter overall survival (OS) than patients of non-African ancestry (non-AFR) in the United States. This disparity is likely due to a combination of clinical, genomic, and socioeconomic factors. We investigated real-world data of patients from a single tertiary cancer center to delineate the contribution of each of those variables. Methods: We analyzed data from 3,995 CRC patients, including 247 AFR and 3,748 non-AFR patients, diagnosed after 2014 and treated at Memorial Sloan Kettering Cancer Center. Every patient had a specimen sequenced with MSK-IMPACT, a targeted DNA sequencing assay that identifies genomic alterations in 341-505 genes. Genetic ancestry was determined using previously published methods by our group. Clinical annotations included sex, age at diagnosis (Dx), stage at Dx, and tumor location. Billing records were used to identify the type of insurance per patient and estimate their Yost Index (YI), a location-dependent socioeconomic status (SES) percentile score based on household incomes, house values, rent, poverty, education, and employment statistics. A multivariate cox proportional hazards model was used to assess the association between clinical variables (stage at Dx, age at Dx, sex, primary tumor location), genomic features (MSI status, BRAF, APC, SMAD4 alterations, chromosome 20Q amplifications), SES (YI) and OS. Propensity score matching (PSM) was performed using all features included in the multivariate model to assess outcome differences after matching for clinical, genomic, and socioeconomic variables. OS was measured in months from time of Dx to last follow-up and compared using the log-rank test. Results: AFR patients had worse OS compared to non-AFR patients (median OS: AFR, 44.9 vs. non-AFR, 64.3, p&amp;lt;0.001). AFR patients were younger at Dx (median 53 vs. 57 yo, p&amp;lt;0.001), had higher rates of right-sided tumors (41.1% vs. 30.2%, p&amp;lt;0.001), and less often had microsatellite unstable (MSI) tumors (5.26% vs 10.0%, p=0.014). Among microsatellite stable cases, AFR patients had a higher frequency of KRAS (57.1% vs. 44.7%, p=0.004) and a lower frequency of BRAF mutations (4.3% vs. 7.7%, p=0.069). Medicaid was more frequent among AFR patients (10.12% vs. 4.87%, p&amp;lt;0.001). AFR patients had lower SES (median YI 42 vs. 17, p&amp;lt;0.001). In a multivariate model accounting for clinical, genomic and socioeconomic features, AFR ancestry remained associated with worse outcomes (HR: 1.35, p = 0.007). AFR patients also had significantly shorter OS than the set of non-AFR patients matched for clinical, genomic, and socioeconomic features (5-yr OS was 31.6% for AFR vs 45.7% for non-AFR, log-rank p-value = 0.014). Conclusions: Colorectal cancer patients of AFR ancestry had significantly shorter OS than patients of other ancestries after accounting for basic clinical, genomic, and socioeconomic variables. Further research is needed in order to understand the causes of this disparity. Citation Format: Sharafudeen D. Abubakar, Henry Walch, Xuechun Bai, Tejiri Agbamu, Michele Waters, Kanika Arora, Farheen Shah, Christopher Fong, Justin Jee, Hannah Williams, Michael F Berger, Karuna Ganesh, Julio Garcia- Aguilar, Nikolaus Schultz, Rona Yaeger, Walid K Chatila, Francisco Sanchez-Vega. Clinical, genomic, and socioeconomic factors underlying low survival rates from colorectal cancer in African American patients [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C154.

High-grade B-cell lymphoma with 11q aberration in the HIV setting: a clinicopathological study of 10 cases and literature review

High-grade B-cell lymphoma with 11q aberration (HGBL-11q) is a distinct lymphoma entity according to the 5th edition of the WHO classification of hematolymphoid tumors. It lacks MYC translocation but carries proximal gains and/or telomeric losses of chromosome 11q. This rare type of B-cell lymphoma is less frequently reported in people living with HIV (PLWH), and its exact frequency remains unclear. Our goal was to retrospectively analyze its frequency in a cohort of aggressive B-cell lymphomas in PLWH, including Burkitt lymphoma (BL, n = 35), diffuse large B-cell lymphoma (DLBCL, n = 48), high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS, n = 13), which was diagnosed as AIDS-related lymphoma (ARL) at our institution. In total, 10/96 (10.4%) cases harbored the typical 11q aberration pattern, predominantly those that had been classified as BL (6/35, 17.1%), DLBCL (2/48, 4.2%), and HGBL, NOS (2/13, 15.4%). We also evaluated 7 cases of AIDS-related HGBL-11q (AR-HGBL-11q) reported in the literature. The median age of our cohort was 35 years, and all the patients were male. Most cases (70%) had a history of HIV infection for over 1 year, and all were involved in lymph nodes (100%), frequently involved extranodal sites (60%), and Ann Arbor stage III/IV. In histomorphology, the cases exhibited diverse cytological features, reminiscent of BL (6 cases), DLBCL (2 cases), and HGBL (2 cases). A comparison of the combined cohort of 17 AR-HGBL-11q cases with 11 ARL cases that lacked both MYC rearrangement and 11q aberration at our institution showed that HGBL-11q cases were characterized by strikingly coarse apoptotic debris (P < 0.001), background rich in eosinophils (P = 0.002), higher expression of the germinal centre marker LMO2 (P = 0.080), lower expression of MUM1 (P = 0.004), BCL2 (P = 0.007), and LEF1 (P = 0.080), and lower positivity for EBER in situ hybridisation (P = 0.027). Notably, one case in our series was EBV-positive, a finding not previously reported in the literature. Furthermore, comparing the prognosis between these two groups, AR-HGBL-11q showed a relatively favorable prognosis (P = 0.15), although the difference was not statistically significant. We analyzed this rare lymphoma entity in the HIV setting and highlighted the importance of integrating histomorphological and immunophenotypic features in its diagnosis and classification.

Clinical and methylomic features of spinal meningiomas.

The objective of our study was to analyze methylomic and clinical features of a cohort of spinal meningiomas (SMs) resected at our institution. This is a retrospective study of patients undergoing SM resection at our institution between 2010 and 2023. Clinical and radiographic characteristics were reviewed and analyzed with standard statistical methods. A Partitioning Around Medoids approach was used to cluster SMs with methylation data in a combined cohort from our institution and a publicly available dataset by methylation profiles. Clinical variables and pathway analyses were compared for the resulting clusters. Sixty-five SMs were resected in 53 patients with median radiographic follow-up of 34 months. Forty-six (87%) patients were female. The median age at surgery was 65 years and median tumor diameter was 1.9cm. The five-year progression-free survival rate was 90%, with subtotal resection being associated with recurrence or progression (p = .017). SMs clustered into hypermethylation, intermediate methylation, and hypomethylation subgroups. Tumors in the hypermethylated subgroup were associated with higher WHO grade (p = .046) and higher risk histological subtypes (p <.001), while tumors in the hypomethylated subgroup were least likely to present with copy-number loss in chromosome 22q (p <.0001). SMs classified as immune-enriched under a previously developed intracranial meningioma classifier did not have increased leukocyte fractions or hypomethylation of genes typically hypomethylated in immune-enriched tumors. SMs are more benign than their intracranial counterparts, and gross-total resection results in long term PFS. Methylation profiling identifies subgroups with differences in clinical variables.

Gain of chromosome 8q and high expression of EZH2 may predict poor prognosis in Chinese patients with uveal melanoma

PurposeTo explore risk factors predicting poor prognosis of uveal melanoma in a Chinese population, with specific emphasis on monosomy 3, 8q gain, and EZH2 staining. MethodsEighty-nine patients with uveal melanoma from 2012 to 2021 were reviewed. Clinical and pathological records were collected and analyzed. Immunohistochemical staining of EZH2, monosomy 3 and 8q gain were respectively conducted in 45, 54, and 57 cases. Survival was evaluated by Kaplan–Meier analysis and log-rank test. Cox proportional hazard regressions were employed to predict risk factors of distant metastasis. ResultsThe median follow-up was 44 months. Altogether, 16 % of patients developed distant metastases and died from disease-related causes. Disease-specific survival at one and three years was 96.6 % and 88.4 % while distant metastasis rates were 7.9 % and 12 %. Univariate Cox regression analysis revealed that age (HR: 1.04), tumor largest basal diameter (HR: 1.21), tumor thickness (HR: 1.21), ciliary body involvement (HR: 3.50), AJCC stage (HR: 5.68), epithelioid cell type (HR: 7.71), 8q gain (HR: 7.48), and high expression of EZH2 (HR: 6.09) were associated with distant metastasis. 8q gain was associated with epithelioid cell type and thicker tumor while EZH2 was correlated with epithelioid cell type. Monosomy 3 lacked a significant correlation with other factors. ConclusionEZH2 and 8q gain could be taken into consideration when calculating poor prognosis in Chinese patients with uveal melanoma. Monosomy 3 showed no significance in distant metastasis, but this may be due to a small sample size.

Low dose lenalidomide versus placebo in non-transfusion dependent patients with low risk, del(5q) myelodysplastic syndromes (SintraREV): a randomised, double-blind, phase 3 trial

Lenalidomide is the standard of care for patients who are transfusion dependent with chromosome 5q deletion (del[5q]) myelodysplastic syndromes. In the SintraREV trial, we aimed to investigate whether an early intervention of low lenalidomide doses for 2 years could delay transfusion dependency in patients with anaemia who were not transfusion dependent. This randomised, double-blind, phase 3 trial, was conducted at 22 sites (University Hospitals) in Spain, France, and Germany. Eligible patients were aged 18 years or older diagnosed with low-risk or intermediate-1-risk del(5q) myelodysplastic syndromes with non-transfusion-dependent anaemia (according to the IPSS), were erythropoietin-stimulating agents naive, and had an ECOG performance status of 2 or less. Patients were randomly assigned (2:1) by means of a telephone system to receive lenalidomide 5 mg daily in 28-day cycles versus placebo for 2 years. The primary endpoint was time to transfusion dependency based on blinded independent central review. Analysis were by intent-to-treat (ITT) and evaluable population. Safety analyses included all participants who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov (NCT01243476) and EudraCT (2009-013619-36) and is complete. Between Feb 15, 2010, and Feb 21, 2018, 61 patients were randomly assigned to receive lenalidomide (n=40; two did not receive treatment) or placebo (n=21). The median age was 72·2 (IQR 65·4-81·9) years, 50 (82%) patients were female, and 11 (18%) were male. The median follow-up time was 60·6 (IQR 32·1-73·9) months. Regarding primary endpoint, median time to transfusion dependency was not reached (95% CI not applicable) in the lenalidomide group versus 11·6 months (95% CI 0·00-30·11) in the placebo group (p=0·0027). Lenalidomide significantly reduced the risk of transfusion dependency by 69·8% (hazard ratio 0·302, 95% CI 0·132-0·692; p=0·0046). The most frequent treatment-related adverse event was neutropenia, occurring in 24 (63%) of 38 patients in the lenalidomide group (grade 3 and 4 in 17 [45%] patients and one [3%], respectively) and in four (19%) of 21 patients in the placebo group (grade 3 in one [5%] patient). Thrombocytopenia was detected in seven (18%) of 38 patients receiving lenalidomide (grade 3 in two [5%] patients). Regarding the non-haematological toxicity, skin disorders (rash nine [23%] of 38 patients) were the most frequently described toxicities among patients receiving lenalidomide, being grade 3 in one (3%) of 38 patients. 19 serious adverse events were reported in 13 patients, 18 in the lenalidomide group and one in the placebo group, five of which were potentially related to the study drug. No treatment-related deaths were identified. An early approach with low doses of lenalidomide across two years delays the time to transfusion dependency and improves the rate and quality of the responses, with a manageable safety profile in patients who are non-transfusion dependent with del(5q) low-risk myelodysplastic syndromes. Bristol Myers Squibb.

The First Fetal Case of Shwachman-Diamond Syndrome Mimicking Vascular Growth Restriction.

Shwachman-Diamond Syndrome (SDS) is a rare autosomal recessive genetic condition with 90% of cases associated with biallelic pathogenic variants in the Shwachman-Bodian-Diamond Syndrome (SBDS) gene on chromosome 7q.11.21. SDS belongs to ribosomopathies since SBDS gene encodes a protein involved in ribosomal maturation. Its phenotypic postnatal hallmark features include growth delay, bone marrow failure, exocrine pancreatic insufficiency, and skeletal abnormalities. We report a first fetal case of Shwachman-Diamond syndrome and extend its phenotype before birth. The clinical features mimicked vascular growth restriction with FGR and shortened long bones, associated with abnormal Doppler indices. Non-restricted fetal autopsy after termination of pregnancy allowed deep phenotyping disclosing the features of fetal skeletal dysplasia. Post-fetopathological trio exome sequencing identified biallelic pathogenic variants in the SBDS gene. Genotype-phenotype correlations confirmed the diagnosis and enabled an adequate genetic counseling of the parents. Our case is another example of the positive impact of fetal autopsy coupled with post-fetopathological genomic studies, even in the cases that were hitherto classified as maternal or fetal vascular malperfusion.

RAD21 promotes oncogenesis and lethal progression of prostate cancer

Higher levels of aneuploidy, characterized by imbalanced chromosome numbers, are associated with lethal progression in prostate cancer. However, how aneuploidy contributes to prostate cancer aggressiveness remains poorly understood. In this study, we assessed in patients which genes on chromosome 8q, one of the most frequently gained chromosome arms in prostate tumors, were most strongly associated with long-term risk of cancer progression to metastases and death from prostate cancer (lethal disease) in 403 patients and found the strongest candidate was cohesin subunit gene, RAD21, with an odds ratio of 3.7 (95% CI 1.8, 7.6) comparing the highest vs. lowest tertiles of mRNA expression and adjusting for overall aneuploidy burden and Gleason score, both strong prognostic factors in primary prostate cancer. Studying prostate cancer driven by the TMPRSS2-ERG oncogenic fusion, found in about half of all prostate tumors, we found that increased RAD21 alleviated toxic oncogenic stress and DNA damage caused by oncogene expression. Data from both organoids and patients indicate that increased RAD21 thereby enables aggressive tumors to sustain tumor proliferation, and more broadly suggests one path through which tumors benefit from aneuploidy.

Use of Mitotic Activity and the Size of Any Dedifferentiated Component for Risk Assessment in MDM2-Amplified Liposarcoma.

The characteristic molecular signature for both atypical lipomatous tumor/well-differentiated liposarcoma and dedifferentiated liposarcoma is amplified sequences derived from chromosome 12q13-15, including MDM2 proto-oncogene (MDM2). As the progression of atypical lipomatous tumor/well-differentiated liposarcoma to the more aggressive dedifferentiated liposarcoma has the potential to adversely affect patient outcomes, the extent of the latter component might be important to evaluate. To investigate the correlation between clinicopathologic characteristics, including tumor size, modified Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grade, molecular data, and outcomes in 123 surgically resected MDM2-amplified liposarcomas. Pathology reports and clinical records were reviewed. A log-rank test was used to compare the survival trends, and univariate logistic regression was performed to identify variables associated with adverse events (distant metastasis and/or death), from which the P value was derived to construct a multivariate regression model. In univariate analysis, the largest single dimension of the dedifferentiated component, the percentage of cells with gain of chromosome 12, mitotic count, and the presence of modified FNCLLC grade 3 were associated with adverse events. In multivariate analysis, the largest single dimension of the dedifferentiated component (odds ratio: 1.169; 95% CI: 1.053, 1.299; P = .003), and a higher mitotic count (odds ratio: 1.133; 95% CI: 1.037, 1.237; P = .006) were correlated with adverse events. There was no statistically significant association between current local recurrence status, overall largest tumor dimension, overall tumor volume, MDM2 copy number, or MDM2 to chromosome 12 centromere probe ratio and adverse outcomes. Staging dedifferentiated liposarcoma based on the size of the dedifferentiated component better predicts the outcome.