PRKDC-Mediated NHEJ May Play a Crucial Role in Aneuploidy of Chromosome 8-Driven Progression of Ovarian Cancer.

High malignancy is a prominent characteristic of epithelial ovarian cancer (EOC), emphasizing the necessity for further elucidation of the potential mechanisms underlying cancer progression. Aneuploidy and copy number variation (CNV) partially contribute to the heightened malignancy observed in EOC; however, the precise features of aneuploidy and their underlying molecular patterns, as well as the relationship between CNV and aneuploidy in EOC, remain unclear. In this study, we employed single-cell sequencing data along with The Cancer Genome Atlas (TCGA) to investigate aneuploidy and CNV in EOC. The technique of fluorescence in situ hybridization (FISH) was employed using specific probes. The copy number variation within the genomic region of chromosome 8 (42754568-47889815) was assessed and utilized as a representative measure for the ploidy status of individual cells in chromosome 8. Differential expression analysis was performed between different subgroups based on chromosome 8 ploidy. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein-protein interaction (PPI), and hub-gene analyses were subsequently utilized to identify crucial genes involved. By classifying enriched tumor cells into distinct subtypes based on chromosome 8 ploidy combined with TCGA data integration, we identified key genes driving chromosome 8 aneuploidy in EOC, revealing that PRKDC gene involvement through the mediated non-homologous end-joining pathway may play a pivotal role in disease progression. Further validation through analysis of the GEO and TCGA database and survival assessment, considering both mRNA expression levels and CNV status of PRKDC, has confirmed its involvement in the progression of EOC. Further functional analysis revealed an upregulation of PRKDC in both ovarian EOC cells and tissues, with its expression showing a significant correlation with the extent of copy number variation (CNV) on chromosome 8. Taken together, CNV amplification and aneuploidy of chromosome 8 are important characteristics of EOC. PRKDC and the mediated NHEJ pathway may play a crucial role in driving aneuploidy on chromosome 8 during the progression of EOC.

Optimal Treatment Approaches to Intestinal Behçet's Disease Complicated by Myelodysplastic Syndrome: The KASID and KSBD Multicenter Study.

PURPOSE: Studies on intestinal Behçet's disease (BD) complicated by myelodysplastic syndrome (MDS) are rare, and no established therapeutic guidelines exist. This study aimed to evaluate the clinical presentation and outcomes of patients with intestinal BD complicated by MDS (intestinal BD-MDS) and suggest a treatment strategy. MATERIALS AND METHODS: Data from patients with intestinal BD-MDS from four referral centers in Korea who were diagnosed between December 2000 and December 2022 were retrospectively analyzed. Clinical features and prognosis of intestinal BD-MDS compared with age-, sex-matched intestinal BD without MDS were investigated. RESULTS: Thirty-five patients with intestinal BD-MDS were included, and 24 (70.6%) had trisomy 8. Among the 35 patients, 23 (65.7%) were female, and the median age at diagnosis for intestinal BD was 46.0 years (range, 37.0-56.0 years). Medical treatments only benefited eight of the 32 patients, and half of the patients underwent surgery due to complications. Compared to 70 matched patients with intestinal BD alone, patients with intestinal BD-MDS underwent surgery more frequently (51.4% vs. 24.3%; p=0.010), showed a poorer response to medical and/or surgical treatment (75.0% vs. 11.4%; p<0.001), and had a higher mortality (28.6% vs. 0%; p<0.001). Seven out of 35 patients with intestinal BD-MDS underwent hematopoietic stem cell transplantation (HSCT), and four out of the seven patients had a poor response to medical treatment prior to HSCT, resulting in complete remission of both diseases. CONCLUSION: Patients with intestinal BD-MDS frequently have refractory diseases with high mortalities. HSCT can be an effective treatment modality for medically refractory patients with intestinal BD-MDS.

A novel genotype-phenotype between persistent-cloaca-related VACTERL and mutations of 8p23 and 12q23.1.

The mechanism underlying anorectal malformations (ARMs)-related VACTERL (vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, and renal and limb abnormalities) remains unclear. Copy number variation (CNV) contributed to VACTERL pathogenicity. Here, we report a novel CNV in 8p23 and 12q23.1 identified in a case of ARMs-related VACTERL association. This 12-year-old girl presented a cloaca (urethra, vagina, and rectum opening together and sharing a single tube length), an isolated kidney, and a perpetuation of the left superior vena cava at birth. Her intelligence, growth, and development were slightly lower than those of normal children of the same age. Array comparative genomic hybridization revealed a 9.6-Mb deletion in 8p23.1-23.3 and a 0.52-Mb duplication in 12q23.1 in her genome. Furthermore, we reviewed the cases involving CNVs in patients with VACTERL, 8p23 deletion, and 12q23.1 duplication, and our case was the first displaying ARMs-related VACTERL association with CNV in 8p23 and 12q23.1. These findings enriched our understanding between VACTERL association and the mutations of 8p23 deletion and 12q23.1 duplication. IMPACT: This is a novel case of a Chinese girl with anorectal malformations (ARMs)-related VACTERL with an 8p23.1-23.3 deletion and 12q23.1 duplication. Cloaca malformation is presented with novel copy number variation in 8p23.1-23.3 deletion and 12q23.1 duplication.

[Prenatal diagnosis and genetic analysis of a special case with complex structural rearrangements of chromosome 8].

OBJECTIVE: To present on a prenatally diagnosed case with complex structural rearrangements of chromosome 8. METHODS: Chromosome karyotyping, chromosomal microarray analysis (CMA) and fluorescence in situ hybridization (FISH) were carried out for a fetus with increased nuchal thickness. RESULTS: The karyotype of the amniotic fluid sample showed extra materials on 8p. FISH revealed a centromeric signal at the terminal of 8p with absence of telomeric signal. CMA revealed partial deletion of 8p23.3 [(208049_2256732)×1], partial duplication of 8p23.3p23.2 [(2259519_3016818)×3], and partial duplication of 8q [8q11.1q12.2(45951900_60989083)×3]. CONCLUSION: The complex structural rearrangements of chromosome 8 in this case has differed from the commonly seen inv dup del(8p).

Cancer aneuploidies are shaped primarily by effects on tumour fitness.

Aneuploidies-whole-chromosome or whole-arm imbalances-are the most prevalent alteration in cancer genomes1,2. However, it is still debated whether their prevalence is due to selection or ease of generation as passenger events1,2. Here we developed a method, BISCUT, that identifies loci subject to fitness advantages or disadvantages by interrogating length distributions of telomere- or centromere-bounded copy-number events. These loci were significantly enriched for known cancer driver genes, including genes not detected through analysis of focal copy-number events, and were often lineage specific. BISCUT identified the helicase-encoding gene WRN as a haploinsufficient tumour-suppressor gene on chromosome 8p, which is supported by several lines of evidence. We also formally quantified the role of selection and mechanical biases in driving aneuploidy, finding that rates of arm-level copy-number alterations are most highly correlated with their effects on cellular fitness1,2. These results provide insight into the driving forces behind aneuploidy and its contribution to tumorigenesis.

A Case of AML1-ETO Positive Acute Myeloid Leukemia Morphologically Similar to Chronic Myelogenous Leukemia.

BACKGROUND: The goal was to study the role of the morphology, immunophenotype, karyotype and fusion gene expression in a patient with diagnosis of AML1-ETO positive acute myeloid leukemia. METHODS: A case of AML1-ETO positive acute myeloid leukemia morphologically similar to chronic myelogenous leukemia was reported. The results of the morphology, immunophenotype, karyotype and fusion gene expression were analyzed by reviewing relevant literature. RESULTS: The patient was a young boy, at the age of 13, with clinical manifestations of intermittent fatigue and fever. Blood routine: White blood cell 142.6 x 109/L, Red blood cell 0.89 x 1012/L, Hemoglobin 41 g/L, Platelet 23 x 109/L, primitive cells account for 5%. Bone marrow smear: Granulocyte system hyperplasia is obvious, visible at each stage, primitive cells account for 17%, eosinophils, basophils, and phagocytic blood cells were observed. Flow cytometry showed myeloid primitive cell population was 4.14%, immature and mature granulocytes cell population was 85.22%, and eosinophil cell population was 0.61%. The results showed that the proportion of myeloid primitive cell was high, the expression of CD34 was enhanced, the expression of CD117 was partially absent, the expression of CD38 was weakened, the expression of CD19 was weak, and a few cells expressed CD56, and the phenotype was abnormal. The proportion of granulocyte series increased and the nucleus shifted to the left. The proportion of erythroid series was decreased, and the expression of CD71 was weakened. The results of fusion gene showed AML1-ETO positive. Karyotype analysis showed clonogenic abnormality t(8;21)(q22;q22). CONCLUSIONS: The peripheral blood and bone marrow images of patients with t(8;21)(q22;q22) AML1-ETO positive are the manifestations of chronic myelogenous leukemia, suggesting that cytogenetics and molecular genetics play an irreplaceable role in the diagnosis of acute myeloid leukemia, and the comprehensive diagnostic efficiency is significantly better than that of morphology.

Recurring germline mosaicism in a family due to reversion of an inherited derivative chromosome 8 from an 8;21 translocation with interstitial telomeric sequences.

BACKGROUND: Mosaicism for chromosomal structural abnormalities, other than marker or ring chromosomes, is rarely inherited. METHODS: We performed cytogenetics studies and breakpoint analyses on a family with transmission of mosaicism for a derivative chromosome 8 (der(8)), resulting from an unbalanced translocation between the long arms of chromosomes 8 and 21 over three generations. RESULTS: The proband and his maternal half-sister had mosaicism for a der(8) cell line leading to trisomy of the distal 21q, and both had Down syndrome phenotypic features. Mosaicism for a cell line with the der(8) and a normal cell line was also detected in a maternal half-cousin. The der(8) was inherited from the maternal grandmother who had four abnormal cell lines containing the der(8), in addition to a normal cell line. One maternal half-aunt had the der(8) and an isodicentric chromosome 21 (idic(21)). Sequencing studies revealed microhomologies at the junctures of the der(8) and idic(21) in the half-aunt, suggesting a replicative mechanism in the rearrangement formation. Furthermore, interstitial telomeric sequences (ITS) were identified in the juncture between chromosomes 8 and 21 in the der(8). CONCLUSION: Mosaicism in the proband, his half-sister and half-cousin resulting from loss of chromosome 21 material from the der(8) appears to be a postzygotic event due to the genomic instability of ITS and associated with selective growth advantage of normal cells. The reversion of the inherited der(8) to a normal chromosome 8 in this family resembles revertant mosaicism of point mutations. We propose that ITS could mediate recurring revertant mosaicism for some constitutional chromosomal structural abnormalities.

Prenatal diagnosis and genetic analysis of a special case with complex structural rearrangements of chromosome 8 / 中华医学遗传学杂志

OBJECTIVE@#To present on a prenatally diagnosed case with complex structural rearrangements of chromosome 8.@*METHODS@#Chromosome karyotyping, chromosomal microarray analysis (CMA) and fluorescence in situ hybridization (FISH) were carried out for a fetus with increased nuchal thickness.@*RESULTS@#The karyotype of the amniotic fluid sample showed extra materials on 8p. FISH revealed a centromeric signal at the terminal of 8p with absence of telomeric signal. CMA revealed partial deletion of 8p23.3 [(208049_2256732)×1], partial duplication of 8p23.3p23.2 [(2259519_3016818)×3], and partial duplication of 8q [8q11.1q12.2(45951900_60989083)×3].@*CONCLUSION@#The complex structural rearrangements of chromosome 8 in this case has differed from the commonly seen inv dup del(8p).

[Clinical and genetic analysis of a child with mosaic chromosome 8 trisomy syndrome].

OBJECTIVE: To explore the genetic etiology of a child featuring recurrent oral ulcer. METHODS: Clinical data of the child was collected. Whole exome sequencing was carried out for her. Candidate variant was verified by low-coverage massive parallel copy number variation sequencing (CNV-seq) of the family trio. RESULTS: The child, a 6-year-old girl, has featured recurrent fever and ulcers of the oral mucosa, vulvar and perianal regions. No pathogenic variant was found by whole exome sequencing. However, analysis of chromosome copy number variation using the whole exome sequencing data has revealed mosaicism of trisomy 8. CNV-seq assay has verified the variant in the child, with the percentage of mosaicism being 73%. No abnormality was found in neither of her parents. CONCLUSION: A case of mosaicism trisomy 8 with recurrent oral ulcer as the first symptom was diagnosed, which has enriched the phenotypic data of trisomy 8 syndrome.

A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation.

Establishing causal links between inherited polymorphisms and cancer risk is challenging. Here, we focus on the single-nucleotide polymorphism rs55705857, which confers a sixfold greater risk of isocitrate dehydrogenase (IDH)-mutant low-grade glioma (LGG). We reveal that rs55705857 itself is the causal variant and is associated with molecular pathways that drive LGG. Mechanistically, we show that rs55705857 resides within a brain-specific enhancer, where the risk allele disrupts OCT2/4 binding, allowing increased interaction with the Myc promoter and increased Myc expression. Mutating the orthologous mouse rs55705857 locus accelerated tumor development in an Idh1R132H-driven LGG mouse model from 472 to 172 days and increased penetrance from 30% to 75%. Our work reveals mechanisms of the heritable predisposition to lethal glioma in ~40% of LGG patients.

[A favorable clinical course of acute myeloid leukemia with t (6;21;8)(p23;q22;q22)].

Variants of the t (8;21) (q22;q22) involving chromosome 8, 21, and other chromosomes account for about 3% of all t (8;21) (q22;q22) in patients with acute myeloid leukemia (AML). However, the prognosis of AML with variant t (8;21) remains unknown due to the scarcity of reported cases. Herein we report a case of AML with t (6;21;8) (p23;q22;q22). Fluorescence in situ hybridization confirmed a RUNX1-RUNX1T1 fusion signal on the derivative chromosome 8. This is the first report on a variant of t (8;21) involving the breakpoint 6p23. After induction chemotherapy, our patient achieved complete remission and has been stable for four years.

UBC9 inhibits myeloid differentiation in collaboration with AML1-MTG8.

The chimeric oncogene AML1-MTG8 (RUNX1-RUNX1T1) is generated in t(8;21) acute myeloid leukemia (AML). Here, we report a novel interaction of MTG8/RUNX1T1/ETO with UBC9/UBE2I. AML1-MTG8 protein also interacted with UBC9, suggesting a role in leukemogenesis. Overexpression of UBC9 in Kasumi-1 attenuated myeloid differentiation induced by all-trans retinoic acid, G-CSF, and GM-CSF (AGGM), which was judged by suppression of CD11b. In addition, the UBC9 inhibitor 2-D08 accelerated myeloid differentiation induced by AGGM in two t(8;21) AML cell lines, Kasumi-1 and SKNO-1. These data suggest that UBC9 may play a role in leukemogenesis in t(8;21) AML by working with AML1-MTG8 to suppress myeloid differentiation. Therefore, UBC9 may be a good target for new differentiation therapy against t(8;21) AML.

Association between genetic variations at 8q24 and prostate cancer risk in Mexican Men.

BACKGROUND: Variants of 8q24 locus have been associated with prostate cancer (PCa) susceptibility. This study aims to analyze the genetic basis of PCa susceptibility in Mexican men by analyzing SNPs in the 8q24 locus for the first time. METHODS: A case-control study was performed in 875 men recruited from the Mexican Social Security Institute, 326 patients with PCa, and 549 non-PCa patients (88 with benign prostatic hyperplasia BPH and 461 healthy controls). The 8q24 locus SNPs: rs16901979, rs16983267, rs1447295, and rs7837328 were genotyped by allelic discrimination assays using TaqMan probes. Statistical analysis was performed using Epi Info statistical 7.0 and SNPstats softwares. RESULTS: All genotype frequencies were in Hardy-Weinberg Equilibrium. No differences were observed in genotype distribution between PCa and non-PCa patients for rs6983267. Under different inheritance models, the rs16901979, rs1447295, and rs7837328 SNPs were associated with PCa (OR = 2.8, 1.8, and 1.72, respectively; Pc < 0.001) when comparing PCa patients against controls. This association remains between PCa and BPH patients under different models (OR = 8.5, 2.2, and 1.9, respectively; Pc < 0.001). There were no significant differences in allele and genotype distribution among BPH patients and controls. The combined effect of the alleles CGAA for the SNPs rs16901979, rs6983267, rs1447295, and rs7837328 showed significant differences between PCa patients and controls (OR = 2.9, 95% CI = 1.48-5.83, Pc = 0.008). Four 8q24 variants were not associated with D'Amico score, age at diagnosis, and bone metastases. CONCLUSIONS: Our study provides the first confirmation that variants rs16901979, rs1447295, and 7837328 at 8q24 locus are associated with PCa susceptibility in Mexican men.

Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24.

BACKGROUND: We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ. MATERIALS AND METHODS: Genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC. RESULTS: CF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings. CONCLUSION: We identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.

SH2D4A downregulation due to loss of chromosome 8p is associated with poor prognosis and low T cell infiltration in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) develops through chromosomal instability (CIN) or microsatellite instability (MSI) due to deficient mismatch-repair (dMMR). We aimed to characterise novel cancer-associated genes that are downregulated upon malignant transformation in microsatellite stable (MSS) CRCs, which typically exhibit CIN with proficient mismatch-repair (pMMR). METHODS: Comprehensive screening was conducted on adenomas, MSI/MSS CRCs and cell lines, followed by copy number analysis, and their genetic and prognostic relevance was confirmed in microarray and RNA-seq cohorts (n = 3262, in total). Immunohistochemistry for SH2D4A was performed in 524 specimens of adenoma, carcinoma in situ and dMMR/pMMR CRC. The functional role of SH2D4A was investigated using CRC cell lines. RESULTS: A set of 11 genes, including SH2D4A, was downregulated during the adenoma-carcinoma sequence in MSS/CIN CRCs, mainly due to chromosome 8p deletions, and their negative prognostic impact was validated in independent cohorts. All adenomas were SH2D4A positive, but a subset of CRCs (5.3%) lacked SH2D4A immunohistochemical staining, correlating with poor prognosis and scarce T cell infiltration. SH2D4A depletion did not affect cell proliferation or IL-6-induced STAT3 phosphorylation. CONCLUSIONS: Our findings suggest that downregulation of multiple genes on chromosome 8p, including SH2D4A, cooperatively contribute to tumorigenesis, resulting in the immune cold tumour microenvironment and poor prognosis.

Chromosome 8 Polysomy Accounting for MYC Over-Expression in Angiosarcoma Arising as Somatic-Type Malignancy in Metastatic Teratoma. Case Report.

MYC over-expression by immunohistochemistry (IHC) is utilised in routine pathology practice as a surrogate marker for MYC amplification, which plays a key oncogenic role in post-irradiation and chronic lymphedema-associated angiosarcoma. We present the case of a 32-year old male, who presented with high-grade angiosarcoma arising in a background of metastatic testicular teratoma. IHC for MYC showed strong nuclear expression in the angiosarcoma cells prompting the consideration of post-irradiation-induced angiosarcoma but our patient did not undergo radiotherapy. Fluorescence in-situ hybridization (FISH) excluded MYC amplification and instead showed Chromosome 8 polysomy, which accounted for the strong MYC IHC expression present, not previously described in the context of germ cell tumours. The occurrence of MYC over-expression due to polysomy illustrates a novel clinical scenario (angiosarcoma arising as somatic malignancy) where strong MYC IHC expression can be found in the absence of underlying amplification or prior radiotherapy exposure.

A new dual translocation of chromosome 14 in a pediatric Burkitt lymphoma/leukemia patient: t(8;14) and t(14;15).

Burkitt lymphoma/leukemia (BL/L) is an aggressive mature B-cell malignancy cytogenetically characterized by the translocation t(8;14)(q24;q32) or its variants, which determines the juxtaposition of the MYC oncogene to one of the three immunoglobulin loci. In addition to MYC translocations, different secondary genetic abnormalities have been described, some of them with prognostic significance. However, dual translocations of chromosome 14, except those involving chromosome 18, are very rare events in this pathology. Herein, we present the coexistence of translocations t(8;14) and t(14;15) in a pediatric BL/L patient. To our knowledge, this is the first report of a translocation t(14;15)(q32;q22) as a secondary alteration in a BL/L patient. The patient had multiple complications at diagnosis but he evolved favorably reaching complete remission. The description of new secondary alterations in this pathology as well as their impact on clinical evolution, add information to the biological characterization of BL, contributing to a higher accuracy in the diagnosis and/or prognosis of the disease.

Familial chylomicronemia syndrome due to a heterozygous deletion of the chromosome 8 treated with the apoCIII inhibitor volanesorsen: A case report.

RATIONALE: Familial chylomicronemia syndrome is a congenital, severe form of hypertriglyceridemia associated with increased risk of acute pancreatitis. Treatment options are limited. PATIENT CONCERNS: A 52-year-old woman was referred with recurrent pancreatitis and severe hypertriglyceridemia to our lipid clinic. DIAGNOSIS: Laboratory examination showed elevated serum triglyceride concentrations of 8090 mg/dL (90 mmol/L). Lipid electrophoresis showed a type V phenotype with positive chylomicrons. Genetic investigation revealed a novel heterozygous large deletion of the lipoprotein lipase gene on chromosome 8. A familial chylomicronemia syndrome was diagnosed. Other causes of hypertriglyceridemia were excluded. INTERVENTIONS: Fibrates and diet did not lower triglyceride levels. Therefore, treatment with the apolipoprotein CIII (apoCIII) inhibitor volanesorsen was initiated. OUTCOMES: After 3 months of treatment, a 90% reduction of triglycerides was observed. ApoCIII concentrations were reduced by 90% in the total and by 61% in the chylomicron-free serum. Treatment was well tolerated with only minor local reaction after the first application. The platelet count was monitored weekly and did not decrease <150 cells/µL. LESSONS: This case report shows that inhibition of apoCIII potently reduces serum triglycerides in patients with heterozygous monogenetic deletion of the lipoprotein lipase gene. Follow-up will show the effect on recurrent episodes of pancreatitis.

Divergent leukaemia subclones as cellular models for testing vulnerabilities associated with gains in chromosomes 7, 8 or 18.

Haematopoietic malignancies are frequently characterized by karyotypic abnormalities. The development of targeted drugs has been pioneered with compounds against gene products of fusion genes caused by chromosomal translocations. While polysomies are equally frequent as translocations, for many of them we are lacking therapeutic approaches aimed at synthetic lethality. Here, we report two new cell lines, named MBU-7 and MBU-8, that differ in complete trisomy of chromosome18, a partial trisomy of chromosome 7 and a tetrasomy of the p-arm of chromosome 8, but otherwise share the same mutational pattern and complex karyotype. Both cell lines are divergent clones of U-937 cells and have the morphology and immunoprofile of monocytic cells. The distinct karyotypic differences between MBU-7 and MBU-8 are associated with a difference in the specific response to nucleoside analogues. Taken together, we propose the MBU-7 and MBU-8 cell lines described here as suitable in vitro models for screening and testing vulnerabilities that are associated with the disease-relevant polysomies of chromosome 7, 8 and 18.