Chromosomal Region 22q11 Research Articles

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.

Partial correlation network analysis identifies coordinated gene expression within a regional cluster of COPD genome-wide association signals.

Chronic obstructive pulmonary disease (COPD) is a complex disease influenced by well-established environmental exposures (most notably, cigarette smoking) and incompletely defined genetic factors. The chromosome 4q region harbors multiple genetic risk loci for COPD, including signals near HHIP, FAM13A, GSTCD, TET2, and BTC. Leveraging RNA-Seq data from lung tissue in COPD cases and controls, we estimated the co-expression network for genes in the 4q region bounded by HHIP and BTC (~70MB), through partial correlations informed by protein-protein interactions. We identified several co-expressed gene pairs based on partial correlations, including NPNT-HHIP, BTC-NPNT and FAM13A-TET2, which were replicated in independent lung tissue cohorts. Upon clustering the co-expression network, we observed that four genes previously associated to COPD: BTC, HHIP, NPNT and PPM1K appeared in the same network community. Finally, we discovered a sub-network of genes differentially co-expressed between COPD vs controls (including FAM13A, PPA2, PPM1K and TET2). Many of these genes were previously implicated in cell-based knock-out experiments, including the knocking out of SPP1 which belongs to the same genomic region and could be a potential local key regulatory gene. These analyses identify chromosome 4q as a region enriched for COPD genetic susceptibility and differential co-expression.

Pitt Hopkins syndrome – TCF4 gene deletion causing severe psychomotor delay

Pitt-Hopkins syndrome (PTHS) is a rare genetic disorder due to haploinsufficiency of TCF4 and is clinically characterized by developmental delay, intellectual disability (ID), autism spectrum disorders, typical facial gestalt, seizures, high myopia and hyperventilation-apneic spells. Approximately in three-fourth cases of PTHS, a de novo pathogenic variant in TCF4 is identified. In other instances, deletion of the chromosome region 18q21.2 in which encompasses TCF4 is responsible and only chromosomal microarray (CMA) can reveal the microdeletion. This report describes the case of a 10 year-old girl with PTHS phenotype caused by a chromosome 18q21.2q22.1 deletion that included the TCF4 gene. The patient had severe developmental and cognitive delay, autistic spectrum disorder, motor difficulties, and behavioral issues, all of which are typical with PTHS. Understanding the phenotypic variation is critical for accurate diagnosis in this syndrome, since deletions in TCF4 may be missed if exome sequencing is sought instead of chromosomal microarray analysis (CMA).

FADD amplification is associated with CD8+ T-cell exclusion and malignant progression in HNSCC.

This study aimed to clarify the relationship between FADD amplification and overexpression and the tumor immune microenvironment. Immunohistochemical staining and bioanalysis were used to analyze the association between FADD expression in tumor cells and cells in tumor microenvironment. RNA-seq analysis was used to detect the differences in gene expression upon FADD overexpression. Flow cytometry and multicolor immunofluorescence staining (mIHC) were used to detect the differences in CD8+ T-cell infiltration in FADD-overexpressed cells or tumor tissues. Overexpression of FADD significantly promoted tumor growth. Cells with high FADD expression presented high expression of CD276 and FGFBP1 and low expression of proinflammatory factors (such as IFIT1-3 and CXCL8), which reduced the percentage of CD8+ T cells and created a "cold tumor" immune microenvironment, thus promoting tumor progression. Invivo and invitro experiment confirmed that tumor tissues with excessive FADD expression exhibited CD8+ T-cell exclusion in the microenvironment. Our preliminary investigation has discovered the association between FADD expression and the immunosuppressive microenvironment in HNSCC. Due to the high frequent amplification of the chromosomal region 11q13.3, where FADD is located, targeting FADD holds promise for improving the immune-inactive state of tumors, subsequently inhibiting HNSCC tumor progression.

Cases of Digeorge Syndrome

Abstract DiGeorge syndrome is a primary immunodeficiency caused by the abnormal growth of the third and fourth pharyngeal pouches throughout prenatal development. It is typified by a triad: hypocalcemia due to hypoparathyroidism, some heart defects, and thymic hypoplasia or aplasia. This syndrome is associated with a microdeletion in the chromosomal region 22q11.2. DiGeorge syndrome together with other dysfunctions like velo-cardio-facial syndrome and Takao syndrome have overlapping traits. The symptoms are hidden under the name CATCH22. It describes signs like a cardiac defect, abnormal facies, thyme hypoplasia, cleft palate, hypocalcemia, and chromosome 22q11.2 deletions. Its incidence is estimated to be approximately 1:3000 live births. The disorder is inherited in an autosomal dominant pattern or arises from de novo mutation. 22q11.2 microdeletion is associated with an increased risk of developing mental diseases, including schizophrenia. In the general population, 1-2% of people suffer from schizophrenia. In DiGeorge syndrome this ratio is much higher, around 25-30%. Nowadays, the fluorescence in situ hybridization (FISH) is a gold standard method for the diagnosis of microdeletion syndrome. Currently, there is no effective therapy to prevent the development of the disease.

CD70/CD27 Signaling Promotes Expansion of Clonal Plasma Cells in Multiple Myeloma and Is a Promising Therapeutic Target in Advanced Disease

Introduction: Multiple Myeloma (MM) is a hematological malignancy characterized by the clonal expansion of malignant plasma cells within the bone marrow (BM). In the last decade, substantial advances in the treatment of MM patients have been made resulting in improved progression-free and overall survival rates. However, to date, MM remains incurable. CD70 and CD27 belong to the TNF receptor family. CD70 is the only known ligand for its receptor CD27. Physiologically, the CD70/CD27 interaction is involved in the regulation of immune cell expansion. However, numerous solid and hematological cancer types overexpress CD70. Aside, CD70 and CD27 co-expression has been described on leukemic stem cells (LSC) in acute myeloid leukemia patients where an autonomous signaling activation drives LSC self-renewal and expansion. While CD70/CD27 signaling plays a key role in the differentiation process of B lymphocytes into plasma cells, only little is known about its impact on myelomagenesis and MM progression. In this study, we analyzed the role of CD70/CD27 signaling in the pathogenesis of MM and studied the possibility to target CD70 by monoclonal antibodies to treat the disease. Materials and Methods: We evaluated CD70 and CD27 gene expression levels and its correlations with overall survival (OS), MM progression and high-risk molecular alterations using different databases (CoMMpass IA15, GSE6477). CD70 and CD27 protein expression patterns were analyzed in a newly established MM tissue microarray (TMA) and a collection of matched BM samples from initial and advanced disease stages (in collaboration with the Institutes of Pathology in Bern, Basel and Tübingen). To assess the functional role of CD70/CD27 signaling on MM initiation and expansion, we generated CD70 knock-out MM cell lines and newly established patient-derived xenografts (PDX) using CRISPR/Cas9 genome editing. CD70-expressing MM cell lines or patient-derived myeloma cells were grown in NOD/SCID (NSG) mice. Moreover, different monoclonal antibodies (Abs) and Ab-derivates were tested including a CD70 blocking antibody (αCD70) and an antibody-dependent cell-mediated cytotoxicity (ADCC) optimized antibody (cusatuzumab, ArgenX) that activates FcγR-expressing effector cells to assess the therapeutic potential of targeting CD70 in MM. Results: High CD70 gene expression levels correlate with increased MKI67 gene expression and elevated lactate dehydrogenase serum levels indicating a more rapid proliferation of CD70-expressing myeloma cells. In addition, high CD70 expression in MM patients correlated with shorter OS. Longitudinal analyses of CD70 gene expression in the precursor stages monoclonal gammopathy of undetermined significance and smoldering myeloma as well as MM and relapsed MM stages showed highest CD70 gene expression levels in relapsed MM patients. Assessment of the molecular background further revealed increased frequencies of the prognostically unfavorable genomic translocations t(4;14) and t(14;16), as well as gain/amplification of the chromosomal region 1q21 (1q+) in CD70 high expressing MM patients. In line with our previous findings, a TMA analysis of over 200 MM core biopsies as well as a longitudinal analysis of matched biopsies from patients at initial diagnosis and MM relapse indicated that CD70 was overexpressed in advanced disease. Functionally, we found that CD70/CD27 signaling promotes plasma cell survival inducing the expansion of MM cell lines and primary malignant plasma cells. CD70 blockade (αCD70) or CD70 knock-out (CD70 KO) resulted in a significant inhibition or complete abrogation of growth of a CD70-expressing MM patient-derived xenograft (PDX) (EMM01 CD70+) compared to controls (Figure 1). Interestingly, in vivo limiting dilution assays revealed that CD70+CD27+ double-positive myeloma subpopulations showed significantly higher cancer stem cell frequencies compared to CD70 negative fractions suggesting that CD70 expression might be related to an immature or stem-cell like phenotype. The ADCC-optimized CD70 specific antibody custatuzumab efficiently eliminated CD70-expressing MM cells in the presence of PBMC-derived natural killer (NK) cells in vitro and in a PDX model in vivo. Conclusion: Our results indicate that CD70-expressing MM cells have a stem-cell like phenotype and propagate the disease. Targeting CD70 is a promising new therapy especially in advanced disease.

Chromosomal rearrangement in the 22q11.2 region: a critical locus for sociability and attentional skills.

Rearrangements of 22q11.2 region, most often deletions and duplications, are responsible for multiple congenital disorders. These rearrangements are involved in syndromes that share some phenotypic similarities. To date, 22q11.2 triplication remains very rare, with few cases described in the literature. Here, we report for the first time the clinical, neurocognitive, social cognition and psychiatric properties of a 6-year-old child with 22q11.2 triplication, in comparison with a patient with 22q11.2 duplication and 16 cases of patients with 22q11.2 deletion. Chromosomal region 22q11.2 seems to be a critical locus for sociability and attentional skills and rearrangements could be interpreted as a predisposing factor for the development of psychotic symptoms (22q11.2 deletion), a protective factor (22q11.2 duplication) or a tendency factor for hypersociability (22q11.2 triplication).

Hsa-miR-323a-3p functions as a tumor suppressor and targets STAT3 in neuroblastoma cells.

Studies conducted in the last decades have revealed a role for the non-coding microRNAs (miRNAs) in cancer development and progression. Several miRNAs within the chromosome region 14q32, a region commonly deleted in cancers, are associated with poor clinical outcome in the childhood cancer neuroblastoma. We have previously identified miR-323a-3p from this region to be downregulated in chemotherapy treated neuroblastoma cells compared to pre-treatment cells from the same patients. Furthermore, in neuroblastoma tumors, this miRNA is downregulated in advanced stage 4 disease compared to stage 1-2. In this study, we attempt to delineate the unknown functional roles of miR-323a-3p in neuroblastoma. Synthetic miRNA mimics were used to overexpress miR-323a-3p in neuroblastoma cell lines. To investigate the functional roles of miR-323a-3p, cell viability assay, flow cytometry, reverse transcription-quantitative polymerase chain reaction, luciferase reporter assay and western blot were conducted on the neuroblastoma cell lines Kelly, SH-SY5Y and SK-N-BE(2)-C. Ectopic expression of miR-323a-3p resulted in marked reduction of cell viability in Kelly, SH-SY5Y and SK-N-BE(2)-C by causing G1-cell cycle arrest in Kelly and SH-SY5Y and apoptosis in all the cell lines tested. Furthermore, mRNA and protein levels of signal transducer and activator of transcription 3 (STAT3) were reduced upon miR-323a-3p overexpression. A direct binding of the miR-323a-3p to the 3'UTR of STAT3 was experimentally validated by luciferase reporter assay, where miR-323a-3p reduced luminescent signal from full length STAT3 3'UTR luciferase reporter, but not from a reporter with mutation in the predicted seed sequence. miR-323a-3p inhibits growth of neuroblastoma cell lines through G1-cell cycle arrest and apoptosis, and the well-known oncogene STAT3 is a direct target of this miRNA.

DNA-methylation and genomic copy number in primary tumors and corresponding lymph node metastases in prostate cancer from patients with low and high Gleason score

In prostate cancer, the indication to irradiate the pelvic lymphatic pathways in clinical node-negative patients is solely based on clinical nomograms. To define biological risk patterns of lymphatic spread, we studied DNA-methylation and genomic copy number in primary tumors and corresponding lymph nodes metastases. DNA-methylation and genomic copy number profiles of primary tumors (PT) and paired synchronous lymph node metastases (LN) from Gleason Score (GS)-6/7a (n=20 LN-positive, n=20 LN-negative) and GS-9/10 patients (LN-positive n=20) after prostatectomy and lymphonodectomy were analyzed. GS-6/7a pN0 PTs and GS-6/7a pN1 PTs differed in histone H3K27me3/H3K9me3 mediated methylation. PTs compared to LNs, in both, GS-6/7a pN1 and GS-9/10 pN1 patients showed large differences in DNA-methylation mediated by histones H3K4me1/2, in addition to copy number changes of chromosomal regions 11q13.1, 14q11.2 and 15q26.1. Between GS-6/7a pN1 and GS-9/10 pN1 patients, methylation levels differed more when comparing LNs than PTs. 16q21-22.1 was specifically lost in GS-9/10 pN0 PTs. Immune system-related pathways characterized the differences between PTs and LNs in both GS-6/7a pN1 and GS-9/10 pN1 patients. Comparing PTs and LKs between GS-6/7a pN1 and GS-9/10 pN1 patients revealed altered transmembrane and G-protein-coupled receptor signaling. Our data suggest that progression of prostate cancer, including lymphatic spread, is associated with histone-mediated DNA-methylation and we hypothesize a methylation signature predicting lymphatic spread in GS-6/7a patients from primary tumors. Lymphatic spread in GS-6/7a patients, flanked by DNA-methylation and CNA alterations, appears to be more complex than in GS-9/10 patients, in whom the primary tumors already appear to bear lymph node metastasis-enabling alterations.

GAB1::ABL1 fusions define a distinctive soft tissue neoplasm, with variable perineurial differentiation, and a predilection for children and young adults.

Although well known as a fusion partner in hematological malignancies, fusion genes involving the ABL proto-oncogene 1 (ABL1), mapping to chromosomal region 9q34.12, have only been anecdotally reported in five soft tissue tumors. These neoplasms have been variously reported as perineurioma, angiofibroma, and solitary fibrous tumor, and all have harbored a GAB1::ABL1 gene fusion; however, the nosology and clinicopathological characteristics of soft tissue tumors carrying this rare fusion have not been delineated. We herein describe eight tumors containing the GAB1::ABL1 fusion and review previously reported cases in a series to define their morphological spectrum, address immunohistochemical evidence for a line of differentiation, with special reference to the presence or absence of a perineurial immunophenotype, and gather insight into their behavior. The patients included four females and four males, aged 13-37 years (median, 24 years). Two cases each originated in the shoulder area, trunk, hands, and lower extremities, with a size range of 1.5-8cm (median, 3.4cm). Four tumors were deep and four superficial. All tumors were morphologically similar, being composed of bland fibroblast-like spindle to ovoid cells diffusely arranged in a paucivascular fibrous to fibromyxoid stroma with variable resemblance to soft tissue perineurioma. Mitotic activity was generally low (0-8 mitoses in 10 high-power fields [HPFs]; median, 1). All lesions had at least focally infiltrative margins, but they otherwise lacked pleomorphism and necrosis. Immunohistochemistry showed focal reactivity for CD34 (5/7), epithelial membrane antigen (EMA) (3/8), claudin1 (2/3), GLUT1 (4/6), and S100 (2/7); other markers, including MUC4 (0/7), desmin (0/9), and smooth muscle actin(SMA) (0/4), were negative. RNA sequencing revealed a GAB1::ABL1 fusion in all cases with exon 6 of GAB1 fused to exon 2 of ABL1. Treatments included various forms of surgical intervention in seven cases; one tumor was biopsied only. Limited follow-up was available for five patients. One tumor regrew rapidly within 1 month to 1.5cm after an initial marginal excision and was re-excised with close margins. Four patients were disease-free at 1, 3, 14, and 25 months of follow-up. Metastases have not, to date, been observed. This series characterizes "GAB1::ABL1 fusion-positive spindle cell neoplasm" as a distinct entity, with overlapping features with soft tissue perineurioma and predilection for children and young adults.

Copy number variants suggest different molecular pathways for the pathogenesis of bladder exstrophy.

Bladder exstrophy is a rare congenital malformation leaving the urinary bladder open in the midline of the abdomen at birth. There is a clear genetic background with chromosome aberrations, but so far, no consistent findings apart from 22q11-duplications detected in about 2%-3% of all patients. Some genes are implicated like the LZTR1, ISL1, CELSR3, and the WNT3 genes, but most are not explained molecularly. We have performed chromosomal microarray analysis on a cohort of 140 persons born with bladder exstrophy to look for submicroscopic chromosomal deletions and duplications. Pathogenic or possibly pathogenic microdeletions or duplications were found in 16 patients (11.4%) and further 9 with unknown significance. Two findings were in regions linked to known syndromes, two findings involved the same gene (MCC), and all other findings were unique. A closer analysis suggests a few gene networks that are involved in the pathogenesis of bladder exstrophy; the WNT-signaling pathway, the chromosome 22q11 region, the RIT2 and POU families, and involvement of the Golgi apparatus. Bladder exstrophy is a rare malformation and is reported to be associated with several chromosome aberrations. Our data suggest involvement of some specific molecular pathways.

Association studies between chromosomal regions 1q21.3, 5q21.3, 14q21.2 and 17q21.31 and numbers of children in Poland

Number of children is an important human trait and studies have indicated associations with single-nucleotide polymorphisms (SNPs). Aim: to give further evidence for four associations using a large sample of Polish subjects. Data from the POPULOUS genetic database was provided from anonymous, healthy, unrelated, Polish volunteers of both sexes (N = 5760). SNPs (n = 173) studied: (a) 69 from the chromosome 17 H1/H2 inversion; (b) six from 1q21.3, 5q21.3 and 14q21.2; and (c) 98 random negative controls. Zero-inflated negative-binomial regression (z.i.) was performed (0–3 numbers of children per individual (NCI) set as non-events; adjustors: year of birth, sex). Significance level p = 0.05 with Bonferroni correction. Statistically-significant differences (with data from both sexes combined) were obtained from highly-linked inversion SNPs: representative rs12373123 gave means: homozygotes TT: 2.31 NCI (n = 1418); heterozygotes CT: 2.35 NCI (n = 554); homozygotes CC: 2.44 NCI (n = 43) (genotype p = 0.01; TTvs.CC p = 0.004; CTvs.CC p = 0.009). (Male data alone gave similar results.) Recessive modeling indicated that H2-homozygotes had 0.118 more children than H1-homozygotes + heterozygotes (z.i.-count estimates ± standard errors: CT, − 0.508 ± 0.194; TT, − 0.557 ± 0.191). The non-over-dispersed count model detected no interactions: of importance there was no significant interaction with age. No positive results were obtained from negative-control SNPs or (b). Conclusions: association between the H1/H2 inversion and numbers of children (previously reported in Iceland) has been confirmed, albeit using a different statistical model. One limitation is the small amount of data, despite initially ~ 6000 subjects. Causal studies require further investigation.

Identification of a Novel Mutation in the Cathepsin K (CTSK) Gene in Iranian Patients with Pycnodysostosis

Background: Pycnodysostosis is a rare autosomal recessive skeletal dysplasia, which is characterized by various skeletal malformations and distinctive facial characteristics. The disorder is caused by mutations in CTSK gene at chromosomal region 1q21, which encodes a lysosomal cysteine protease, cathepsin K.&#x0D; Purpose: To describe the clinical, radiological, and molecular findings in a consanguineous Iranian family with 2 affected individuals demonstrating pycnodysostosis.&#x0D; Methods: Whole exome sequencing (WES) was utilized to detect disease-causing variants. To prove the impact of the identified variants, in silico analysis using SIFT and PROVEAN web servers were carried out. The effects of the novel mutation on the protein structure was evaluated by Chimera software using normal and mutated structures derived from SWISS model web server.&#x0D; Results: We identified the novel homozygous mutation, c.830C&gt;A, in exon 7 of the CTSK gene. This missense mutation leads to the substitution of the amino acid alanine at position 277 by glutamic acid (p.A277E) in cathepsin K protease. Sanger sequencing analysis confirmed this mutation in the affected individuals and revealed that the parents were heterozygous for this gene mutation. Bioinformatics databases and the variant’s protein structure proved the deleterious effect of this novel mutation on the enzymatic activity of cathepsin K protease.

Genetics of otosclerosis: finally catching up with other complex traits?

Otosclerosis is a relatively common cause of hearing impairment, characterized by abnormal bone remodeling of the middle and inner ear. In about 50-60% of the patients, the disease is present in a familial form. In most of these families, otosclerosis seems to be caused by a small number of genetic factors (oligogenic) while only in a small number of families the disease seems to be truly monogenic. In the remaining patients a complex genetic form of otosclerosis is present. Several studies have aimed to identify the genetic factors underlying otosclerosis, which has led to the identification of eight published loci for monogenic otosclerosis, as well as several genes and one chromosomal region (11q13.1) with a clear association with otosclerosis. Implementation of next-generation sequencing (NGS) in otosclerosis research has led to the identification of pathogenic variants in MEPE, ACAN and SERPINF1, although the pathogenic role of the latter is under debate. In addition, a recent GWAS can be considered a breakthrough for otosclerosis as it identified several strong associations with otosclerosis and suggested new potential candidate genes. These recent findings are important for unraveling the genetic architecture of otosclerosis. More future studies will help to understand the complete pathogenesis of the disease.

Molecular characterization of amplification of 11q13 region in patients with operable esophageal squamous cell carcinoma.

e16053 Background: The efficacy of programmed cell death 1 (PD-1) targeted therapy had showed effective treatment in patients (pts) with locally advanced or metastatic esophageal squamous cell carcinoma (ESCC). Meanwhile some studies have shown that PD-1 as neoadjuvant therapy showed promising anti-tumor activity with acceptable tolerance for locally advanced ESCC. Previous studies have shown genomic amplification of 11q13 region may serve as a negative predictive marker for ESCC patients receiving anti-PD-1 based immunotherapy. However, related molecular characterization study of amplification of 11q13 region in patients with operable ESCC is rare reported. Methods: The study recruited pts with operable ESCC whose tissues were send to perform target-capture deep sequencing with the pan-cancer panel and immunohistochemistry of PD-L1 with 22C3 assay. Pair-wise comparison of TMB and PD-L1 was analyzed in pts with 11q13 amplification and pts without 11q13 amplification. Results: 58 operable ESCC pts (cT1-T3N0) were enrolled, median age at diagnosis was 63 years(yrs) (45-73). Copy number analysis identified 30 out of 58 (52%) patients with amplifications of four genes located in chromosome 11q13 region, including CCND1(Cyclin D1) and fibroblast growth factor family members ( FGF3/4/19). Among the 11q13 amplification cohort, four genes amplified together were occurred in 27(90%) pts, 1(3%) patient had amplification of three genes ( CCND1 and FGF3/4), 2 (7%) pts had amplification of one gene that are FGF3 and CCND1 respectively. The prevalence rate of 11q13 amplification was not significantly different between older age (≥ 63 yrs) and young age ( &lt; 63 yrs). Among 58 pts with TMB evaluated, median TMB was 5.76 muts/Mb (range: 0 - 20.16 muts/Mb). The prevalence of TMB-H and microsatellite instability was 12% (7/58) and 0% (0/58). TMB and expression of PD-L1 showed no significantly difference between 11q13 amplification cohort and 11q13 wild cohort. The most frequently mutated genes were TP53 (96.7%, 29/30 pts), NOTCH1 (33.3%, 10/30 pts), CDKN2A (23.3%, 7/30 pts) and MLL2 (20%, 6/30 pts) in 11q13 amplification cohort, while TP53 (89.3%, 25/28), NOTCH1 (39.3%,11/28), MLL2 (28.6%, 8/28), FAT1 (25%,7/28) were the most frequently mutated genes in 11q13 wild cohort. Conclusions: Amplification of 11q13 region was a high prevalence event in operable ESCC and there was show no age bias. Molecular characterization of amplification of 11q13 region in patients receiving PD-1 as neoadjuvant therapy before surgery may be meaningful.

Molecular Dissection of the Neurodevelopmental Risk Locus 22q11.2 in Zebrafish Reveals Multiple Genes With Effect on Behavior

As schizophrenia is highly heritable, genetic risk factors remain an attractive avenue for furthering our understanding of its pathophysiology. Deletion of a region of chromosome 22q11.2 encompassing 45 protein-coding genes is the greatest known genetic risk factor for schizophrenia. However, the molecular mechanisms underlying this substantial risk are incompletely understood and only a fraction of the genes within the region have been tested for behavioral phenotypes in rodents.

Identification of protein/mRNA network involving the PSORS1 locus gene CCHCR1 and the PSORS4 locus gene HAX1

CCHCR1 (Coiled-Coil alpha-Helical Rod 1), maps to chromosomal region 6p21.3, within the major psoriasis susceptibility locus PSORS1. CCHCR1 itself is a plausible psoriasis candidate gene, however its role in psoriasis pathogenesis remains unclear. We previously demonstrated that CCHCR1 protein acts as a cytoplasmic docking site for RNA polymerase II core subunit 3 (RPB3) in cycling cells, suggesting a role for CCHCR1 in vesicular trafficking between cellular compartments.Here, we report a novel interaction between CCHCR1 and the RNA binding protein HAX1. HAX1 maps to chromosomal region 1q21.3 within the PSORS4 locus and is over-expressed in psoriasis. Both CCHCR1 and HAX1 share subcellular co-localization with mitochondria, nuclei and cytoplasmic vesicles as P-bodies. By a series of ribonucleoprotein immunoprecipitation (RIP) assays, we isolated a pool of mRNAs complexed with HAX1 and/or CCHCR1 proteins. Among the mRNAs complexed with both CCHCR1 and HAX1 proteins, there are Vimentin mRNA, previously described to be bound by HAX1, and CAMP/LL37 mRNA, whose gene product is over-expressed in psoriasis.

BRD4 modulates vulnerability of triple-negative breast cancer to targeting of integrin-dependent signaling pathways

PurposeStemming from a myriad of genetic and epigenetic alterations, triple-negative breast cancer (TNBC) is tied to poor clinical outcomes and aspires for individualized therapies. Here we investigated the therapeutic potential of co-inhibiting integrin-dependent signaling pathway and BRD4, a transcriptional and epigenetic mediator, for TNBC.MethodsTwo independent patient cohorts were subjected to bioinformatic and IHC examination for clinical association of candidate cancer drivers. The efficacy and biological bases for co-targeting these drivers were interrogated using cancer cell lines, a protein kinase array, chemical inhibitors, RNAi/CRISPR/Cas9 approaches, and a 4 T1-Balb/c xenograft model.ResultsWe found that amplification of the chromosome 8q24 region occurred in nearly 20% of TNBC tumors, and that it coincided with co-upregulation or amplification of c-Myc and FAK, a key effector of integrin-dependent signaling. This co-upregulation at the mRNA or protein level correlated with a poor patient survival (p < 0.0109 or p < 0.0402, respectively). Furthermore, we found that 14 TNBC cell lines exhibited high vulnerabilities to the combination of JQ1 and VS-6063, potent pharmacological antagonists of the BRD4/c-Myc and integrin/FAK-dependent pathways, respectively. We also observed a cooperative inhibitory effect of JQ1 and VS-6063 on tumor growth and infiltration of Ly6G+ myeloid-derived suppressor cells in vivo. Finally, we found that JQ1 and VS-6063 cooperatively induced apoptotic cell death by altering XIAP, Bcl2/Bcl-xl and Bim levels, impairing c-Src/p130Cas-, PI3K/Akt- and RelA-associated signaling, and were linked to EMT-inducing transcription factor Snail- and Slug-dependent regulation.ConclusionBased on our results, we conclude that the BRD4/c-Myc- and integrin/FAK-dependent pathways act in concert to promote breast cancer cell survival and poor clinical outcomes. As such, they represent promising targets for a synthetic lethal-type of therapy against TNBC.

Update on the genetic architecture of schizophrenia

Abstract A long-established hypothesis is that schizophrenia has a strong genetic component. In the early 1990s, the first genetic variant that substantially increases risk for psychosis was identified. Since this initial reporting of deletions in the chromosomal region 22q11.2, nearly two decades passed until substantial insights into schizophrenia’s genetic architecture were gained. Schizophrenia is a polygenic disorder and genetic risk is conferred by both common and rare alleles distributed across the genome. A small number of rare, deleterious copy number variants (CNVs) are associated with moderate to substantial increases in individual risk to schizophrenia. These deletions and duplications are also associated with a range of neurodevelopmental disorders. The diagnostic investigation of CNVs in patients with schizophrenia is likely to represent one of the first examples of genetic testing in clinical psychiatry. The prerequisites for this are currently being defined.

Abstract IA49: Advancing cancer disparities research through data integration: The Multiethnic Cohort Study

Abstract The Multiethnic Cohort Study was established in 1993-1996 with the goal of examining lifestyle risk factors, especially diet and nutrition, as well as genetic susceptibility in relation to the development of cancer. The cohort comprises more than 215,000 adult men and women from five major U.S. racial/ethnic groups—African American, Japanese American, Latino, Native Hawaiian, and white—residing in Hawaii and California. It is one of the largest racially/ethnically diverse cohorts of its kind. Over the past 25 years, a wealth of questionnaire information has been surveyed from MEC participants and biologic specimens, including blood and urine samples, have been collected from more than 70,000 participants. Incident cancer cases in the MEC are identified annually through linkage with the NCI SEER Hawaii and California cancer registries. The cohort has been linked to medical claim data (Medicare) and hospital discharge diagnoses (in CA), allowing the study of many non-cancer endpoints. This rich resource has led to numerous important findings on racial/ethnic differences in the risk of breast, colorectal, and prostate cancers in relation to diet and lifestyle factors. In addition, seminal findings have been achieved in discovering and characterizing genetic risk loci for cancer and identifying ancestry-specific risk regions such as the chromosome 8q24 region that contributes to the racial/ethnic disparities in prostate cancer. Recent advances in omics technologies have led to innovative studies within the MEC that examine the roles of the exposome, genome, methylome, metabolome, and gut microbiome in understanding ethnic differences in the relationships of smoking and obesity with cancer. Participation in consortia has allowed us to leverage the data available for non-whites in multiple other studies. Furthermore, development of geospatial resources and methodologies coupled with the extensive residential histories of MEC participants has enabled new studies of the neighborhood social and built environments, air pollutant exposures, and cancer. To gain better insight on the biologic, behavioral, and environmental influences of cancer disparities, data integration across multiple scientific domains, using a “cells-to-society” framework, serves as a powerful approach and provides an opportunity to consider the intersection of multilevel determinants of cancer risk and survival. This presentation will provide an overview of the range of data resources within the MEC, share key findings in cancer disparities research at the individual and neighborhood level, and discuss future directions for large data integrative studies of cancer in diverse populations. Citation Format: Iona Cheng, Scarlett Lin Gomez, Salma Shariff-Marco, Anna H. Wu, Sung-Shim Lani Park, Christopher A. Haiman, Lynne Wilkens, Loic Le Marchand. Advancing cancer disparities research through data integration: The Multiethnic Cohort Study [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr IA49.