7084 results for "canc*"

in 19.32 milliseconds.

• B cell receptor silencing reveals origin and dependencies of high-grade B cell lymphomas with MYC and BCL2 rearrangements

  High-grade B cell lymphomas with MYC and BCL2 rearrangements (HGBCL-DH-BCL2) represent highly aggressive Germinal center (GC) derived B cell malignancies with dismal prognosis and limited therapeutic options. In the present study, we investigated the expression of BCR complex components, including immunoglobulin (IG) heavy (H) and light (L) chains, and CD79A and CD79B signaling subunits in HGBCL-DH-BCL2, scoring 65% of cases with undetectable IGH immunoreactivity (IGHUND). Transcriptomics (bulk RNA-seq) and genetic (whole exome/genome sequencing) analyses indicated that IGHUND and IGH+ HGBCL-DH-BCL2 lymphomas represent distinct biological entities. Specifically, IGHUND HGBCL-DH-BCL2 exhibit a GC DZ-like molecular program, and select subset-specific gene mutations pointing to distinct evolutionary trajectories respect to the IGH+ counterparts. IG profiling revealed that IGHUND HGBCL-DH-BCL2 preserved potentially productive, hypermutated IGH variable (V) gene rearrangements, indicating a selective advantage conferred to the malignant B cells by residual IGH molecules. Accordingly, disruption of the productively rearranged IGHG1 gene in BCRnull HGBCL-DH-BCL2 cell line model confirmed the dependency on IGH expression for optimal fitness. Using transcriptomics and in situ RNA-scope analysis, we reported that IGHUND HGBCL-DH-BCL2 originated from IG-class switched GC B cells, while IGH-expressing tumors were selected for continuous IGM expression. Moreover, while IGH+ HGBCL-DH-BCL2 favor IGM/IG-Kappa expression, IGHUND counterparts complete IG-Lambda light chain rearrangements. Notably, BCR silencing, caused by accelerated IGH turnover and reduced IGH expression, precedes HGBCL-DH-BCL2 onset, inducing RAG1/2-dependent IG light chain editing and eventually facilitating t(8;22)/IGL::MYC translocations. Finally, IGH silencing observed in HGBCL-DH-BCL2 cell models, which leads to intracellular retention/silencing of CD79B, results in reduced sensitivity to the CD79B-targeting antibody-drug conjugate Polatuzumab-vedotin. Collectively, HGBCL-DH-BCL2 originates from isotype-switched t(14;18)+ GC B cells that undergo IG light chain editing fuelling intra-clonal diversification, BCR silencing, and the acquisition of t(8;22) translocation, while preserving IGH dependency.

  Study EGAS50000001047

• Genomic determinants of response and resistance to inotuzumab in B-ALL

  Inotuzumab Ozogamicin (InO) is an antibody-drug conjugate which delivers calicheamicin to CD22-expressing cells. In a retrospective cohort of InO treated B-cell acute lymphoblastic leukemia (B-ALL) patients, we sought to understand the genomic determinants of response to InO. Acquired CD22 mutations were observed in 11% (3/27) of post-InO relapsed samples. CD22 mutation types were diverse (frameshift, nonsense, missense and stoploss) and we identified multiple mechanisms of mutation induced CD22 escape, including protein truncation, protein destabilization, and epitope alteration. Accelerated acquisition of mutations by error-prone DNA damage repair could drive CD22 mutation and escape. Acquired loss-of-function mutations in TP53, ATM and CDKN2A were observed, suggesting compromise of the G1/S DNA damage checkpoint as a mechanism of evading InO-induced apoptosis. In conclusion, genetic alterations modulating CD22 expression and DNA damage response influence InO efficacy. The diverse mechanisms of CD22 escape advocates for a refined approach for monitoring CD22-targeted therapy.

  Study EGAS50000000067

• Pyjacker identifies enhancer hijacking events in acute myeloid leukemia including MNX1 activation via deletion 7q

  Acute myeloid leukemia with complex karyotype (ckAML) is characterized by high genomic complexity, including frequent TP53 mutations and chromothripsis. We hypothesized that the numerous genomic rearrangements could reposition active enhancers near proto-oncogenes, leading to their aberrant expression. We developed pyjacker, a computational tool for the detection of enhancer hijacking events, and applied it to a cohort of 39 ckAML samples. Pyjacker identified motor neuron and pancreas homeobox 1 (MNX1), a gene aberrantly expressed in 1.4% of AML patients, often as a result of del(7)(q22q36) associated with hijacking of a CDK6 enhancer. MNX1-activated cases show significant co-occurrence with BCOR mutations and a gene signature shared with t(7;12)(q36;p13) pediatric AML. We demonstrated that MNX1 is a dependency gene, as its knockdown in a xenograft model reduces leukemia cell fitness. In conclusion, enhancer hijacking is a frequent mechanism for oncogene activation in AML.

  Study EGAS50000000743

• DHODH is a synthetic-lethal vulnerability in BCOR-deficient acute myeloid leukemia

  Acute Myeloid Leukemia (AML) remains challenging to treat, especially in cases with mutations in the BCL-6 co- repressor (BCOR), which are associated with poor prognosis and chemo-resistance. In this study, we reveal a synthetic lethal interaction between BCOR and dihydroorotate dehydrogenase (DHODH). We demonstrate that BCOR-deficient cells have a heightened sensitivity to DHODH inhibitors such as brequinar and leflunomide, that are already in clinical use. We confirm that DHODH inhibition selectively induces cell death in BCOR-mutant cells in multiple cellular models, in malignant and non-malignant cells, through chemical and genetic manipulation. Interestingly, we find that the dependency on DHODH does not stem from its role in de novo pyrimidine biosynthesis disruption. Rather, DHODH’s role in the electron transport chain, essential for mitigating reactive oxygen species, may be the physiological vulnerability that pushes BCOR-mutant cells toward cell death when DHODH is inhibited. DHODH inhibitors could be repurposed as targeted therapies for BCOR-mutant tumors, offering a promising strategy for precision medicine in AML and other cancers.

  Study EGAS50000001108

• Somatic Mutation in Normal Bladder Study

  Adult human somatic tissues are landscapes of mutant clones, but little is known about how these landscapes are shaped by known cancer risk factors. The goal of this study was to determine how the main bladder cancer risk factors (sex and smoking) change the mutational landscape of the normal urothelium. We collected normal urothelium from 45 donors at autopsy by brushing ~2cm² of the surface epithelium in the upper part (dome) and lower part (trigone) of the bladder (79 samples total). To identify mutations with high sensitivity we employed ultradeep (~5000x) DNA error-correcting duplex-sequencing on a panel of 15 protein coding genes and the TERT promoter, previously described to be under positive selection in normal urothelium or relevant to bladder cancer. We identified thousands of clonal driver mutations, which demonstrate pervasive positive selection in the normal urothelium. Males showed a significantly higher number of driver truncating mutations in RBM10, CDKN1A and ARID1A, despite similar rates of non-coding mutations, indicating stronger positive selection and clonal expansion in the male urothelium. We also discovered clonal expansions driven by activating TERT promoter mutations in the normal bladder, which were strongly associated with age and smoking. These results demonstrate that sex and smoking shape the clonal landscape of the normal bladder and indicate that the high mutational content of normal tissues might be leveraged to study the effect of mutations in vivo (i.e. natural saturation mutagenesis). We will deposit in dbGaP de-identified relevant clinical information from the 45 donors and the fastq files derived from duplex sequencing of the 79 samples in the study. We will also deposit fastq files derived from duplex sequencing of 3 control cord blood samples.

  Study phs004105

• Epigenetic Control of Topoisomerase 1 by MacroH2A1.1

  DNA transactions introduce torsional constraints that pose an inherent risk to genome integrity. While topoisomerase 1 (TOP1) activity is essential for removing DNA supercoiling, aberrant stabilization of TOP1:DNA cleavage complexes (TOP1ccs) can result in cytotoxic single-stranded DNA lesions (SSLs). What protects the genome from aberrant TOP1 activity remains unknown. Using a combination of CUT&RUN and TOP1 Covalent Adduct Detection (CAD) Seq in MDA-MB-231 breast cancer cells (American Type Culture Collection, ATCC), we identified chromatin context as an essential means to ensure TOP1cc resolution at TOP1 hot spots. Through its ability to bind poly(ADP-ribose) (PAR), a protein modification required for TOP1cc repair, the histone variant macroH2A1.1 establishes a TOP1-permissive chromatin environment, while the alternatively spliced macroH2A1.2 isoform is unable to bind PAR or protect from TOP1ccs. MacroH2A1 isoform-specific analyses were based on reconstitution of macroH2A1.1 knockout cells with wild-type or PAR binding-deficient FLAG-tagged macroH2A1.1 in human breast cancer cells. Mechanistically, we find that macroH2A1.1 facilitates the recruitment of the TOP1cc repair factor XRCC1 in response to both endogenous and drug-induced topological stress. Impaired macroH2A1.1 splicing, a frequent cancer feature, was predictive of increased sensitivity to TOP1 poisons in a pharmaco-genomic screen in breast cancer cells, and macroH2A1.1 inactivation mirrored this effect in breast and ovarian cancer cells. Consistent with this, low macroH2A1.1 expression correlated with improved survival in cancer patients treated with TOP1 inhibitors (TOP1i). We propose that macroH2A1 alternative splicing serves as an epigenetic modulator of TOP1-associated genome maintenance and a potential cancer vulnerability.

  Study phs003729

• Genomic Characterization of Duke Melanoma Brain Metastases

  Previous work has shown that melanoma brain metastases (MBM) have a unique molecular profile compared to extracranial metastases (ECM). Description of the biology of MBM and associations between biological features and clinical outcomes will facilitate the design of rational therapies for patients with MBM. To better characterize the molecular profile of MBM, we conducted whole exome sequencing (WES) and total RNA sequencing on MBM tissues obtained from an independent cohort of 14 patients from Duke University Medical Center. This cohort adds valuable patient samples to the field and enables strengthened investigation of somatic mutations and gene expression profiles within and between cohorts. The mutational landscape and gene expression of MBM from the Duke cohort resembled those previously reported in a previously published dataset of WES and RNA sequencing in MBM and matched ECM tissues from UT MD Anderson Cancer Center (Fischer et al., 2019 30787016). Duke MBM demonstrated similar rates of mutations in genes associated with melanoma, including BRAF, NRAS, and PTEN, as the MD Anderson cohort. Immune populations in MBM were similar between Duke and MD Anderson MBM, though Duke samples demonstrated more resting CD4+ memory T cells. The ratio of M2 to M1 macrophages in the Duke cohort was similar to that of the MD Anderson cohort. In MBM, a higher M2:M1 ratio may contribute to an immune-suppressive tumor microenvironment. Sequencing data and sample attributes from MBM tissues obtained from 14 patients from Duke University Medical Center will be available through dbGaP.

  Study phs003009

• Nanopore whole-genome sequencing of human sarcomas

  We performed single and multi-region nanopore whole-genome sequencing on human sarcoma samples from adult and paediatric patients.

  Study EGAS50000000651

• Myeloid cell networks govern re-establishment of original immune landscapes in recurrent ovarian cancer

  Immunotherapy has produced disappointing results in recurrent ovarian cancer (OC). However, the prognostic value of tumour-infiltrating lymphocytes (TILs) is largely based on the analysis of treatment-naive tumours. To understand the immunobiology of recurrent cancers, and their evolution, we profiled a total of 697 OC tumour samples (566 primary and 131 recurrent including 69 patient-matched samples) from 595 patients of five independent multi-institutional cohorts. By capturing heterogeneous TIL distributions, we identified four immune phenotypes associated with differential prognosis, TILs states and TILs:myeloid networks, which dictate malignant progression after chemotherapy and recurrence. Notably, recurrent tumours recapitulate the immunogenic landscapes of original cancers. Mirroring inflamed human OC, preclinical recurrent Brca1mut tumours maintained activated TILs:dendritic cells (DCs) niches but evaded immune control through COX/PGE2 signaling upregulation. Conversely, recurrent Brca1wt tumours displayed loss of TILs:DCs niches and accumulated immunosuppressive myeloid networks featuring Trem2/ApoEhigh TAMs and Nduf4l2high/Galectin3high malignant states. Our study highlights that persistent immunogenicity in recurrent OC is governed by the BRCA-dependent crosstalk between dissimilar myeloid cells and TILs. We propose new targets to modulate the malignant and TAM compartments which improve efficacy of standard of care chemotherapy in mouse OC models with HR deficiency.

  Study EGAS50000001069

• RNAseq dataset of ovarian cancer patients

  Dataset of transcriptomics data from a cohort of individuals diagnosed with ovarian cancer. This dataset includes RNAseq sequencing data from 68 individuals. A total of 109 tumor samples were sequenced. Samples were prepared with the Illumina TruSeq Stranded RNA library. Sequencing data are paired end.

  Dataset EGAD50000001556