Publications by authors named "Bram Boeckx"

63 Publications

Single-cell Transcriptomics Uncover a Novel Role of Myeloid Cells and T-lymphocytes in the Fibrotic Microenvironment in Peyronie's Disease.

Eur Urol Focus 2021 May 4. Epub 2021 May 4.

Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium; Department of Urology, University Hospitals Leuven, Leuven, Belgium.

Background: Peyronie's disease (PD) is an acquired fibrotic disease affecting the penile tunica albuginea that can lead to curvature and deformities, shortening, and erectile dysfunction. Although immunological mechanisms have been suggested for the pathophysiology of PD, these have not been investigated using single-cell transcriptomics.

Objective: To investigate the immunological signature of plaques from PD patients using immunohistochemistry (IHC) and single-cell RNA sequencing (scRNA-Seq).

Design, Setting, And Participants: Tunica albuginea biopsy was performed in patients undergoing penile surgery for either PD (n = 12) or plication or penile cancer (control, n = 6). The inclusion criteria for PD patients were stable chronic disease (≥12 mo in duration) and no previous penile surgery or intralesional injection therapy.

Outcome Measurements And Statistical Analysis: IHC was performed on surgical samples from ten patients with PD and five control subjects. An additional two PD and one control sample were used for scRNA-Seq (droplet-based; 10X Genomics). Cell clusters were visualised using heatmaps and t-distributed stochastic neighbour embedding plots (BioTuring v2.7.5).

Results And Limitations: IHC revealed the presence of myeloid dendritic cells (DCs; CD68, TLR4, CD206), cytotoxic T lymphocytes (CTLs; CD3, CD8), and B lymphocytes (CD20) in PD plaques, which were absent in controls. scRNA-Seq yielded results for 3312 PD and 5658 control cells. Cell clusters contained fibroblasts (COL1A2), myofibroblasts (COL1A2, ACTA2), smooth muscle cells (ACTA2, DES), endothelial cells (VWF), myeloid cells (CD14), T lymphocytes (CD3D), and neutrophils (ALPL). Myeloid cell subclustering showed infiltration of monocyte-derived cells; control tissue contained classical DCs and resident macrophages. Lymphocyte subclustering revealed mucosal-associated invariant T (MAIT) cells and CTLs in PD. Differential gene expression suggests an increase in inflammatory and immune responses in chronic PD. The study is limited by the small scRNA-seq sample size (n = 3) for IHC, mitigated by a larger cohort of historic paraffin-embedded samples (n = 15), which showed largely parallel findings. Owing to tissue stiffness and extracellular matrix adhesion, our single-cell yield was lower for PD than for the control sample.

Conclusions: Our data suggest that even in the chronic PD stage (painless and stable curvature) there is a sustained inflammatory reaction. While vascularisation and collagen production are elevated, the inflammation is driven by specialised monocyte-derived CTL and MAIT cells. These findings could uncover new avenues for medical treatment of PD.

Patient Summary: We looked at the role of the immune system in patients suffering from Peyronie's disease, a condition causing shortening and curvature of the penis. We found that even in a stable, chronic stage of the disease, there is activation of the immune system. Our results suggest that there is potential for novel treatments for this condition.
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http://dx.doi.org/10.1016/j.euf.2021.04.012DOI Listing
May 2021

A single-cell map of intratumoral changes during anti-PD1 treatment of patients with breast cancer.

Nat Med 2021 05 6;27(5):820-832. Epub 2021 May 6.

Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium.

Immune-checkpoint blockade (ICB) combined with neoadjuvant chemotherapy improves pathological complete response in breast cancer. To understand why only a subset of tumors respond to ICB, patients with hormone receptor-positive or triple-negative breast cancer were treated with anti-PD1 before surgery. Paired pre- versus on-treatment biopsies from treatment-naive patients receiving anti-PD1 (n = 29) or patients receiving neoadjuvant chemotherapy before anti-PD1 (n = 11) were subjected to single-cell transcriptome, T cell receptor and proteome profiling. One-third of tumors contained PD1-expressing T cells, which clonally expanded upon anti-PD1 treatment, irrespective of tumor subtype. Expansion mainly involved CD8 T cells with pronounced expression of cytotoxic-activity (PRF1, GZMB), immune-cell homing (CXCL13) and exhaustion markers (HAVCR2, LAG3), and CD4 T cells characterized by expression of T-helper-1 (IFNG) and follicular-helper (BCL6, CXCR5) markers. In pre-treatment biopsies, the relative frequency of immunoregulatory dendritic cells (PD-L1), specific macrophage phenotypes (CCR2 or MMP9) and cancer cells exhibiting major histocompatibility complex class I/II expression correlated positively with T cell expansion. Conversely, undifferentiated pre-effector/memory T cells (TCF7, GZMK) or inhibitory macrophages (CX3CR1, C3) were inversely correlated with T cell expansion. Collectively, our data identify various immunophenotypes and associated gene sets that are positively or negatively correlated with T cell expansion following anti-PD1 treatment. We shed light on the heterogeneity in treatment response to anti-PD1 in breast cancer.
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http://dx.doi.org/10.1038/s41591-021-01323-8DOI Listing
May 2021

Prdm16 Supports Arterial Flow Recovery by Maintaining Endothelial Function.

Circ Res 2021 Apr 27. Epub 2021 Apr 27.

Cardiovascular Sciences, Centre for Molecular and Vascular Biology, Endothelial Cell Biology Unit, KU Leuven, BELGIUM.

Understanding the mechanisms that regulate arterial flow recovery is important to design treatment options for peripheral arterial disease (PAD) patients ineligible for invasive revascularization. Transcriptional orchestrators of this recovery process represent an appealing target for treatment design. We previously identified positive regulatory domain-containing protein (Prdm)16 as an arterial-specific endothelial transcription factor but its in vivo role in arteries remains completely unknown. To unravel the role of Prdm16 in arteries under physiological and pathological conditions, more specifically during PAD. Methods and Results: Within the vasculature, Prdm16 expression was strictly expressed by arterial endothelial and smooth muscle cells. Heterozygous loss of Prdm16 caused a modest reduction of the inner arterial diameter and smooth muscle cell coating without compromising vasomotor function. Upon femoral artery ligation, Prdm16 mice featured significantly impaired flow recovery to ischemic limbs. This impairment was recapitulated in mice with a Prdm16 deletion specifically in endothelial cells (EC-Prdm16) but not smooth muscle cells. Structural ollateral remodeling was normal in both Prdm16 and
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http://dx.doi.org/10.1161/CIRCRESAHA.120.318501DOI Listing
April 2021

MicroRNAs Possibly Involved in the Development of Bone Metastasis in Clear-Cell Renal Cell Carcinoma.

Cancers (Basel) 2021 Mar 28;13(7). Epub 2021 Mar 28.

Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, 3000 Leuven, Belgium.

Bone metastasis in clear-cell renal cell carcinoma (ccRCC) leads to substantial morbidity through skeletal related adverse events and implicates worse clinical outcomes. MicroRNAs (miRNA) are small non-protein coding RNA molecules with important regulatory functions in cancer development and metastasis. In this retrospective analysis we present dysregulated miRNA in ccRCC, which are associated with bone metastasis. In particular, miR-23a-3p, miR-27a-3p, miR-20a-5p, and miR-335-3p specifically correlated with the earlier appearance of bone metastasis, compared to metastasis in other organs. In contrast, miR-30b-3p and miR-139-3p were correlated with less occurrence of bone metastasis. These miRNAs are potential biomarkers and attractive targets for miRNA inhibitors or mimics, which could lead to novel therapeutic possibilities for bone targeted treatment in metastatic ccRCC.
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http://dx.doi.org/10.3390/cancers13071554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036650PMC
March 2021

Molecular Biomarkers of Response to Eribulin in Patients with Leiomyosarcoma.

Clin Cancer Res 2021 Jun 1;27(11):3106-3115. Epub 2021 Apr 1.

Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.

Purpose: A randomized phase III study evaluated the efficacy of eribulin versus dacarbazine in patients with advanced liposarcoma and leiomyosarcoma. Improved overall survival (OS) led to approval of eribulin for liposarcoma, but not for leiomyosarcoma.

Experimental Design: We explored the molecular profile of 77 archival leiomyosarcoma samples from this trial to identify potential predictive biomarkers, utilizing low-coverage whole-genome and whole-exome sequencing. Tumor molecular profiles were correlated with clinical data, and disease control was defined as complete/partial response or stable disease (RECIST v1.1).

Results: Overall, 111 focal copy-number alterations were observed in leiomyosarcoma. Gain of chromosome 17q12 was the most common event, present in 43 of 77 cases (56%). In the eribulin-treated group, gains of 4q26, 20p12.2, 13q13.3, 8q22.2, and 8q13.2 and loss of 1q44 had a negative impact on progression-free survival (PFS), while loss of 2p12 correlated with better prognosis. Gains of 4q22.1 and losses of 3q14.2, 2q14.1, and 11q25 had a negative impact on OS in patients with leiomyosarcoma receiving eribulin. The most commonly mutated genes were (38%), (32%), and (17%). The presence of mutations had a negative impact on PFS in both treatment arms; however, the correlation with worse OS was observed only in the eribulin-treated patients. mutations were associated with longer PFS on eribulin.

Conclusions: Leiomyosarcoma has a complex genetic background, with multiple copy-number alterations and mutations affecting genes implicated in tumorigenesis. We identified several molecular changes with potential impact on survival of patients with leiomyosarcoma when treated with eribulin.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4315DOI Listing
June 2021

Genome-wide CRISPR screening identifies TMEM106B as a proviral host factor for SARS-CoV-2.

Nat Genet 2021 04 8;53(4):435-444. Epub 2021 Mar 8.

KU Leuven Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute, Leuven, Belgium.

The ongoing COVID-19 pandemic has caused a global economic and health crisis. To identify host factors essential for coronavirus infection, we performed genome-wide functional genetic screens with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human coronavirus 229E. These screens uncovered virus-specific as well as shared host factors, including TMEM41B and PI3K type 3. We discovered that SARS-CoV-2 requires the lysosomal protein TMEM106B to infect human cell lines and primary lung cells. TMEM106B overexpression enhanced SARS-CoV-2 infection as well as pseudovirus infection, suggesting a role in viral entry. Furthermore, single-cell RNA-sequencing of airway cells from patients with COVID-19 demonstrated that TMEM106B expression correlates with SARS-CoV-2 infection. The present study uncovered a collection of coronavirus host factors that may be exploited to develop drugs against SARS-CoV-2 infection or future zoonotic coronavirus outbreaks.
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http://dx.doi.org/10.1038/s41588-021-00805-2DOI Listing
April 2021

CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers.

Br J Cancer 2021 02 26;124(4):842-854. Epub 2021 Jan 26.

Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk.

Methods: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry.

Results: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 × 10); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 × 10).

Conclusions: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.
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http://dx.doi.org/10.1038/s41416-020-01185-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884683PMC
February 2021

Discriminating mild from critical COVID-19 by innate and adaptive immune single-cell profiling of bronchoalveolar lavages.

Cell Res 2021 03 21;31(3):272-290. Epub 2021 Jan 21.

Laboratory of Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium.

How the innate and adaptive host immune system miscommunicate to worsen COVID-19 immunopathology has not been fully elucidated. Here, we perform single-cell deep-immune profiling of bronchoalveolar lavage (BAL) samples from 5 patients with mild and 26 with critical COVID-19 in comparison to BALs from non-COVID-19 pneumonia and normal lung. We use pseudotime inference to build T-cell and monocyte-to-macrophage trajectories and model gene expression changes along them. In mild COVID-19, CD8 resident-memory (T) and CD4 T-helper-17 (T) cells undergo active (presumably antigen-driven) expansion towards the end of the trajectory, and are characterized by good effector functions, while in critical COVID-19 they remain more naïve. Vice versa, CD4 T-cells with T-helper-1 characteristics (T-like) and CD8 T-cells expressing exhaustion markers (T-like) are enriched halfway their trajectories in mild COVID-19, where they also exhibit good effector functions, while in critical COVID-19 they show evidence of inflammation-associated stress at the end of their trajectories. Monocyte-to-macrophage trajectories show that chronic hyperinflammatory monocytes are enriched in critical COVID-19, while alveolar macrophages, otherwise characterized by anti-inflammatory and antigen-presenting characteristics, are depleted. In critical COVID-19, monocytes contribute to an ATP-purinergic signaling-inflammasome footprint that could enable COVID-19 associated fibrosis and worsen disease-severity. Finally, viral RNA-tracking reveals infected lung epithelial cells, and a significant proportion of neutrophils and macrophages that are involved in viral clearance.
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http://dx.doi.org/10.1038/s41422-020-00455-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027624PMC
March 2021

Characterization of Stromal Tumor-infiltrating Lymphocytes and Genomic Alterations in Metastatic Lobular Breast Cancer.

Clin Cancer Res 2020 12 17;26(23):6254-6265. Epub 2020 Sep 17.

Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Leuven, Belgium.

Purpose: Invasive lobular carcinoma (ILC) represents the second most common histologic breast cancer subtype after invasive ductal carcinoma (IDC). While primary ILC has been extensively studied, metastatic ILC has been poorly characterized at the genomic and immune level.

Experimental Design: We retrospectively assembled the multicentric EuroILC series of matched primary and metastatic samples from 94 patients with estrogen receptor (ER)-positive ILC. Stromal tumor-infiltrating lymphocytes (sTILs) were assessed by experienced pathologists. Targeted sequencing and low pass whole-genome sequencing were conducted to detect mutations and copy-number aberrations (CNAs). We compared the frequencies of the alterations in EuroILC with those from patients with ER-positive metastatic ILC ( = 135) and IDC ( = 563) from MSK-IMPACT.

Results: Low sTIL levels were observed in ILC metastases, with higher levels in the mixed nonclassic histology. Considering ILC metastases from EuroILC and MSK-IMPACT, we observed that >50% of tumors harbor genomic alterations that have previously been associated with endocrine resistance. A matched primary/metastasis comparison in EuroILC revealed mutations (, or ) and CNAs ( or deletion, amplification) associated with endocrine resistance that were private to the metastasis in 22% (7/32) and 19% (4/21) of patients, respectively. An increase in , and mutations, in deletions and a decrease in mutations was observed in ILC as compared with IDC metastases.

Conclusions: ILC metastases harbor genomic alterations that may potentially explain endocrine resistance in a large proportion of patients, and present genomic differences as compared with IDC metastases.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2268DOI Listing
December 2020

Single-cell transcriptome analysis of the Akimba mouse retina reveals cell-type-specific insights into the pathobiology of diabetic retinopathy.

Diabetologia 2020 10 30;63(10):2235-2248. Epub 2020 Jul 30.

Oxurion NV, Gaston Geenslaan 1, B-3001, Leuven, Belgium.

Aims/hypothesis: Diabetic retinopathy is a common complication of diabetes and a leading cause of visual impairment and blindness. Despite recent advances, our understanding of its pathophysiology remains incomplete. The aim of this study was to provide deeper insight into the complex network of molecular and cellular changes that underlie diabetic retinopathy by systematically mapping the transcriptional changes that occur in the different cellular compartments of the degenerating diabetic mouse retina.

Methods: Single-cell RNA sequencing was performed on retinal tissue from 12-week-old wild-type and Akimba (Ins2×Vegfa) mice, which are known to replicate features of clinical diabetic retinopathy. This resulted in transcriptome data for 9474 retinal cells, which could be annotated to eight distinct retinal cell types. Using STRING analysis, we studied differentially expressed gene networks in neuronal, glial and immune cell compartments to create a comprehensive view on the pathological changes that occur in the Akimba retina. Using subclustering analysis, we further characterised macroglial and inflammatory cell subpopulations. Prominent findings were confirmed at the protein level using immunohistochemistry, western blotting and ELISA.

Results: At 12 weeks, the Akimba retina was found to display degeneration of rod photoreceptors and presence of inflammatory cells, identified by subclustering analysis as monocyte, macrophage and microglial populations. Analysis of differentially expressed genes in the rod, cone, bipolar cell and macroglial compartments indicated changes in cell metabolism and ribosomal gene expression, gliosis, activation of immune system pathways and redox and metal ion dyshomeostasis. Experiments at the protein level supported a metabolic shift from glycolysis to oxidative phosphorylation (glyceraldehyde 3-phosphate dehydrogenase), activation of microglia/macrophages (isolectin-B4), metal ion and oxidative stress response (metallothionein and haem oxygenase-1) and reactive macroglia (glial fibrillary acidic protein and S100) in the Akimba retina, compared with wild-type mice. Our single-cell approach also indicates macroglial subpopulations with distinct fibrotic, inflammatory and gliotic profiles.

Conclusions/interpretation: Our study identifies molecular pathways underlying inflammatory, metabolic and oxidative stress-mediated changes in the Akimba mouse model of diabetic retinopathy and distinguishes distinct functional subtypes of inflammatory and macroglial cells.

Data Availability: RNA-seq data have been deposited in the ArrayExpress database at EMBL-EBI ( www.ebi.ac.uk/arrayexpress ) under accession number E-MTAB-9061. Graphical abstract.
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http://dx.doi.org/10.1007/s00125-020-05218-0DOI Listing
October 2020

A pan-cancer blueprint of the heterogeneous tumor microenvironment revealed by single-cell profiling.

Cell Res 2020 09 19;30(9):745-762. Epub 2020 Jun 19.

VIB Center for Cancer Biology, Leuven, Belgium.

The stromal compartment of the tumor microenvironment consists of a heterogeneous set of tissue-resident and tumor-infiltrating cells, which are profoundly moulded by cancer cells. An outstanding question is to what extent this heterogeneity is similar between cancers affecting different organs. Here, we profile 233,591 single cells from patients with lung, colorectal, ovary and breast cancer (n = 36) and construct a pan-cancer blueprint of stromal cell heterogeneity using different single-cell RNA and protein-based technologies. We identify 68 stromal cell populations, of which 46 are shared between cancer types and 22 are unique. We also characterise each population phenotypically by highlighting its marker genes, transcription factors, metabolic activities and tissue-specific expression differences. Resident cell types are characterised by substantial tissue specificity, while tumor-infiltrating cell types are largely shared across cancer types. Finally, by applying the blueprint to melanoma tumors treated with checkpoint immunotherapy and identifying a naïve CD4 T-cell phenotype predictive of response to checkpoint immunotherapy, we illustrate how it can serve as a guide to interpret scRNA-seq data. In conclusion, by providing a comprehensive blueprint through an interactive web server, we generate the first panoramic view on the shared complexity of stromal cells in different cancers.
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http://dx.doi.org/10.1038/s41422-020-0355-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608385PMC
September 2020

Phylogenetic reconstruction of breast cancer reveals two routes of metastatic dissemination associated with distinct clinical outcome.

EBioMedicine 2020 Jun 5;56:102793. Epub 2020 Jun 5.

J.C. Heuson Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Bld de Waterloo 121, 1000, Brussels, Belgium. Electronic address:

Background: In breast cancer (BC), axillary lymph node (ALN) involvement is one of the strongest adverse prognostic factors. However, it is unclear whether loco-regional lymph node deposits are effectively the root of secondary metastases or only an indicator of competence of the primary tumour to spread to distant organs.

Methods: Here, we investigated the evolutionary trajectories of primary tumour, ALN and distant metastasis samples from 16 estrogen-receptor (ER)-positive lymph node-positive BC patients. Low-pass whole genome sequencing was performed to infer somatic copy number aberrations and the phylogenetic profiles for all patients were obtained.

Findings: We show that lymph nodes and distant metastases shared a common origin in only 25% of the cases highlighting that the predominant route of metastatic dissemination is the direct seeding of tumour cells from the primary tumour to distant organs, independently of lymph node metastasis. Noticeably, patients sharing a common origin significantly have worse prognosis.

Interpretation: Our results shed light on the routes on which tumour cells metastasize and their role in disease progression in ER-positive BC.

Funding: This work has received financial support from Les Amis de l'Institut Bordet, MEDIC, the Breast Cancer Research Foundation (BCRF), the Belgian Fonds National de la Recherche Scientifique (F.R.S-FNRS) and from a grant of the Région Wallonne.
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http://dx.doi.org/10.1016/j.ebiom.2020.102793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281848PMC
June 2020

Lineage-dependent gene expression programs influence the immune landscape of colorectal cancer.

Nat Genet 2020 06 25;52(6):594-603. Epub 2020 May 25.

Systems Biology and Data Analytics, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.

Immunotherapy for metastatic colorectal cancer is effective only for mismatch repair-deficient tumors with high microsatellite instability that demonstrate immune infiltration, suggesting that tumor cells can determine their immune microenvironment. To understand this cross-talk, we analyzed the transcriptome of 91,103 unsorted single cells from 23 Korean and 6 Belgian patients. Cancer cells displayed transcriptional features reminiscent of normal differentiation programs, and genetic alterations that apparently fostered immunosuppressive microenvironments directed by regulatory T cells, myofibroblasts and myeloid cells. Intercellular network reconstruction supported the association between cancer cell signatures and specific stromal or immune cell populations. Our collective view of the cellular landscape and intercellular interactions in colorectal cancer provide mechanistic information for the design of efficient immuno-oncology treatment strategies.
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http://dx.doi.org/10.1038/s41588-020-0636-zDOI Listing
June 2020

Developing Organoids from Ovarian Cancer as Experimental and Preclinical Models.

Stem Cell Reports 2020 04 2;14(4):717-729. Epub 2020 Apr 2.

Laboratory of Tissue Plasticity in Health and Disease, Cluster of Stem Cell and Developmental Biology, Department of Development and Regeneration, KU Leuven (University of Leuven), 3000 Leuven, Belgium. Electronic address:

Ovarian cancer (OC) represents the most dismal gynecological cancer. Pathobiology is poorly understood, mainly due to lack of appropriate study models. Organoids, defined as self-developing three-dimensional in vitro reconstructions of tissues, provide powerful tools to model human diseases. Here, we established organoid cultures from patient-derived OC, in particular from the most prevalent high-grade serous OC (HGSOC). Testing multiple culture medium components identified neuregulin-1 (NRG1) as key factor in maximizing OC organoid development and growth, although overall derivation efficiency remained moderate (36% for HGSOC patients, 44% for all patients together). Established organoid lines showed patient tumor-dependent morphology and disease characteristics, and recapitulated the parent tumor's marker expression and mutational landscape. Moreover, the organoids displayed tumor-specific sensitivity to clinical HGSOC chemotherapeutic drugs. Patient-derived OC organoids provide powerful tools for the study of the cancer's pathobiology (such as importance of the NRG1/ERBB pathway) as well as advanced preclinical tools for (personalized) drug screening and discovery.
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http://dx.doi.org/10.1016/j.stemcr.2020.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160357PMC
April 2020

Transcriptome-wide association study of breast cancer risk by estrogen-receptor status.

Genet Epidemiol 2020 07 1;44(5):442-468. Epub 2020 Mar 1.

Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.

Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.
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http://dx.doi.org/10.1002/gepi.22288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987299PMC
July 2020

An Integrated Gene Expression Landscape Profiling Approach to Identify Lung Tumor Endothelial Cell Heterogeneity and Angiogenic Candidates.

Cancer Cell 2020 01;37(1):21-36.e13

Laboratory for Precision Cancer Medicine, Translational Cell & Tissue Research, Department of Imaging & Pathology, KU Leuven, Leuven 3000, Belgium.

Heterogeneity of lung tumor endothelial cell (TEC) phenotypes across patients, species (human/mouse), and models (in vivo/in vitro) remains poorly inventoried at the single-cell level. We single-cell RNA (scRNA)-sequenced 56,771 endothelial cells from human/mouse (peri)-tumoral lung and cultured human lung TECs, and detected 17 known and 16 previously unrecognized phenotypes, including TECs putatively regulating immune surveillance. We resolved the canonical tip TECs into a known migratory tip and a putative basement-membrane remodeling breach phenotype. Tip TEC signatures correlated with patient survival, and tip/breach TECs were most sensitive to vascular endothelial growth factor blockade. Only tip TECs were congruent across species/models and shared conserved markers. Integrated analysis of the scRNA-sequenced data with orthogonal multi-omics and meta-analysis data across different human tumors, validated by functional analysis, identified collagen modification as a candidate angiogenic pathway.
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http://dx.doi.org/10.1016/j.ccell.2019.12.001DOI Listing
January 2020

The genomic landscape of nonsmall cell lung carcinoma in never smokers.

Int J Cancer 2020 06 10;146(11):3207-3218. Epub 2019 Dec 10.

Laboratory of Medical and Molecular Oncology (LMMO), Department of Medical Oncology, Oncologisch Centrum, UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium.

Lung cancer is the number one cause of cancer-related death worldwide with cigarette smoking as its major risk factor. Although the incidence of lung cancer in never smokers is rising, this subgroup of patients is underrepresented in genomic studies of lung cancer. Here, we assembled a prospective cohort of 46 never-smoking, nonsmall cell lung cancer (NSCLC) patients and performed whole-exome and low-coverage whole-genome sequencing on tumors and matched germline DNA. We observed fewer somatic mutations, genomic breakpoints and a smaller fraction of the genome with chromosomal instability in lung tumors from never smokers compared to smokers. The lower number of mutations, enabled us to identify TSC22D1 as a potential driver gene in NSCLC. On the other hand, the frequency of mutations in actionable genes such as EGFR and ERBB2 and of amplifications in MET were higher, while the mutation rate of TP53, which is a negative prognostic factor, was lower in never smokers compared to smokers. Together, these observations suggest a more favorable prognosis for never smokers with NSCLC. Classification of somatic mutations into six-substitution type patterns or into 96-substitution type signatures revealed distinct clusters between smokers and never smokers. Particularly, we identified in never smokers signatures related to aging, homologous recombination damage and APOBEC/AID activity as the most important underlying processes of NSCLC. This further indicates that second-hand smoking is not driving NSCLC pathogenesis in never smokers.
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http://dx.doi.org/10.1002/ijc.32797DOI Listing
June 2020

Patient-derived organoids from endometrial disease capture clinical heterogeneity and are amenable to drug screening.

Nat Cell Biol 2019 08 1;21(8):1041-1051. Epub 2019 Aug 1.

Laboratory of Tissue Plasticity in Health and Disease, Stem Cell and Developmental Biology Cluster, Department of Development and Regeneration, KU Leuven, Leuven, Belgium.

Endometrial disorders represent a major gynaecological burden. Current research models fail to recapitulate the nature and heterogeneity of these diseases, thereby hampering scientific and clinical progress. Here we developed long-term expandable organoids from a broad spectrum of endometrial pathologies. Organoids from endometriosis show disease-associated traits and cancer-linked mutations. Endometrial cancer-derived organoids accurately capture cancer subtypes, replicate the mutational landscape of the tumours and display patient-specific drug responses. Organoids were also established from precancerous pathologies encompassing endometrial hyperplasia and Lynch syndrome, and inherited gene mutations were maintained. Endometrial disease organoids reproduced the original lesion when transplanted in vivo. In summary, we developed multiple organoid models that capture endometrial disease diversity and will provide powerful research models and drug screening and discovery tools.
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http://dx.doi.org/10.1038/s41556-019-0360-zDOI Listing
August 2019

CRAF mutations in lung cancer can be oncogenic and predict sensitivity to combined type II RAF and MEK inhibition.

Oncogene 2019 08 8;38(31):5933-5941. Epub 2019 Jul 8.

Laboratory of Molecular Oncology and Department of Medical Oncology, Oncologisch Centrum, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium.

Two out of 41 non-small cell lung cancer patients enrolled in a clinical study were found with a somatic CRAF mutation in their tumor, namely CRAF and CRAF. To our knowledge, both mutations are novel in lung cancer and CRAF has not been previously reported in cancer. Expression of CRAF in HEK293T cells and BEAS-2B lung epithelial cells led to increased ERK pathway activation in a dimer-dependent manner, accompanied with loss of CRAF phosphorylation at the negative regulatory S259 residue. Moreover, stable expression of CRAF in mouse embryonic fibroblasts and BEAS-2B cells led to anchorage-independent growth. Consistent with a previous report, we could not observe a gain-of-function with CRAF. Type II but not type I RAF inhibitors suppressed the CRAF-induced ERK pathway activity in BEAS-2B cells, and combinatorial treatment with type II RAF inhibitors and a MEK inhibitor led to a stronger ERK pathway inhibition and growth arrest. Our findings suggest that the acquisition of a CRAF mutation can provide oncogenic properties to cells, and that such cells are sensitive to combined MEK and type II RAF inhibitors. CRAF mutations should be diagnostically and therapeutically explored in lung and perhaps other cancers.
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http://dx.doi.org/10.1038/s41388-019-0866-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756226PMC
August 2019

Patient-derived cell line models revealed therapeutic targets and molecular mechanisms underlying disease progression of high grade serous ovarian cancer.

Cancer Lett 2019 09 28;459:1-12. Epub 2019 May 28.

Translational Gynecology Group, Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, 1090, Vienna, Austria. Electronic address:

High grade serous ovarian cancer (HGSOC) is the most frequent type of ovarian cancer. Most patients have primary response to platinum-based chemotherapy but frequently relapse, which leads to patient death. A lack of well documented and characterized patient-derived HGSOC cell lines is so far a major barrier to define tumor specific therapeutic targets and to study the molecular mechanisms underlying disease progression. We established 34 patient-derived HGSOC cell lines and characterized them at cellular and molecular level. Particularly, we demonstrated that a cancer-testis antigen PRAME and Estrogen Receptor could serve as therapeutic targets. Notably, data from the cell lines did not demonstrate acquired resistance due to tumor recurrence that matched with clinical observations. Finally, we presented that all HGSOC had no or very low CDKN1A (p21) expression due to loss of wild-type TP53, suggesting that loss of cell cycle control is the determinant for tumorigenesis and progression. In conclusion, patient-derived cell lines reveal that PRAME is a potential tumor specific therapeutic target in HGSOC and counteracting the down-regulation of p21 caused by loss of wild-type TP53 might be the key to impede disease progression.
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http://dx.doi.org/10.1016/j.canlet.2019.05.032DOI Listing
September 2019

Establishment and Characterization of Histologically and Molecularly Stable Soft-tissue Sarcoma Xenograft Models for Biological Studies and Preclinical Drug Testing.

Mol Cancer Ther 2019 06 8;18(6):1168-1178. Epub 2019 Apr 8.

Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, and Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium.

Soft-tissue sarcomas (STS) represent a heterogeneous group of rare, malignant tumors of mesenchymal origin. Reliable sarcoma research models are scarce. We aimed to establish and characterize histologically and molecularly stable patient-derived xenograft (PDX) models from a broad variety of STS subtypes. A total of 188 fresh tumor samples from consenting patients with localized or advanced STS were transplanted subcutaneously in NMRI-nu/nu-immunodeficient mice. Once tumor growth was observed, the material was passaged to a next generation of mice. A patient-derived tumor sample was considered "successfully engrafted" whenever the sample was transplanted to passage 1. A PDX model was considered "established" when observing stable morphologic and molecular features for at least two passages. With every passage, histologic and molecular analyses were performed. Specific genomic alterations and copy-number profile were assessed by FISH and low coverage whole-genome sequencing. The tumor engraftment rate was 32% (61/188) and 188 patient samples generated a total of 32 PDX models, including seven models of myxofibrosarcoma, five dedifferentiated liposarcoma, five leiomyosarcoma, three undifferentiated pleomorphic sarcoma, two malignant peripheral nerve sheet tumor models, and single models of synovial sarcoma and some other (ultra)rare subtypes. Seventeen additional models are in early stages of engraftment (passage 1-2). Histopathologic and molecular features were compared with the original donor tumor and were stable throughout passaging. The platform is used for studies on sarcoma biology and suited for preclinical drug testing as illustrated by a number of completed and ongoing laboratory studies.
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http://dx.doi.org/10.1158/1535-7163.MCT-18-1045DOI Listing
June 2019

Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events.

Circ Genom Precis Med 2019 04 21;12(4):e002471. Epub 2019 Mar 21.

Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital (M.H.).

Background: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.

Methods: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD.

Results: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUS-CHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction <0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09).

Conclusions: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.
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http://dx.doi.org/10.1161/CIRCGEN.119.002471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625876PMC
April 2019

Subsequent Event Risk in Individuals With Established Coronary Heart Disease.

Circ Genom Precis Med 2019 04 21;12(4):e002470. Epub 2019 Mar 21.

Department of Pharmacotherapy and Translational Research, Centre for Pharmacogenomics (Y.G., R.M.C.-D., J.A.J.), University of Florida, Gainesville.

Background: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD.

Methods: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events.

Results: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints.

Conclusions: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.
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http://dx.doi.org/10.1161/CIRCGEN.119.002470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629546PMC
April 2019

Genomic, Transcriptomic, Epigenetic, and Immune Profiling of Mucinous Breast Cancer.

J Natl Cancer Inst 2019 07;111(7):742-746

Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, U-CRC, Brussels, Belgium.

Although invasive ductal breast cancer (IDC) represents the most common histological type of breast cancer, minor subtypes exist such as mucinous breast cancer (MuBC). MuBC are distinguished by tumor cells floating in extracellular mucin. MuBC patients are generally older and associated with a favorable prognosis. To unravel the molecular architecture of MuBC, we applied low-pass whole-genome sequencing and microscopic evaluation of stromal tumor infiltrating lymphocytes to 30 MuBC from a retrospective institutional cohort. We further analyzed two independent datasets from the International Cancer Genomics Consortium and The Cancer Genome Atlas. Genomic data (n = 26 MuBC, n = 535 estrogen receptor [ER] positive/HER2-negative IDC), methylation data (n = 28 MuBC, n = 529 ER-positive/HER2-negative IDC), and transcriptomic data (n = 27 MuBC, n = 467 ER-positive/HER2-negative IDC) were analyzed. MuBC was characterized by low tumor infiltrating lymphocyte levels (median = 0.0%, average = 3.4%, 95% confidence interval = 1.9% to 4.9%). Compared with IDC, MuBC had a lower genomic instability (P = .01, two-sided Mann-Whitney U test) and a decreased prevalence of PIK3CA mutations (39.7% in IDC vs 6.7% in MuBC, P = .01 in the International Cancer Genomics Consortium; and 34.8% vs 0.0%, P = .02 in The Cancer Genome Atlas, two-sided Fisher's exact test). Finally, our report identifies aberrant DNA methylation of MUC2 as a possible cause of extracellular production of mucin in MuBC.
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http://dx.doi.org/10.1093/jnci/djz023DOI Listing
July 2019

Genome-wide association study of germline variants and breast cancer-specific mortality.

Br J Cancer 2019 03 21;120(6):647-657. Epub 2019 Feb 21.

Lund University, Department of Cancer Epidemiology, Clinical Sciences, Lund, Sweden.

Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry.

Methods: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP).

Results: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10, HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster.

Conclusions: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.
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http://dx.doi.org/10.1038/s41416-019-0393-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461853PMC
March 2019

Identification, clinical-pathological characteristics and treatment outcomes of patients with metastatic breast cancer and somatic human epidermal growth factor receptor 2 (ERBB2) mutations.

Breast Cancer Res Treat 2019 Feb 19;174(1):55-63. Epub 2018 Nov 19.

Department of Oncology, KU Leuven - University of Leuven, Herestraat 49, 3000, Leuven, Belgium.

Purpose: The human epidermal growth factor receptor 2 (ERBB2) may harbour somatic mutations that drive breast tumorigenesis. Here, we study prevalence, tumour characteristics and disease outcome of ERBB2 mutations in a large unselected cohort of metastatic breast cancer (mBC) patients.

Methods: We retrospectively included all mBC patients with sufficient primary breast tumour, diagnosed between 2000 and 2015 (n = 775). Genomic DNA was subjected to a targeted-resequencing assay to identify hotspot mutations in exon 8, 17, 19, 20, and 21 of ERBB2. We studied demographics, tumour characteristics, median distant disease-free survival (DDFS), using a time-to-event analysis and time to progression (TTP) and overall survival (OS) upon metastasis, using Kaplan-Meier and log-rank statistics to assess differences between ERBB2-mutation statuses.

Results: ERBB2 mutations were observed in 1.8% of the samples (13/721). Patient and tumour characteristics were independent of ERBB2 mutations. Luminal ERBB2-mutated (ERBB2) cases (n = 5) had a shorter DDFS than ERBB2 cases (median DDFS 0.8 vs. > 4.0 years, p = 0.02). ER-positive ERBB2 patients who received an aromatase inhibitor (AI) as first-line treatment (stage IV disease) had a worse TTP vs. ERBB2 patients (n = 3 vs. 156; median TTP 103 vs. 311 days, p = 0.04). OS for all subtypes was lower for ERBB2 vs. ERBB2 cases (n = 11 vs. 669; median OS 1.1 vs. 2.3 years, p = 0.46).

Conclusion: ERBB2 are rare in patients in whom mBC developed and no evidence was found for an association with specific types of BC or patient characteristics, although outcomes of ERBB2 carriers might be worse. The latter, however, needs to be validated in larger populations.
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http://dx.doi.org/10.1007/s10549-018-5049-7DOI Listing
February 2019

The genetic landscape of 5T models for multiple myeloma.

Sci Rep 2018 10 9;8(1):15030. Epub 2018 Oct 9.

Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussel, 1090, Belgium.

Murine models for multiple myeloma (MM) are often used to investigate pathobiology of multiple myeloma and disease progression. Unlike transgenic mice models, where it is known which oncogene is driving MM disease, the somatic aberrations of spontaneous syngeneic 5T models of MM have not yet been reported. Here, we analyzed the copy-number alterations (CNA) and mutational landscape of 5T2, 5T33vv and 5TGM1 murine MM models using whole-genome and whole-exome sequencing. Forty four percent of the genome of 5T2 cells is affected by CNAs while this was only 11% and 17% for 5T33vv and 5TGM1 cells, respectively. We found that up to 69% of the genes linked to gain of 1q or deletion of 13q in MM patients are present as respectively gains in 5T2 cells or deletions in 5T33 and 5TGM1 cells. Exome sequencing furthermore revealed mutations of genes involved in RAS/MAPK, PI3K/AKT1 and JAK/STAT signaling, DNA damage response, cell cycle, epigenetic regulation and extracellular matrix organization. We observed a statistically significant overlap of genes mutated in the 5T models and MM patients. Overall, the genetic landscape of the 5T models is heterogeneous with a high number of aberrations involving genes in various multiple myeloma-related pathways.
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http://dx.doi.org/10.1038/s41598-018-33396-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177465PMC
October 2018

Copy number load predicts outcome of metastatic colorectal cancer patients receiving bevacizumab combination therapy.

Nat Commun 2018 10 5;9(1):4112. Epub 2018 Oct 5.

Department of Medicine II, University Hospital Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.

Increased copy number alterations (CNAs) indicative of chromosomal instability (CIN) have been associated with poor cancer outcome. Here, we study CNAs as potential biomarkers of bevacizumab (BVZ) response in metastatic colorectal cancer (mCRC). We cluster 409 mCRCs in three subclusters characterized by different degrees of CIN. Tumors belonging to intermediate-to-high instability clusters have improved outcome following chemotherapy plus BVZ versus chemotherapy alone. In contrast, low instability tumors, which amongst others consist of POLE-mutated and microsatellite-instable tumors, derive no further benefit from BVZ. This is confirmed in 81 mCRC tumors from the phase 2 MoMa study involving BVZ. CNA clusters overlap with CRC consensus molecular subtypes (CMS); CMS2/4 xenografts correspond to intermediate-to-high instability clusters and respond to FOLFOX chemotherapy plus mouse avastin (B20), while CMS1/3 xenografts match with low instability clusters and fail to respond. Overall, we identify copy number load as a novel potential predictive biomarker of BVZ combination therapy.
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http://dx.doi.org/10.1038/s41467-018-06567-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173768PMC
October 2018