Publications by authors named "Daniel Birnbaum"

323 Publications

High-grade Follicular Lymphomas Exhibit Clinicopathologic, Cytogenetic, and Molecular Diversity Extending Beyond Grades 3A and 3B.

Am J Surg Pathol 2021 Oct;45(10):1324-1336

Pathology and Tumor Immunology, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm U1068, CNRS UMR7258, Aix-Marseille University, Marseille.

Although follicular lymphoma (FL) is usually graded as FL1-2, FL3A, and FL3B, some borderline cases can be observed and led us to investigate the clinicopathologic diversity of grade 3 FL (FL3). Among 2449 FL patients enrolled in Lymphoma Study Association (LYSA) trials, 1921 cases with sufficient material underwent a central pathologic review. The resulting diagnoses comprised 89.6% FL1-2 (n=1723), 7.2% FL3A (n=138), and 0.5% purely follicular FL3B (n=9). The remaining 51 unclassifiable cases (2.7%) exhibited high-grade features but did not meet WHO criteria for either FL3A or FL3B; and were considered as "unconventional" high-grade FL (FL3U). FL3U morphological pattern consisted of nodular proliferation of large cleaved cells or small-sized to medium-sized blast cells. Compared with FL3A, FL3U exhibited higher MUM1 and Ki67 expression, less BCL2 breaks and more BCL6 rearrangements, together with a higher number of cases without any BCL2, BCL6 or MYC rearrangement. FL3U harbored less frequent mutations in BCL2, KMT2D, KMT2B, and CREBBP than FL3A. MYC and BCL2 were less frequently mutated in FL3U than FL3B. Rituximab cyclophosphamide, doxorubicin, vincristine, and prednisone treated FL3U patients had a worse survival than FL1-2 patients with similar follicular lymphoma international prognostic index and treatment. These results suggest that high-grade FLs encompass a heterogeneous spectrum of tumors with variable morphology and genomic alterations, including FL3U cases that do not strictly fit WHO criteria for either FL3A or FL3B, and display a worse outcome than FL1-2. The distinction of FL3U may be useful to allow a better comprehension of high-grade FLs and to design clinical trials.
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http://dx.doi.org/10.1097/PAS.0000000000001726DOI Listing
October 2021

WEE1 Dependency and Pejorative Prognostic Value in Triple-Negative Breast Cancer.

Adv Sci (Weinh) 2021 Sep 6;8(17):e2101030. Epub 2021 Jul 6.

Laboratory of Predictive Oncology, Institut Paoli-Calmettes, Comprehensive Cancer Center, Aix-Marseille Univ, Marseille, 13009, France.

The WEE1 G2 checkpoint kinase acts as a negative cell cycle regulator for entry into mitosis (G2-to-M transition). This comment extends a recent Advanced Science paper by reporting higher WEE1-dependency of triple negative breast cancer (TNBC) cell lines, pejorative prognostic value of WEE1 expression in TNBC clinical samples as well as higher expression of biomarkers of sensitivity to WEE1 inhibitor.
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http://dx.doi.org/10.1002/advs.202101030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425927PMC
September 2021

Hybrid Living Capsules Autonomously Produced by Engineered Bacteria.

Adv Sci (Weinh) 2021 06 3;8(11):2004699. Epub 2021 May 3.

Department of Chemistry and Chemical Biology Northeastern University Boston MA 02115 USA.

Bacterial cellulose (BC) has excellent material properties and can be produced sustainably through simple bacterial culture, but BC-producing bacteria lack the extensive genetic toolkits of model organisms such as (). Here, a simple approach is reported for producing highly programmable BC materials through incorporation of engineered . The acetic acid bacterium is cocultured with engineered in droplets of glucose-rich media to produce robust cellulose capsules, which are then colonized by the upon transfer to selective lysogeny broth media. It is shown that the encapsulated can produce engineered protein nanofibers within the cellulose matrix, yielding hybrid capsules capable of sequestering specific biomolecules from the environment and enzymatic catalysis. Furthermore, capsules are produced which can alter their own bulk physical properties through enzyme-induced biomineralization. This novel system uses a simple fabrication process, based on the autonomous activity of two bacteria, to significantly expand the functionality of BC-based living materials.
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http://dx.doi.org/10.1002/advs.202004699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188213PMC
June 2021

Immune landscape of inflammatory breast cancer suggests vulnerability to immune checkpoint inhibitors.

Oncoimmunology 2021 05 23;10(1):1929724. Epub 2021 May 23.

Predictive Oncology Laboratory, "Equipe Labellisée Ligue Contre Le Cancer", Centre De Recherche En Cancérologie De Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Aix-Marseille Université, Marseille, France.

. Anti-PD1/PDL1 immune checkpoint inhibitors (ICIs) showed promising results in breast cancer, and exploration of additional actionable immune checkpoints is ongoing. Inflammatory breast cancer (IBC) is an aggressive form of disease, the immune tumor microenvironment (TME) of which is poorly known. We aimed at providing the first comprehensive immune portrait of IBCs. . From the gene expression profiles of 137 IBC and 252 non-IBC clinical samples, we measured the fractions of 22 immune cell types, expression of signatures associated with tertiary lymphoid structures (TLS) and with the response to ICIs (T cell-inflamed signature: TIS) and of 18 genes coding for major actionable immune checkpoints. The IBC/non-IBC comparison was adjusted upon the clinicopathological variables. . The immune profiles of IBCs were heterogeneous. CIBERSORT analysis showed profiles rich in macrophages, CD8+ and CD4 + T-cells, with remarkable similarity with melanoma TME. The comparison with non-IBCs showed significant enrichment in M1 macrophages, γδ T-cells, and memory B-cells. IBCs showed higher expression of TLS and TIS signatures. The TIS signature displayed values in IBCs close to those observed in other cancers sensitive to ICIs. Two-thirds of actionable immune genes (, and ) were overexpressed in IBCs as compared to normal breast and two-thirds were overexpressed in IBCs non-IBCs, with very frequent co-overexpression. For most of them, the overexpression was associated with better pathological response to chemotherapy. . Our results suggest the potential higher vulnerability of IBC to ICIs. Clinical trials.
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http://dx.doi.org/10.1080/2162402X.2021.1929724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158040PMC
May 2021

Prospective high-throughput genome profiling of advanced cancers: results of the PERMED-01 clinical trial.

Genome Med 2021 May 18;13(1):87. Epub 2021 May 18.

Department of Medical Oncology, Gustave Roussy Cancer Campus, UMR981 Inserm, Villejuif, France.

Background: The benefit of precision medicine based on relatively limited gene sets and often-archived samples remains unproven. PERMED-01 (NCT02342158) was a prospective monocentric clinical trial assessing, in adults with advanced solid cancer, the feasibility and impact of extensive molecular profiling applied to newly biopsied tumor sample and based on targeted NGS (t-NGS) of the largest gene panel to date and whole-genome array-comparative genomic hybridization (aCGH) with assessment of single-gene alterations and clinically relevant genomic scores.

Methods: Eligible patients with refractory cancer had one tumor lesion accessible to biopsy. Extracted tumor DNA was profiled by t-NGS and aCGH. We assessed alterations of 802 "candidate cancer" genes and global genomic scores, such as homologous recombination deficiency (HRD) score and tumor mutational burden. The primary endpoint was the number of patients with actionable genetic alterations (AGAs). Secondary endpoints herein reported included a description of patients with AGA who received a "matched therapy" and their clinical outcome, and a comparison of AGA identification with t-NGS and aCGH versus whole-exome sequencing (WES).

Results: Between November 2014 and September 2019, we enrolled 550 patients heavily pretreated. An exploitable complete molecular profile was obtained in 441/550 patients (80%). At least one AGA, defined in real time by our molecular tumor board, was found in 393/550 patients (71%, two-sided 90%CI 68-75%). Only 94/550 patients (17%, 95%CI 14-21) received an "AGA-matched therapy" on progression. The most frequent AGAs leading to "matched therapy" included PIK3CA mutations, KRAS mutations/amplifications, PTEN deletions/mutations, ERBB2 amplifications/mutations, and BRCA1/2 mutations. Such "matched therapy" improved by at least 1.3-fold the progression-free survival on matched therapy (PFS2) compared to PFS on prior therapy (PFS1) in 36% of cases, representing 6% of the enrolled patients. Within patients with AGA treated on progression, the use of "matched therapy" was the sole variable associated with an improved PFS2/PFS1 ratio. Objective responses were observed in 19% of patients treated with "matched therapy," and 6-month overall survival (OS) was 62% (95%CI 52-73). In a subset of 112 metastatic breast cancers, WES did not provide benefit in term of AGA identification when compared with t-NGS/aCGH.

Conclusions: Extensive molecular profiling of a newly biopsied tumor sample identified AGA in most of cases, leading to delivery of a "matched therapy" in 17% of screened patients, of which 36% derived clinical benefit. WES did not seem to improve these results.

Trial Registration: ID-RCB identifier: 2014-A00966-41; ClinicalTrials.gov identifier: NCT02342158 .
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http://dx.doi.org/10.1186/s13073-021-00897-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132379PMC
May 2021

The CINSARC signature predicts the clinical outcome in patients with Luminal B breast cancer.

NPJ Breast Cancer 2021 May 5;7(1):48. Epub 2021 May 5.

Laboratoire d'Oncologie Prédictive, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Marseille, France.

CINSARC, a multigene expression signature originally developed in sarcomas, was shown to have prognostic impact in various cancers. We tested the prognostic value for disease-free survival (DFS) of CINSARC in a series of 6035 early-stage invasive primary breast cancers. CINSARC had independent prognostic value in the Luminal B subtype and not in the other subtypes. In Luminal B patients receiving adjuvant endocrine therapy but no chemotherapy, CINSARC identified patients with different 5-year DFS (90% [95%CI 86-95] in low-risk vs. 79% [95%CI 75-84] in high-risk, p = 1.04E-02). Luminal B CINSARC high-risk tumors were predicted to be less sensitive to endocrine therapy and CDK4/6 inhibitors, but more vulnerable to homologous recombination targeting and immunotherapy. We concluded that CINSARC adds prognostic information to that of clinicopathological features in Luminal B breast cancers, which might improve patients' stratification and better orient adjuvant treatment. Moreover, it identifies potential therapeutic avenues in this aggressive molecular subtype.
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http://dx.doi.org/10.1038/s41523-021-00256-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099860PMC
May 2021

EFA6B regulates a stop signal for collective invasion in breast cancer.

Nat Commun 2021 04 13;12(1):2198. Epub 2021 Apr 13.

CNRS UMR7275, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Université Côte d'Azur, Valbonne, France.

Cancer is initiated by somatic mutations in oncogenes or tumor suppressor genes. However, additional alterations provide selective advantages to the tumor cells to resist treatment and develop metastases. Their identification is of paramount importance. Reduced expression of EFA6B (Exchange Factor for ARF6, B) is associated with breast cancer of poor prognosis. Here, we report that loss of EFA6B triggers a transcriptional reprogramming of the cell-to-ECM interaction machinery and unleashes CDC42-dependent collective invasion in collagen. In xenograft experiments, MCF10 DCIS.com cells, a DCIS-to-IDC transition model, invades faster when knocked-out for EFA6B. In addition, invasive and metastatic tumors isolated from patients have lower expression of EFA6B and display gene ontology signatures identical to those of EFA6B knock-out cells. Thus, we reveal an EFA6B-regulated molecular mechanism that controls the invasive potential of mammary cells; this finding opens up avenues for the treatment of invasive breast cancer.
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http://dx.doi.org/10.1038/s41467-021-22522-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044243PMC
April 2021

Clinical and genomic analysis of a large Chinese family with familial cortical myoclonic tremor with epilepsy and intronic repeat expansion.

Epilepsia Open 2021 03 2;6(1):102-111. Epub 2021 Feb 2.

Translational and Functional Genomics Branch National Human Genome Research Institute National Institutes of Health Bethesda MD USA.

Objective: Our goal was to perform detailed clinical and genomic analysis of a large multigenerational Chinese family with 21 individuals showing symptoms of Familial Cortical Myoclonic Tremor with Epilepsy (FCMTE) that we have followed for over 20 years.

Methods: Patients were subjected to clinical evaluation, routine EEG, and structural magnetic resonance imaging. Whole exome sequencing, repeat-primed PCR, long-range PCR, and PacBio sequencing were performed to characterize the disease-causing mutation in this family.

Results: All evaluated patients manifested adult-onset seizures and presented with progressive myoclonic postural tremors starting after the third or fourth decade of life. Seizures typically diminished markedly in frequency with implementation of antiseizure medications but did not completely cease. The electroencephalogram of affected individuals showed generalized or multifocal spikes and slow wave complexes. An expansion of TTTTA motifs with addition of TTTCA motifs in intron 4 of was identified to segregate with the disease phenotype in this family. Furthermore, we found that the mutant allele is unstable and can undergo both contraction and expansion by changes in the number of repeat motifs each time it is passed to the next generation. The size of mutant allele varied from 5 to 5.5 kb with 549-603 copies of TTTTA and 287-343 copies of TTTCA repeat motifs in this family.

Significance: Our study provides a detailed description of clinical progression of FCMTE symptoms and its management with antiseizure medications. Our method of repeat analysis by PacBio sequencing of long-range PCR products does not require high-quality DNA and hence can be easily applied to other families to elucidate any correlation between the repeat size and phenotypic variables, such as, age of onset, and severity of symptoms.
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http://dx.doi.org/10.1002/epi4.12450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918340PMC
March 2021

Transcriptomic Analysis of Laser Capture Microdissected Tumors Reveals Cancer- and Stromal-Specific Molecular Subtypes of Pancreatic Ductal Adenocarcinoma.

Clin Cancer Res 2021 Apr 5;27(8):2314-2325. Epub 2021 Feb 5.

Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) lethality is multifactorial; although studies have identified transcriptional and genetic subsets of tumors with different prognostic significance, there is limited understanding of features associated with the minority of patients who have durable remission after surgical resection. In this study, we performed laser capture microdissection (LCM) of PDAC samples to define their cancer- and stroma-specific molecular subtypes and identify a prognostic gene expression signature for short-term and long-term survival.

Experimental Design: LCM and RNA sequencing (RNA-seq) analysis of cancer and adjacent stroma of 19 treatment-naïve PDAC tumors was performed. Gene expression signatures were tested for their robustness in a large independent validation set. An RNA-ISH assay with pooled probes for genes associated with disease-free survival (DFS) was developed to probe 111 PDAC tumor samples.

Results: Gene expression profiling identified four subtypes of cancer cells (C1-C4) and three subtypes of cancer-adjacent stroma (S1-S3). These stroma-specific subtypes were associated with DFS ( = 5.55E-07), with S1 associated with better prognoses when paired with C1 and C2. Thirteen genes were found to be predominantly expressed in cancer cells and corresponded with DFS in a validation using existing RNA-seq datasets. A second validation on an independent cohort of patients using RNA-ISH probes to six of these prognostic genes demonstrated significant association with overall survival (median 17 vs. 25 months; < 0.02).

Conclusions: Our results identified specific signatures from the epithelial and the stroma components of PDAC, which add clarity to the nature of PDAC molecular subtypes and may help predict survival.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118131PMC
April 2021

Theranostic Targeting of CUB Domain Containing Protein 1 (CDCP1) in Pancreatic Cancer-Letter.

Clin Cancer Res 2020 10;26(20):5539

Laboratory of Predictive Oncology, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, Aix-Marseille Université, INSERM UMR1068, CNRS UMR725, Marseille, France.

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http://dx.doi.org/10.1158/1078-0432.CCR-20-1969DOI Listing
October 2020

Genomic landscape of inflammatory breast cancer identifies potential actionable genetic alterations.

Oncoscience 2020 Jul 30;7(7-8):57-59. Epub 2020 Jun 30.

Laboratoire d'Oncologie Prédictive, Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068, CNRS UMR7258, Institut Paoli-Calmettes, Aix-Marseille Université, Marseille F-13009, France.

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http://dx.doi.org/10.18632/oncoscience.515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458333PMC
July 2020

Revisiting the Concept of Stress in the Prognosis of Solid Tumors: A Role for Stress Granules Proteins?

Cancers (Basel) 2020 Sep 1;12(9). Epub 2020 Sep 1.

Predictive Oncology Laboratory, Cancer Research Center of Marseille (CRCM), Inserm U1068, CNRS UMR7258, Institut Paoli-Calmettes, Aix Marseille Université, 13009 Marseille, France.

Cancer treatments are constantly evolving with new approaches to improve patient outcomes. Despite progresses, too many patients remain refractory to treatment due to either the development of resistance to therapeutic drugs and/or metastasis occurrence. Growing evidence suggests that these two barriers are due to transient survival mechanisms that are similar to those observed during stress response. We review the literature and current available open databases to study the potential role of stress response and, most particularly, the involvement of Stress Granules (proteins) in cancer. We propose that Stress Granule proteins may have prognostic value for patients.
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http://dx.doi.org/10.3390/cancers12092470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564653PMC
September 2020

Neoplastic-Stromal Cell Cross-talk Regulates Matrisome Expression in Pancreatic Cancer.

Mol Cancer Res 2020 12 1;18(12):1889-1902. Epub 2020 Sep 1.

Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly desmoplastic reaction, warranting intense cancer-stroma communication. In this study, we interrogated the contribution of the BET family of chromatin adaptors to the cross-talk between PDAC cells and the tumor stroma. Short-term treatment of orthotopic xenograft tumors with CPI203, a small-molecule inhibitor of BET proteins, resulted in broad changes in the expression of genes encoding components of the extracellular matrix (matrisome) in both cancer and stromal cells. Remarkably, more than half of matrisome genes were expressed by cancer cells. cocultures of PDAC cells and cancer-associated fibroblasts (CAF) demonstrated that matrisome expression was regulated by BET-dependent cancer-CAF cross-talk. Disrupting this cross-talk resulted in diminished growth of orthotopic patient-derived xenograft tumors, reduced proliferation of cancer cells, and changes in collagen structure consistent with that of patients who experienced better survival. Examination of matrisome gene expression in publicly available data sets of 573 PDAC tumors identified a 65-gene signature that was able to distinguish long- and short-term PDAC survivors. Importantly, the expression of genes predictive of short-term survival was diminished in the cancer cells of orthotopic xenograft tumors of mice treated with CPI203. Taken together, these results demonstrate that inhibiting the activity BET proteins results in transcriptional and structural differences in the matrisome are associated with better patient survival. IMPLICATIONS: These studies highlight the biological relevance of the matrisome program in PDAC and suggest targeting of epigenetically driven tumor-stroma cross-talk as a potential therapeutic avenue.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0439DOI Listing
December 2020

ERBB2b mRNA isoform encodes a nuclear variant of the ERBB2 oncogene in breast cancer.

J Cell Biochem 2020 Jul 6. Epub 2020 Jul 6.

INSERM UMR1090 TAGC, Aix-Marseille University, Marseille, France.

The presence of nuclear ERBB2 receptor-type tyrosine kinase is one of the causes of the resistance to membrane ERBB2-targeted therapy in breast cancers. It has been previously reported that this nuclear location arises through at least two different mechanisms: proteolytic shedding of the extracellular domain of the full-length receptor and translation of the messenger RNA (mRNA)-encoding ERBB2 from internal initiation codons. Here, we report a new mechanism and function where a significant portion of nuclear ERBB2 results from the translation of the variant ERBB2 mRNA under the transcriptional control of a distal promoter that is actively used in breast cancer cells. We show that both membrane ERBB2a and nuclear ERBB2b isoforms are prevalently expressed in breast cancer cell lines and carcinoma samples. The ERBB2b isoform, which is translated from mRNA variant 2, can directly translocate into the nucleus due to the lack of the signal peptide which is required for an intermediate membrane location. Small interfering RNA-mediated gene silencing showed that ERBB2b can repress ERBB2a expression, encoded by variant 1, whereas ERBB2a activates ERBB2b. Nuclear ERBB2 binding to its own promoter was revealed by chromatin immunoprecipitation assay. Altogether, our results provide new insights into the origin and function of nuclear ERBB2 where it can participate at the same time in a positive or a negative feedback autoregulatory loop, dependent on which of its promoters this bona fide transcription factor is acting. They also provide a new understanding for the resistance to therapies targeting the membrane-anchored ERBB2 in breast cancer.
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http://dx.doi.org/10.1002/jcb.29762DOI Listing
July 2020

The mutational constraint spectrum quantified from variation in 141,456 humans.

Nature 2020 05 27;581(7809):434-443. Epub 2020 May 27.

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes. Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases.
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http://dx.doi.org/10.1038/s41586-020-2308-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334197PMC
May 2020

Human erythroleukemia genetics and transcriptomes identify master transcription factors as functional disease drivers.

Blood 2020 08;136(6):698-714

Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.

Acute erythroleukemia (AEL or acute myeloid leukemia [AML]-M6) is a rare but aggressive hematologic malignancy. Previous studies showed that AEL leukemic cells often carry complex karyotypes and mutations in known AML-associated oncogenes. To better define the underlying molecular mechanisms driving the erythroid phenotype, we studied a series of 33 AEL samples representing 3 genetic AEL subgroups including TP53-mutated, epigenetic regulator-mutated (eg, DNMT3A, TET2, or IDH2), and undefined cases with low mutational burden. We established an erythroid vs myeloid transcriptome-based space in which, independently of the molecular subgroup, the majority of the AEL samples exhibited a unique mapping different from both non-M6 AML and myelodysplastic syndrome samples. Notably, >25% of AEL patients, including in the genetically undefined subgroup, showed aberrant expression of key transcriptional regulators, including SKI, ERG, and ETO2. Ectopic expression of these factors in murine erythroid progenitors blocked in vitro erythroid differentiation and led to immortalization associated with decreased chromatin accessibility at GATA1-binding sites and functional interference with GATA1 activity. In vivo models showed development of lethal erythroid, mixed erythroid/myeloid, or other malignancies depending on the cell population in which AEL-associated alterations were expressed. Collectively, our data indicate that AEL is a molecularly heterogeneous disease with an erythroid identity that results in part from the aberrant activity of key erythroid transcription factors in hematopoietic stem or progenitor cells.
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http://dx.doi.org/10.1182/blood.2019003062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215330PMC
August 2020

Gains of EPOR and ERG genes in adult erythroleukaemia.

Br J Haematol 2020 05 29;189(4):e174-e177. Epub 2020 Mar 29.

Laboratoire d'Oncologie Prédictive, Centre de Recherche en Cancérologie de Marseille (CRCM), UMR 1068 Inserm, CNRS UMR7258, Institut Paoli-Calmettes, Aix-Marseille Université UM105, Marseille, France.

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http://dx.doi.org/10.1111/bjh.16586DOI Listing
May 2020

The therapeutic response of ER+/HER2- breast cancers differs according to the molecular Basal or Luminal subtype.

NPJ Breast Cancer 2020 6;6. Epub 2020 Mar 6.

Laboratoire d'Oncologie Prédictive, Centre de Recherche en Cancérologie de Marseille, Inserm U1068, CNRS UMR7258, Institut Paoli-Calmettes, Aix-Marseille Université, Marseille, France.

The genomics-based molecular classifications aim at identifying more homogeneous classes than immunohistochemistry, associated with a more uniform clinical outcome. We conducted an in silico analysis on a meta-dataset including gene expression data from 5342 clinically defined ER+/HER2- breast cancers (BC) and DNA copy number/mutational and proteomic data. We show that the Basal (16%) versus Luminal (74%) subtypes as defined using the 80-gene signature differ in terms of response/vulnerability to systemic therapies of BC. The Basal subtype is associated with better chemosensitivity, lesser benefit from adjuvant hormone therapy, and likely better sensitivity to PARP inhibitors, platinum salts and immune therapy, and other targeted therapies under development such as FGFR inhibitors. The Luminal subtype displays potential better sensitivity to CDK4/6 inhibitors and vulnerability to targeted therapies such as PIK3CA, AR and Bcl-2 inhibitors. Expression profiles are very different, showing an intermediate position of the ER+/HER2- Basal subtype between the ER+/HER2- Luminal and ER- Basal subtypes, and let suggest a different cell-of-origin. Our data suggest that the ER+/HER2- Basal and Luminal subtypes should not be assimilated and treated as a homogeneous group.
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http://dx.doi.org/10.1038/s41523-020-0151-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060267PMC
March 2020

Cancer-testis Antigen FATE1 Expression in Adrenocortical Tumors Is Associated with A Pervasive Autoimmune Response and Is A Marker of Malignancy in Adult, but Not Children, ACC.

Cancers (Basel) 2020 Mar 14;12(3). Epub 2020 Mar 14.

NEOGENEX-CANCER CNRS International Associated Laboratory, 660 route des Lucioles, Sophia Antipolis, 06560 Valbonne, France; 1532 Av. Silva Jardim, Curitiba PR 80250-200, Brazil.

The SF-1 transcription factor target gene encodes a cancer-testis antigen that has an important role in regulating apoptosis and response to chemotherapy in adrenocortical carcinoma (ACC) cells. Autoantibodies directed against FATE1 were previously detected in patients with hepatocellular carcinoma. In this study, we investigated the prevalence of circulating anti-FATE1 antibodies in pediatric and adult patients with adrenocortical tumors using three different methods (immunofluorescence, ELISA and Western blot). Our results show that a pervasive anti-FATE1 immune response is present in those patients. Furthermore, expression is a robust prognostic indicator in adult patients with ACC and is associated with increased steroidogenic and decreased immune response gene expression. These data can open perspectives for novel strategies in ACC immunotherapy.
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http://dx.doi.org/10.3390/cancers12030689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140037PMC
March 2020

EBV+ diffuse large B-cell lymphoma associated with chronic inflammation expands the spectrum of breast implant-related lymphomas.

Blood 2020 05;135(22):2004-2009

Department of Biopathology and Tumor Immunology, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille, INSERM U1068, Centre National de la Recherche Scientifique UMR 7258, Aix-Marseille University, UM105, Marseille, France.

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http://dx.doi.org/10.1182/blood.2019003408DOI Listing
May 2020

Overexpression of Annexin A1 Is an Independent Predictor of Longer Overall Survival in Epithelial Ovarian Cancer.

In Vivo 2020 Jan-Feb;34(1):177-184

Anatomic Pathology Department, Salah Azaiez Institute, Tunis, Tunisia.

Background: Epithelial ovarian cancer (EOC) is the major gynecological cause of cancer deaths. Annexin A1 (ANXA1) protein has been implicated in the aggressiveness of several cancer types.

Materials And Methods: This study retrospectively assessed ANXA1 expression in epithelial cells of 156 pre-chemotherapy EOC samples and 34 normal ovarian samples from patients treated at Salah Azaiez Institute. Using immunohistochemistry, ANXA1 expression was compared in normal versus cancer samples; correlations with clinicopathological features, including overall survival, were sought.

Results: Fifty-two percent of tumor samples showed epithelial ANXA1 staining versus only 26% of normal samples (Fisher's exact test, p=0.00794). Epithelial ANXA1 expression was correlated with better overall survival in both univariate and multivariate analyses.

Conclusion: The possible contribution of ANXA1 overexpression to EOC outcome may be relevant to therapeutic strategies.
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http://dx.doi.org/10.21873/invivo.11759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984120PMC
June 2020

NOTCH and DNA repair pathways are more frequently targeted by genomic alterations in inflammatory than in non-inflammatory breast cancers.

Mol Oncol 2020 03 5;14(3):504-519. Epub 2020 Feb 5.

Translational Cancer Research Unit and Center for Oncological Research (CORE), Faculty of Medicine and Health Sciences, GZA Hospitals Sint-Augustinus and University of Antwerp Wilrijk, Antwerp, Belgium.

Inflammatory breast cancer (IBC) is the most pro-metastatic form of breast cancer. Better understanding of its pathophysiology and identification of actionable genetic alterations (AGAs) are crucial to improve systemic treatment. We aimed to define the DNA profiles of IBC vs noninflammatory breast cancer (non-IBC) clinical samples in terms of copy number alterations (CNAs), mutations, and AGAs. We applied targeted next-generation sequencing (tNGS) and array-comparative genomic hybridization (aCGH) to 57 IBC and 50 non-IBC samples and pooled these data with four public datasets profiled using NGS and aCGH, leading to a total of 101 IBC and 2351 non-IBC untreated primary tumors. The respective percentages of each molecular subtype [hormone receptor-positive (HR+)/HER2-, HER2+, and triple-negative] were 68%, 15%, and 17% in non-IBC vs 25%, 35%, and 40% in IBC. The comparisons were adjusted for both the molecular subtypes and the American Joint Committee on Cancer (AJCC) stage. The 10 most frequently altered genes in IBCs were TP53 (63%), HER2/ERBB2 (30%), MYC (27%), PIK3CA (21%), BRCA2 (14%), CCND1 (13%), GATA3 (13%), NOTCH1 (12%), FGFR1 (11%), and ARID1A (10%). The tumor mutational burden was higher in IBC than in non-IBC. We identified 96 genes with an alteration frequency (p < 5% and q < 20%) different between IBC and non-IBC, independently from the molecular subtypes and AJCC stage; 95 were more frequently altered in IBC, including TP53, genes involved in the DNA repair (BRCA2) and NOTCH pathways, and one (PIK3CA) was more frequently altered in non-IBC. Ninety-seven percent of IBCs displayed at least one AGA. This percentage was higher than in non-IBC (87%), notably for drugs targeting DNA repair, NOTCH signaling, and CDK4/6, whose pathways were more frequently altered (DNA repair) or activated (NOTCH and CDK4/6) in IBC than in non-IBC. The genomic landscape of IBC is different from that of non-IBC. Enriched AGAs in IBC may explain its aggressiveness and provide clinically relevant targets.
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http://dx.doi.org/10.1002/1878-0261.12621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053236PMC
March 2020

Gene alterations in epigenetic modifiers and JAK-STAT signaling are frequent in breast implant-associated ALCL.

Blood 2020 01;135(5):360-370

Institut Mondor de Recherche Biomédicale, INSERM U955, Université Paris-Est, Créteil, France.

The oncogenic events involved in breast implant-associated anaplastic large cell lymphoma (BI-ALCL) remain elusive. To clarify this point, we have characterized the genomic landscape of 34 BI-ALCLs (15 tumor and 19 in situ subtypes) collected from 54 BI-ALCL patients diagnosed through the French Lymphopath network. Whole-exome sequencing (n = 22, with paired tumor/germline DNA) and/or targeted deep sequencing (n = 24) showed recurrent mutations of epigenetic modifiers in 74% of cases, involving notably KMT2C (26%), KMT2D (9%), CHD2 (15%), and CREBBP (15%). KMT2D and KMT2C mutations correlated with a loss of H3K4 mono- and trimethylation by immunohistochemistry. Twenty cases (59%) showed mutations in ≥1 member of the JAK/STAT pathway, including STAT3 (38%), JAK1 (18%), and STAT5B (3%), and in negative regulators, including SOCS3 (6%), SOCS1 (3%), and PTPN1 (3%). These mutations were more frequent in tumor-type samples than in situ samples (P = .038). All BI-ALCLs expressed pSTAT3, regardless of the mutational status of genes in the JAK/STAT pathway. Mutations in the EOMES gene (12%) involved in lymphocyte development, PI3K-AKT/mTOR (6%), and loss-of-function mutations in TP53 (12%) were also identified. Copy-number aberration (CNA) analysis identified recurrent alterations, including gains on chromosomes 2, 9p, 12p, and 21 and losses on 4q, 8p, 15, 16, and 20. Regions of CNA encompassed genes involved in the JAK/STAT pathway and epigenetic regulators. Our results show that the BI-ALCL genomic landscape is characterized by not only JAK/STAT activating mutations but also loss-of-function alterations of epigenetic modifiers.
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http://dx.doi.org/10.1182/blood.2019001904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059458PMC
January 2020

MARCKS protein overexpression is associated with poor prognosis in male breast cancer.

Cancer Biomark 2019 ;26(4):513-522

Department of Immuno-Histo-Cytology, Salah Azaiez Institute, Tunis, Tunisia.

Background: Male breast cancer (MBC) is a rare and aggressive disease. Thus, identification of new therapeutic targets is crucial.

Objective: Our objective was to evaluate the protein expression of MARCKS (Myristoylated Alanine-Rich C-Kinase Substrate) in MBC and to investigate its prognostic value.

Materials And Methods: MARCKS protein expression in tumor and stromal cells was analyzed by immunohistochemistry (IHC) in a retrospective series of 96 pre-chemotherapy MBC samples and 80 normal breast samples, from Tunisian patients treated at Salah Azaiez Institute. Correlations were searched between MARCKS expression and clinicopathological features including overall survival (OS).

Results: MARCKS was overexpressed in epithelial tumor cells in 66% of the MBC samples versus 26% of normal samples (p= 1.40 × 10-7). Such positive MARCKS expression in epithelial tumor cells was associated with positive HER2 status (p= 4.0 × 10-3). It was associated with shorter OS in uni-and multivariate analysis. By contrast, stromal IHC MARCKS expression was correlated only with tumor grade.

Conclusion: MARCKS tumor cell overexpression might in part explain the aggressiveness and the poor prognosis of MBC. MARCKS can represent a potential therapeutic target for MBC.
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http://dx.doi.org/10.3233/CBM-190637DOI Listing
June 2020

expression is associated with longer postoperative, survival in adrenocortical carcinoma.

Oncoimmunology 2019;8(11):e1655362. Epub 2019 Aug 28.

Laboratoire Oncologie Prédictive, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, INSERM UMR1068, CNRS UMR725, Aix-Marseille Université, Marseille, France.

Adrenocortical carcinomas (ACCs) are heterogeneous cancers associated with a very poor prognosis. The improvement of prognostic tools and systemic therapy are urgently needed. Targeting the immune system using checkpoint inhibitors such as PD1/PDL1 inhibitors is an attractive novel therapeutic strategy for poor-prognosis tumors. Multiple clinical trials are ongoing, including in advanced ACC. However, PDL1 expression has been studied in ACC in only one heterogeneous series of 28 clinical samples. Here, we have retrospectively analyzed mRNA expression in 146 clinical ACC samples and searched for correlations between expression and biological and clinicopathological data, including post-operative disease-free survival (DFS). mRNA expression was heterogeneous across samples. "PDL1-high" tumors were not associated with the classical prognostic variables but were associated with longer DFS in both uni- and multivariate analyses. High PDL1 mRNA expression was associated with biological signs of the cytotoxic local immune response. Supervised analysis between "PDL1-high" and "PDL1-low" tumors identified a robust 370-gene signature whose ontology analysis suggested the existence in "PDL1-high" tumors of a cytotoxic T-cell response, however, associated with some degree of T-cell exhaustion. In conclusion, mRNA expression refines the prognostication in ACC and high expression is associated with longer DFS. Clinical validation at the protein level and functional validation are required to fully understand the role of PDL1 in ACC. Reactivation of dormant tumor-infiltrating lymphocytes by PDL1-inhibitors could represent a promising strategy in "PDL1-high" ACCs, supporting the ongoing clinical trials.
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http://dx.doi.org/10.1080/2162402X.2019.1655362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791455PMC
August 2019

Epigenetic down-regulation of the HIST1 locus predicts better prognosis in acute myeloid leukemia with NPM1 mutation.

Clin Epigenetics 2019 10 12;11(1):141. Epub 2019 Oct 12.

Epigenetic Factors in Normal and Malignant Hematopoiesis Team, Aix Marseille University, CNRS, Inserm, Institut Paoli-Calmettes, CRCM, 27 Boulevard Lei Roure, 13273, Marseille Cedex 09, France.

Background: The epigenetic machinery is frequently altered in acute myeloid leukemia. Focusing on cytogenetically normal (CN) AML, we previously described an abnormal H3K27me3 enrichment covering 70 kb on the HIST1 cluster (6.p22) in CN-AML patient blasts. Here, we further investigate the molecular, functional, and prognosis significance of this epigenetic alteration named H3K27me3 HIST1 in NPM1-mutated (NPM1mut) CN-AML.

Results: We found that three quarter of the NPM1mut CN-AML patients were H3K27me3 HIST1. H3K27me3 HIST1 group of patients was associated with a favorable outcome independently of known molecular risk factors. In gene expression profiling, the H3K27me3 HIST1 mark was associated with lower expression of the histone genes HIST1H1D, HIST1H2BG, HIST1H2AE, and HIST1H3F and an upregulation of genes involved in myelomonocytic differentiation. Mass spectrometry analyses confirmed that the linker histone protein H1d, but not the other histone H1 subtypes, was downregulated in the H3K27me3 HIST1 group of patients. H1d knockdown primed ATRA-mediated differentiation of OCI-AML3 and U937 AML cell lines, as assessed on CD11b/CD11c markers, morphological and gene expression analyses.

Conclusions: Our data suggest that NPM1mut AML prognosis depends on the epigenetic silencing of the HIST1 cluster and that, among the H3K27me3 silenced histone genes, HIST1H1D plays a role in AML blast differentiation.
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http://dx.doi.org/10.1186/s13148-019-0738-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790061PMC
October 2019

Acute erythroid leukemias have a distinct molecular hierarchy from non-erythroid acute myeloid leukemias.

Haematologica 2020 07 10;105(7):e340-e342. Epub 2019 Oct 10.

Laboratoire d'Oncologie Prédictive, Centre de Recherche en Cancérologie de Marseille UMR1068 Inserm, Institut Paoli-Calmettes, CNRS UMR7258, Aix-Marseille Université UM105, Marseille.

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http://dx.doi.org/10.3324/haematol.2019.231142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327663PMC
July 2020

Machine-Learning Classification Suggests That Many Alphaproteobacterial Prophages May Instead Be Gene Transfer Agents.

Genome Biol Evol 2019 10;11(10):2941-2953

Department of Biological Sciences, Dartmouth College, Hanover, New Hampshire.

Many of the sequenced bacterial and archaeal genomes encode regions of viral provenance. Yet, not all of these regions encode bona fide viruses. Gene transfer agents (GTAs) are thought to be former viruses that are now maintained in genomes of some bacteria and archaea and are hypothesized to enable exchange of DNA within bacterial populations. In Alphaproteobacteria, genes homologous to the "head-tail" gene cluster that encodes structural components of the Rhodobacter capsulatus GTA (RcGTA) are found in many taxa, even if they are only distantly related to Rhodobacter capsulatus. Yet, in most genomes available in GenBank RcGTA-like genes have annotations of typical viral proteins, and therefore are not easily distinguished from their viral homologs without additional analyses. Here, we report a "support vector machine" classifier that quickly and accurately distinguishes RcGTA-like genes from their viral homologs by capturing the differences in the amino acid composition of the encoded proteins. Our open-source classifier is implemented in Python and can be used to scan homologs of the RcGTA genes in newly sequenced genomes. The classifier can also be trained to identify other types of GTAs, or even to detect other elements of viral ancestry. Using the classifier trained on a manually curated set of homologous viruses and GTAs, we detected RcGTA-like "head-tail" gene clusters in 57.5% of the 1,423 examined alphaproteobacterial genomes. We also demonstrated that more than half of the in silico prophage predictions are instead likely to be GTAs, suggesting that in many alphaproteobacterial genomes the RcGTA-like elements remain unrecognized.
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http://dx.doi.org/10.1093/gbe/evz206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821227PMC
October 2019
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