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• Djerroudi et al., E-cadherin inactivation shapes tumor microenvironment specificities in invasive lobular carcinoma

  Invasive lobular breast carcinoma (ILC) shows specific stromal features, T lymphocyte infiltration (TIL) being associated with poor prognosis. Here, we reveal the involved mechanism by performing single cell RNA sequencing, combined immunohistochemistry, deconvolution of bulk RNA sequencing from large retrospective ILC series, and functional assays using primary cells. We show that ILC accumulate FAP+ inflammatory cancer-associated fibroblasts (iCAF) through a previously undescribed mechanism mediated by E-cadherin/CDH1 on CAF plasticity. Indeed, CDH1 inactivation in ILC cancer cells prevents differentiation of iCAF into myofibroblastic CAF (myCAF), leading to iCAF accumulation. In turn, iCAF increase TIL infiltration and shape their spatial organization in ILC. Subsequently, CDH1-inactivated ILC cancer cells promote immune escape by lack of retention and activation of ITGAE-expressing resident memory CD8+ T lymphocytes (TRM). Hence, our study uncovers reciprocal interactions between CDH1-inactivated cancer cells, iCAF and CD8+ TRM, revealing why and how TILs have a poor prognosis in ILC patients, a mechanism extrapolated to other CDH1-mutated cancer types.

  Study EGAS50000000761

• Reading about genomic analysis of pan-neuroblastoma

  There are virtually no research fields that do not benefit from the large-scale genomic analysis that are so popular nowadays. For research into diseases with highly diverse clinical behavior like pediatric neuroblastoma, nevertheless, this type of approach has been a game-changer. Samuel W. Brady and colleagues, from St. Jude Children’s Research Hospital in Memphis, have gathered data from 702 neuroblastomas which were profiled by whole genome sequencing (WGS, n = 205), whole exome sequencing (WES, n = 539), and/or RNA-Seq. Less than half of the samples were generated during this study, while the others were obtained from previous work. Part of the WES data was indeed deposited in EGA in 2012 (EGA study EGAS00001000213). A scratchy summary about the huge work from Samuel W. Brady and colleagues, published in Nature Communications this October 2020 “These findings suggest that the sympathetic nervous system, the tissue from which neuroblastoma arises, is susceptible to different oncogenic insults at different times during development, which could be explored in future investigations using animal models.” Conclude the authors, highlighting the importance of their findings. Pediatric neuroblastomas are classified according to clinical and molecular features into low, intermediate, and high risk. Age plays a critical role in the classification, with younger children having an overall better prognosis. The samples included in this study belonged to all ages and risk-groups: the aim of such set up is the identification of age-associated molecular aberrations. The authors defined a mutational landscape of pediatric neuroblastoma including rare driver events, impossible to pick with a smaller data set. Interestingly, most driver mutations' frequency was found to be age-related. Those include alterations on MYCN, TERT, PTPRD, and Ras pathway, in addition to the previously reported ATRX. In addition, the large data set allowed the authors to define co-existence relations between the mutations (mutual exclusion or co-occurrence) which is a crucial puzzle piece to unravel the mechanisms driving the pathogenesis. Enjoy this really interesting article, open source on Pubmed.

  Blog genomic-analysis-of-pan-neuroblastoma

• Genomic Analyses Identify Recurrent MEF2D Fusions in Acute Lymphoblastic Leukemia

  Chromosomal rearrangements are initiating events in acute lymphoblastic leukemia (ALL). Here, using RNA-sequencing (RNAseq) of 560 ALL cases, we identify rearrangements between MEF2D (myocyte enhancer factor 2D) and five genes (BCL9, CSF1R, DAZAP1, HNRNPUL1 and SS18) in 22 B progenitor ALL (B-ALL) cases with a distinct gene expression profile, the most common of which is MEF2D-BCL9. Examination of an extended cohort of 1164 B-ALL cases identified 30 cases with MEF2D rearrangements which include an additional fusion partner, FOXJ2, thus MEF2D-rearranged cases comprise 5.3% of cases lacking recurring alterations. MEF2D-rearranged ALL is characterized by a distinct immunophenotype, DNA copy number alterations at the rearrangement sites, older diagnosis age, and poor outcome. The rearrangements result in enhanced MEF2D transcriptional activity, lymphoid transformation, activation of HDAC9 expression and sensitive to histone deacetylase inhibitors treatment. Thus, MEF2D-rearranged ALL represents a distinct form of high-risk leukemia, for which new therapeutic approaches should be considered.

  Study EGAS00001001952

• Comprehensive analyses of somatic TP53 mutation in tumors with variable mutant allele frequency

  Somatic mutation of the tumor suppressor gene TP53 is reported in at least 50% of human malignancies. Most high-grade serous ovarian cancers (HGSC) have a mutant TP53 allele. Accurate detection of these mutants in heterogeneous tumor tissue is paramount as therapies emerge to target mutant p53. We used a Fluidigm Access Array™ System with Massively Parallel Sequencing (MPS) to analyze DNA extracted from 76 serous ovarian tumors. This dataset has been made available to researchers through the European Genome-phenome Archive (EGA). Herein, we present detailed analyses of this dataset using HaplotypeCaller and MuTect2 through the Broad Institute’s Genome Analysis Toolkit (GATK). We also present comparisons of the ability to detect TP53 mutation by MPS and Sanger sequencing in these tumors. We anticipate that this TP53 mutation dataset will be useful to researchers developing and testing new software to accurately determine high and low frequency variant alleles in heterogeneous aneuploid tumor tissue. Further, the analysis pipeline we present provides a valuable framework for determining somatic variants more broadly in tumor tissue.

  Study EGAS00001002200

• Population_dynamics_in_abnormal_haematopoiesis

  Background: Our recent study has made direct insight into the clonal dynamics of blood cell production in an unperturbed setting in a human. Using whole genome sequencing to track acquired somatic mutations, we were able to construct a phylogenetic tree of different stem and progenitor cells and used this tree to determine the dynamics of mature blood cell production in longitudinal samples. These data set the baseline for understanding population dynamics in abnormal haematopoiesis, and how malignant clones outcompete their normal counterparts to drive haematological malignancies. Aim: This study will measure population dynamics in abnormal human haematopoiesis in patients with clonal blood stem cell disorders. Methods: From patient bone marrow or peripheral blood, we have isolated colonies grown from single blood stem cells/progenitors. Colony DNA will be analysed by whole-genome sequencing to build (or populate) a phylogenetic tree to determine clonal relationships and track stem cell contribution to mature blood cell production. These data will also reveal disease-associated genomic features (mutational burden and mutational signatures) in haematopoietic cells.

  Study EGAS00001003181

• DERMATLAS__SG_basal_cell_adenoma_and_adenocarcinoma_WES

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are SG basal cell adenomas and adenocarcinomas.

  Study EGAS00001007745

• DERMATLAS__Hidradenoma_papilliferum_WES

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are hidradenoma papilliferums.

  Study EGAS00001005714

• DERMATLAS__Porocarcinoma_WES

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are porocarcinomas.

  Study EGAS00001005720

• DERMATLAS__Poroma_RNAseq

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are poromas.

  Study EGAS00001005759

• Clonal hematopoiesis is associated with adverse outcomes in patients with COVID-19

  Clonal hematopoiesis of indeterminate potential (CHIP) is defined as the occurrence of an expanded proportion of mature blood cells derived from a mutant hematopoietic precursor without evidence of hematological malignancies. The principle behind this is that the somatic mutation confers a fitness advantage to the cell in which it arose. Different clinical consequences are linked with this expansion. Early evidence of an association with higher mortality risk was provided. This was not related to higher rates of cancer but was associated in particular with increased cardiovascular mortality. Mechanistically, inflammatory processes are not only related to the development of clonal hematopoiesis, but in turn it is also a driver of inflammation. Besides pulmonary symptoms, COVID-19 evokes complex extra-pulmonary manifestations driving the pathophysiology. Among them, both inflammatory and cardiac-associated mechanisms have been deciphered. With the aim of assessing the impact of clonal hematopoiesis on the pathophysiology of COVID-19, hospitalized patients with severe or critical course were evaluated for the presence of CHIP driver mutations and, more importantly, the association with the clinical picture.

  Study EGAS00001006218