Temporal and regional X-linked gene reactivation in the mouse germline reveals site-specific retention of epigenetic silencing.

Random X-chromosome inactivation is a hallmark of female mammalian somatic cells. This epigenetic mechanism, mediated by the long noncoding RNA Xist, occurs in the early embryo and is stably maintained throughout life, although inactivation is lost during primordial germ cell (PGC) development. Using a combination of single-cell allele-specific RNA sequencing and low-input chromatin profiling on developing mouse PGCs, we provide a detailed map of X-linked gene reactivation.

Nanopore Sequencing as a Cutting-Edge Technology for Medulloblastoma Classification.

Background: Medulloblastoma (MB) is one of the most prevalent embryonal malignant brain tumors. Current classification organizes these tumors into four molecular subgroups (WNT, SHH, Group 3, and Group 4 MB). Recently, a comprehensive classification has been established, identifying numerous subtypes, some of which exhibit a poor prognosis.

Suite of Biochemical and Cell-Based Assays for the Characterization of Kirsten Rat Sarcoma (KRAS) Inhibitors and Degraders.

KRAS is an important oncogenic driver which is mutated in numerous cancers. Recent advances in the selective targeting of KRAS mutants via small molecule inhibitors and targeted protein degraders have generated an increase in research activity in this area in recent years. As such, there is a need for new assay platforms to profile next generation inhibitors which improve on the potency and selectivity of existing drug candidates, while evading the emergence of resistance.

TREMSUCS-TCGA - an integrated workflow for the identification of biomarkers for treatment success.

Many publicly available databases provide disease related data, that makes it possible to link genomic data to medical and meta-data. The cancer genome atlas (TCGA), for example, compiles tens of thousand of datasets covering a wide array of cancer types. Here we introduce an interactive and highly automatized TCGA-based workflow that links and analyses epigenomic and transcriptomic data with treatment and survival data in order to identify possible biomarkers that indicate treatment success.

Copy number alterations in metastatic and early breast tumours: prognostic and acquired biomarkers of resistance to CDK4/6 inhibitors.

Background: Copy number alterations (CNA) are acquired during the evolution of cancers from their early stage to metastatic stage. This study aims at analysing the clinical value of the identified metastasis-associated CNAs both in metastatic breast cancers (mBCs) and early breast cancers (eBCs).

Methods: Single-nucleotide polymorphism (SNP)-array was performed on 926 biopsies from mBC patients, enrolled in SAFIR02-BREAST prospective trial.

Metastatic renal cell carcinoma with occult primary: a multicenter prospective cohort.

Metastatic carcinoma of presumed renal origin (rCUP) has recently emerged as a new entity within the heterogeneous entity of Cancers of Unknown Primary (CUP) but their biological features and optimal therapeutic management remain unknown. We report the molecular characteristics and clinical outcome of a series of 25 rCUP prospectively identified within the French National Multidisciplinary Tumor Board for CUP. This cohort strongly suggests that rCUP share similarities with common RCC subtypes and benefit from renal-tailored systemic treatment.

Escape from X inactivation is directly modulated by levels of Xist non-coding RNA.

In placental females, one copy of the two X chromosomes is largely silenced during a narrow developmental time window, in a process mediated by the non-coding RNA Xist. Here, we demonstrate that Xist can initiate X-chromosome inactivation (XCI) well beyond early embryogenesis. By modifying its endogenous level, we show that Xist has the capacity to actively silence genes that escape XCI both in neuronal progenitor cells (NPCs) and , in mouse embryos.

p4EBP1 staining predicts outcome in ER-positive endocrine-resistant metastatic breast cancer patients treated with everolimus and exemestane.

Background: To identify patients most likely to respond to everolimus, a mammalian target of rapamycin (mTOR) inhibitor, a prospective biomarker study was conducted in hormone receptor-positive endocrine-resistant metastatic breast cancer patients treated with exemestane-everolimus therapy.

Methods: Metastatic tumor biopsies were processed for immunohistochemical staining (p4EBP1, PTEN, pAKT, LKB1, and pS6K). ESR1, PIK3CA and AKT1 gene mutations were detected by NGS.

Chromatin state transitions in the Drosophila intestinal lineage identify principles of cell-type specification.

Tissue homeostasis relies on rewiring of stem cell transcriptional programs into those of differentiated cells. Here, we investigate changes in chromatin occurring in a bipotent adult stem cells. Combining mapping of chromatin-associated factors with statistical modeling, we identify genome-wide transitions during differentiation in the adult Drosophila intestinal stem cell (ISC) lineage.

Molecular underpinnings and environmental drivers of loss of heterozygosity in Drosophila intestinal stem cells.

During development and aging, genome mutation leading to loss of heterozygosity (LOH) can uncover recessive phenotypes within tissue compartments. This phenomenon occurs in normal human tissues and is prevalent in pathological genetic conditions and cancers. While studies in yeast have defined DNA repair mechanisms that can promote LOH, the predominant pathways and environmental triggers in somatic tissues of multicellular organisms are not well understood.

Patient Derived Xenografts (PDX) Models as an Avatar to Assess Personalized Therapy Options in Uveal Melanoma: A Feasibility Study.

Uveal melanoma is the most common primary intraocular malignancy in adults. Up to 50% of UM patients develop metastatic disease, usually in the liver. When metastatic, the prognosis is poor, and few treatment options exist.

Virilization at puberty in adolescent girls may reveal a 46,XY disorder of sexual development.

Although hyperandrogenism is a frequent cause of consultation in adolescent girls, more severe forms with virilization must lead to suspicion of an adrenal or ovarian tumor. However, they may also reveal a 46,XY disorder of sexual development (DSD). Here, we describe four adolescent girls referred for pubertal virilization and in whom we diagnosed a 46,XY DSD.

Multi-omics comparison of malignant and normal uveal melanocytes reveals molecular features of uveal melanoma.

Uveal melanoma (UM) is a rare cancer resulting from the transformation of melanocytes in the uveal tract. Integrative analysis has identified four molecular and clinical subsets of UM. To improve our molecular understanding of UM, we performed extensive multi-omics characterization comparing two aggressive UM patient-derived xenograft models with normal choroidal melanocytes, including DNA optical mapping, specific histone modifications, and DNA topology analysis using Hi-C.

Nivolumab plus chemoradiotherapy in locally-advanced cervical cancer: the NICOL phase 1 trial.

Concurrent chemoradiotherapy (CRT) with blockade of the PD-1 pathway may enhance immune-mediated tumor control through increased phagocytosis, cell death, and antigen presentation. The NiCOL phase 1 trial (NCT03298893) is designed to determine the safety/tolerance profile and the recommended phase-II dose of nivolumab with and following concurrent CRT in 16 women with locally advanced cervical cancer. Secondary endpoints include objective response rate (ORR), progression free survival (PFS), disease free survival, and immune correlates of response.

Adaptive nanopore sequencing to determine pathogenicity of exonic duplication.

and are tumour suppressor genes that have been characterised as predisposition genes for the development of hereditary breast and ovarian cancers among other malignancies. The molecular diagnosis of this predisposition syndrome is based on the detection of inactivating variants of any type in those genes. But in the case of structural variants, functional consequences can be difficult to assess using standard molecular methods, as the precise resolution of their sequence is often impossible with short-read next generation sequencing techniques.