Deep multi-omics integration approach reveals new molecular features of uterine leiomyosarcoma.

Uterine leiomyosarcoma (uLMS) is a rare and aggressive cancer representing approximately 25 % of all uterine malignancies. The molecular heterogeneity and pathogenesis of uLMS are not well understood, and translational studies aimed at discovering the vulnerabilities of this tumor type are of high priority. We conducted an innovative comprehensive multi-omics integration study from DNA to protein using freshly frozen tumors.

Exploring Molecular Drivers of PARPi Resistance in BRCA1-Deficient Ovarian Cancer: The Role of LY6E and Immunomodulation.

Approximately 50% of patients diagnosed with ovarian cancer harbor tumors with mutations in BRCA1, BRCA2, or other genes involved in homologous recombination repair (HR). The presence of homologous recombination deficiency (HRD) is an approved biomarker for poly-ADP-ribose polymerase inhibitors (PARPis) as a maintenance treatment following a positive response to initial platinum-based chemotherapy. Despite this treatment option, the development of resistance to PARPis is common among recurrent disease patients, leading to a poor prognosis.

p53 Abnormal (Copy Number High) Endometrioid Endometrial Carcinoma Has a Prognosis Indistinguishable From Serous Carcinoma.

Among the 4 molecular subgroups of endometrial carcinoma, the p53 abnormal (copy number high) subgroup has the worst prognosis; however, the histologic characteristics of this subgroup are not well established. Also, it is not well established whether low-grade tumors can belong to the p53 abnormal molecular subgroup and if so, what is the prognostic significance of the p53-mutated molecular subgroup in low-grade tumors. In the current study, we included 146 p53-mutated endometrial carcinomas and performed molecular subgrouping either based on a combination of immunohistochemical studies for p53 and MMR protein expression and POLE mutation testing (81 cases) or based on array-based and sequencing-based technologies (65 cases).

A comprehensive population-based study of malignant ovarian tumors, including histologic and immunohistochemical review, in children and adolescents 0-19 years old in Sweden between 1970 and 2014.

Objectives: Ovarian tumors in the pediatric population are rare. The incidence and frequency of subtypes differ between children and adults. Although not all tumors are aggressive, they may still lead to morbidity.

Brazilian XP-E siblings carrying a novel DDB2 variant developed early-onset melanoma: a case report.

Background: Xeroderma pigmentosum group E (XP-E) is one of the least common forms of XP, a rare syndrome where patients are prone to develop skin cancer in exposed sunlight areas. XP-E patients are generally not diagnosed until they are adults due to the mild phenotype.

Case Presentation: two XP-E siblings, female, 23 years, and male, 25 years, from a Brazilian consanguineous family carrying the novel missense pathogenic variant in DDB2 gene, NM_000107.

FOXL2 Mutation Status in Sex Cord-stromal Tumors Cannot be Predicted by Morphology.

Granulosa-cell tumors (GCTs) are the most common type of malignant ovarian sex cord-stromal tumor (SCST). The histopathologic diagnosis of these tumors can be challenging. A recurrent somatic mutation of the forkhead box L2 (FOXL2) gene has been identified in adult GCT.

Genomic mutation landscape of skin cancers from DNA repair-deficient xeroderma pigmentosum patients.

Xeroderma pigmentosum (XP) is a genetic disorder caused by mutations in genes of the Nucleotide Excision Repair (NER) pathway (groups A-G) or in Translesion Synthesis DNA polymerase η (V). XP is associated with an increased skin cancer risk, reaching, for some groups, several thousand-fold compared to the general population. Here, we analyze 38 skin cancer genomes from five XP groups.

MMP14 expression and collagen remodelling support uterine leiomyosarcoma aggressiveness.

Fibrillar collagen deposition, stiffness and downstream signalling support the development of leiomyomas (LMs), common benign mesenchymal tumours of the uterus, and are associated with aggressiveness in multiple carcinomas. Compared with epithelial carcinomas, however, the impact of fibrillar collagens on malignant mesenchymal tumours, including uterine leiomyosarcoma (uLMS), remains elusive. In this study, we analyse the network morphology and density of fibrillar collagens combined with the gene expression within uLMS, LM and normal myometrium (MM).

The Expression of the Immunoproteasome Subunit PSMB9 Is Related to Distinct Molecular Subtypes of Uterine Leiomyosarcoma.

Background: Uterine leiomyosarcoma (uLMS) are rare and malignant tumors that arise in the myometrium cells and whose diagnosis is based on histopathological features. Identifying diagnostic biomarkers for uLMS is a challenge due to molecular heterogeneity and the scarcity of samples. In vivo and in vitro models for uLMS are urgently needed.

XPC and POLH/XPV Genes Mutated in a Genetic Cluster of Xeroderma Pigmentosum Patients in Northeast Brazil.

Xeroderma pigmentosum (XP) is a rare genetic condition in which exposure to sunlight leads to a high tumor incidence due to defective DNA repair machinery. Herein, we investigated seven patients clinically diagnosed with XP living in a small city, Montanhas (Rio Grande do Norte), in the Northeast region of Brazil. We performed high-throughput sequencing and, surprisingly, identified two different mutated genes.

Precision Oncology of High-Grade Ovarian Cancer Defined through Targeted Sequencing.

Background: We examined whether molecular characterization of high-grade epithelial ovarian cancer can inform the diagnosis and/or identify potential actionable targets.

Methods: All of the consecutively sequenced high-grade ovarian tumours with consent between 2014 until 2019 were included. A total of 274 tumours underwent next generation sequencing using a targeted panel.

Germline Compound Heterozygous Variants Identified in the Gene Leading to a Familial Hemophagocytic Lymphohistiocytosis Type 5: A Case Report.

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, potentially fatal autosomal-recessive immunodeficiency, and mutations have been associated with FHL type 5 (FHL-5). Here, we report a case of a 2-year-old boy who presented with recurrent fever, hepatosplenomegaly, pancytopenia, hyperferritinemia, and hypofibrinogenemia since 4 months of age. His genetic analysis revealed a compound heterozygosity of the gene with a described pathogenic mutation, c.

Prevalence of extracapsular extension in metastatic sentinel lymph nodes in breast cancer.

Introduction: Axillary lymph node involvement is recognized as a key prognostic factor for invasive breast cancer. Retrospective analyzes have shown that extracapsular extension (ECE) is correlated with negative prognostic factors in this neoplasia.

Objective: to evaluate the measurement of ECE and its relationship with the number of affected non-sentinel lymph nodes, as well as to investigate the association between ECE with other clinical and pathological prognostic factors.

The hMsh2-hMsh6 complex acts in concert with monoubiquitinated PCNA and Pol η in response to oxidative DNA damage in human cells.

Posttranslational modification of PCNA by ubiquitin plays an important role in coordinating the processes of DNA damage tolerance during DNA replication. The monoubiquitination of PCNA was shown to facilitate the switch between the replicative DNA polymerase with the low-fidelity polymerase eta (η) to bypass UV-induced DNA lesions during replication. Here, we show that in response to oxidative stress, PCNA becomes transiently monoubiquitinated in an S phase- and USP1-independent manner.

Human DNA polymerase iota protects cells against oxidative stress.

Human DNA polymerase iota (poliota) is a unique member of the Y-family of specialised polymerases that displays a 5'deoxyribose phosphate (dRP) lyase activity. Although poliota is well conserved in higher eukaryotes, its role in mammalian cells remains unclear. To investigate the biological importance of poliota in human cells, we generated fibroblasts stably downregulating poliota (MRC5-pol iota(KD)) and examined their response to several types of DNA-damaging agents.

Genotoxicity induced by saponified coconut oil surfactant in prokaryote systems.

Surfactants are amphiphilic substances with special properties and chemical structures that allow a reduction in interfacial tension, which permits an increase in molecule solubilization. The critical micelle concentration (CMC) is an important characteristic of surfactants that determines their aggregate state, which is generally related to its functional mechanism. In this work the genotoxic potential of saponified coconut oil (SCO), a surfactant obtained from Cocos nucifera, was analyzed using prokaryote systems.