NGS detection of gene rearrangements and METexon14 mutations in liquid biopsy of advanced NSCLC patients: A study of two Italian centers.

Introduction: ctDNA is a useful tool for NGS molecular profiling in advanced NSCLC patients. Its clinical applicability in patients with gene rearrangements is still limited due to a lower detection rate of these types of alterations compared to single SNVs or small indels. To this purpose, we performed a study in two Italian centers to assess the concordance between tissue and plasma samples in the detection of genes fusions (, , ) and mutations in advanced NSCLC patients.

Liquid Biopsy and 18F-FDG PET/CT Derived Parameters as Predictive Factors of Osimertinib Treatment in Advanced EGFR-Mutated NSCLC.

Objectives: Despite the outstanding results achieved by osimertinib for the treatment of advanced EGFR-mutated NSCLC, the development of resistance is almost inevitable. While molecular mechanism responsible for osimertinib resistance are being mostly revealed, the definition of predictive biomarkers is crucial in order to identify patients at higher risk of progression and optimize treatment strategy.

Materials And Methods: This is a prospective single-center study aimed to assess the potential role of liquid biopsy and 18F-FDG PET/CT derived metabolic parameters as noninvasive predictive biomarkers of osimertinib outcomes in advanced EGFR-mutated NSCLC patients.

Role of ctDNA for the detection of minimal residual disease in resected non-small cell lung cancer: a systematic review.

Background: Operable stage I-III non-small cell lung cancer (NSCLC) has a high risk of recurrence, mainly due to remnant clones of the disease defined as minimal residual disease (MRD). Adjuvant chemotherapy has a limited efficacy in reducing the risk of relapse, and prognostic as well as predictive biomarkers in this context are currently missing.

Methods: We performed a systematic review to evaluate the state of the art about the role of circulating tumor DNA detection through liquid biopsy for the assessment of MRD in resected early-stage NSCLC patients.

HLA-DRB1∗16 and -DQB1∗05 alleles are strongly associated with autoimmune pancreatitis in a cohort of hundred patients.

Background/objectives: Autoimmune diseases are often associated with human leukocyte antigen (HLA) haplotypes, indicating that changes in major histocompatibility complex (MHC)-dependent self-peptide or antigen presentation contribute to autoimmunity. In our study, we aimed to investigate HLA alleles in a large European cohort of autoimmune pancreatitis (AIP) patients.

Methods: Hundred patients with AIP, diagnosed and classified according to the International Consensus Diagnostic Criteria (ICDC), were prospectively enrolled in the study.

Biological Role and Clinical Implications of microRNAs in BRCA Mutation Carriers.

Women with pathogenic germline mutations in and genes have an increased risk to develop breast and ovarian cancer. There is, however, a high interpersonal variability in the modality and timing of tumor onset in those subjects, thus suggesting a potential role of other individual's genetic, epigenetic, and environmental risk factors in modulating the penetrance of BRCA mutations. MicroRNAs (miRNAs) are small noncoding RNAs that can modulate the expression of several genes involved in cancer initiation and progression.

PD-L1 SNPs as biomarkers to define benefit in patients with advanced NSCLC treated with immune checkpoint inhibitors.

Objective: To investigate the role of (programmed death-1), and (programmed death-ligand 1) single nucleotide polymorphisms (SNPs) in predicting clinical outcome of patients with advanced non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs).

Methods: A total of 166 consecutive patients were included. We correlated SNPs with clinical benefit, progression-free survival, time to treatment failure, and overall survival and evaluated the incidence of SNPs in nonresponder and long clinical benefit groups.

Deciphering the pathogenesis of the COL4-related hematuric nephritis: A genotype/phenotype study.

Background: Alport syndrome (ATS) is a hereditary progressive hematuric nephropathy associated with sensorineural deafness and ocular abnormalities, which is caused by mutations in the COL4A5 gene (X-linked ATS) and in two autosomal genes, COL4A4 and COL4A3, responsible of both recessive ATS and, when present in heterozygosity, of a spectrum of phenotypes ranging from isolated hematuria to frank renal disease.

Methods: Retrospective analysis of the clinical and genetic features of 76 patients from 34 unrelated ATS families (11 with mutations in COL4A5, 11 in COL4A3, and 12 in COL4A4) and genotype/phenotype correlation for the COL4A3/COL4A4 heterozygotes (34 patients from 14 families).

Results: Eight (24%) of the 34 heterozygous COL4A3 and COL4A4 carriers developed renal failure at a mean age of 57 years, with a significantly lower risk than hemizygous COL4A5 or double heterozygous COL4A3/COL4A4 carriers (p < 0.

Unmasking selective path integration deficits in Alzheimer's disease risk carriers.

Alzheimer's disease (AD) manifests with progressive memory loss and spatial disorientation. Neuropathological studies suggest early AD pathology in the entorhinal cortex (EC) of young adults at genetic risk for AD ( ε4-carriers). Because the EC harbors grid cells, a likely neural substrate of path integration (PI), we examined PI performance in ε4-carriers during a virtual navigation task.

Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach.

Spectrum of X-linked intellectual disabilities and psychiatric symptoms in a family harbouring a Xp22.12 microduplication encompassing the gene.

Microduplications of the X chromosome are a rare cause of X-linked intellectual disability (XLID), a clinically and genetically heterogeneous spectrum of disorders. In the present study, a 950-kb Xp22.12 microduplication including the gene was detected in affected members of a family, including the proband (male), his mother and one maternal uncle.

Association of a polymorphism of the Fcγ-receptor 2A (FCGR2A) gene with chronic periaortitis.

Objectives: Chronic periaortitis (CP) is an inflammatory disease associated in 20-60% of the cases with IgG4 related disease. Current evidence supports an autoimmune nature for CP. Fc gamma receptors (FcγRs) are involved in several immune system activities and are associated with autoimmunity in general.

FCGR2A single nucleotide polymorphism confers susceptibility to childhood-onset idiopathic nephrotic syndrome.

Childhood-onset idiopathic nephrotic syndrome affects 1.15-3.4 children/100,000 children/year in Western Countries.

Patterns of Novel Alleles and Genotype/Phenotype Correlations Resulting from the Analysis of 108 Previously Undetected Mutations in Patients Affected by Neurofibromatosis Type I.

Neurofibromatosis type I, a genetic disorder due to mutations in the gene, is characterized by a high mutation rate (about 50% of the cases are de novo) but, with the exception of whole gene deletions associated with a more severe phenotype, no specific hotspots and few solid genotype/phenotype correlations. After retrospectively re-evaluating all gene variants found in the diagnostic activity, we studied 108 patients affected by neurofibromatosis type I who harbored mutations that had not been previously reported in the international databases, with the aim of analyzing their type and distribution along the gene and of correlating them with the phenotypic features of the affected patients. Out of the 108 previously unreported variants, 14 were inherited by one of the affected parents and 94 were de novo.

Monogenic Autoinflammatory Diseases with Mendelian Inheritance: Genes, Mutations, and Genotype/Phenotype Correlations.

Autoinflammatory diseases (AIDs) are a genetically heterogeneous group of diseases caused by mutations of genes encoding proteins, which play a pivotal role in the regulation of the inflammatory response. In the pathogenesis of AIDs, the role of the genetic background is triggered by environmental factors through the modulation of the innate immune system. Monogenic AIDs are characterized by Mendelian inheritance and are caused by highly penetrant genetic variants in single genes.

A Genome-wide Association Study Identifies Risk Alleles in Plasminogen and P4HA2 Associated with Giant Cell Arteritis.

Giant cell arteritis (GCA) is the most common form of vasculitis in individuals older than 50 years in Western countries. To shed light onto the genetic background influencing susceptibility for GCA, we performed a genome-wide association screening in a well-powered study cohort. After imputation, 1,844,133 genetic variants were analyzed in 2,134 case subjects and 9,125 unaffected individuals from ten independent populations of European ancestry.

Genetic Susceptibility to ANCA-Associated Vasculitis: State of the Art.

ANCA-associated vasculitis (AAV) is a group of disorders that is caused by inflammation affecting small blood vessels. Both arteries and veins are affected. AAV includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) renamed from Wegener's granulomatosis, and eosinophilic granulomatosis with polyangiitis (EGPA), renamed from Churg-Strauss syndrome.

Genetics of ANCA-associated vasculitides: HLA and beyond.

The pathogenesis of ANCA-associated vasculitis (AAV) is multifactorial and most likely involves the interaction of environmental and genetic factors. During the past few years, a number of studies have investigated genetic associations with AAV; earlier studies explored associations with single nucleotide polymorphisms (SNPs) at genes of potential pathogenetic interest ('candidate gene' studies), whereas more recent larger studies analysed associations with SNPs covering ~90% of the human genome (genome-wide association studies - GWAS). The latter studies have significantly advanced our understanding of the genetic aspects of AAV, confirming some previously reported findings and uncovering new genetic associations.

TLR-4 and VEGF polymorphisms in chronic periaortitis.

Objective: Chronic periaortitis (CP) is a rare disease that is characterised by fibro-inflammatory tissue surrounding the abdominal aorta and has both non-aneurysmal (idiopathic retroperitoneal fibrosis [IRF]) and aneurysmal forms (inflammatory abdominal aortic aneurysm [IAAA]). We investigated whether toll-like receptor 4 (TLR-4) and vascular endothelial growth factor (VEGF) polymorphisms were associated with susceptibility to, and the clinical features of CP.

Methods: One hundred and two CP patients and 200 healthy controls were molecularly genotyped for TLR-4 gene polymorphism (+896 A/G) (rs4986790), VEGF mutations +936 C/T (rs3025039) and -634 C/G (rs2010963), and an 18 base pair (bp) insertion/deletion (I/D) polymorphism at -2549 of the VEGF promoter region.

PTPN22 R620W polymorphism in the ANCA-associated vasculitides.

Objectives: PTPN22 is involved in T-cell activation and its R620W single-nucleotide polymorphism (SNP) has been shown to predispose to different autoimmune diseases. The aims of this study were to investigate the role of the PTPN22 R620W SNP in conferring susceptibility to the ANCA-associated vasculitides (AAVs), and to explore potential associations between the PTPN22 genotype and the disease manifestations.

Methods: PTPN22 R620W SNP was genotyped in a cohort of 344 AAV patients [143 with granulomatosis with polyangiitis (Wegener's) (GPA), 102 with microscopic polyangiitis (MPA) and 99 with Churg-Strauss syndrome (CSS)] and in 945 healthy controls.

IgG4 immune response in Churg-Strauss syndrome.

Objective: T-helper type 2 responses are crucial in Churg-Strauss syndrome (CSS) and may enhance the production of IgG4 antibodies. The authors assessed the IgG4 immune response in CSS patients.

Methods: The authors included 46 consecutive patients with CSS (24 with active and 22 with quiescent disease), 26 with granulomatosis with polyangiitis (GPA, Wegener's), 25 with atopic asthma and 20 healthy controls and determined serum IgG, IgM, IgA, IgE and IgG subclass levels.