Network approach in liquidomics landscape.

Tissue-based biopsy is the present main tool to explore the molecular landscape of cancer, but it also has many limits to be frequently executed, being too invasive with the risk of side effects. These limits and the ability of cancer to constantly evolve its genomic profile, have recently led to the need of a less invasive and more accurate alternative, such as liquid biopsy. By searching Circulating Tumor Cells and residues of their nucleic acids or other tumor products in body fluids, especially in blood, but also in urine, stools and saliva, liquid biopsy is becoming the future of clinical oncology. Despite the current lack of a standardization for its workflows, that makes it hard to be reproduced, liquid biopsy has already obtained promising results for cancer screening, diagnosis, prognosis, and risk of recurrence.Through a more accessible molecular profiling of tumors, it could become easier to identify biomarkers predictive of response to treatment, such as EGFR mutations in non-small cell lung cancer and KRAS mutations in colorectal cancer, or Microsatellite Instability and Mismatch Repair as predictive markers of pembrolizumab response.By monitoring circulating tumor DNA in longitudinal repeated sampling of blood we could also predict Minimal Residual Disease and the risk of recurrence in already radically resected patients.In this review we will discuss about the current knowledge of limitations and strengths of the different forms of liquid biopsies for its inclusion in normal cancer management, with a brief nod to their newest biomarkers and its future implications.

CHAMP1-related disorders: pathomechanisms triggered by different genomic alterations define distinct nosological categories.

Loss-of-function variants in CHAMP1 were recently described as cause of a neurodevelopmental disorder characterized by intellectual disability (ID), autism, and distinctive facial characteristics. By exome sequencing (ES), we identified a truncating variant in CHAMP1, c.1858A > T (p.Lys620*), in a patient who exhibited a similar phenotype of severe ID and dysmorphisms. Whether haploinsufficiency or a dominant negative effect is the underlying pathomechanism in these cases is a question that still needs to be addressed. By array-CGH, we detected a 194 kb deletion in 13q34 encompassing CHAMP1, CDC16 and UPF3, in another patient who presented with borderline neurodevelopmental impairment and with no dysmorphisms. In a further patient suffering from early onset refractory seizures, we detected by ES a missense variant in CHAMP1, c.67 G > A (p.Gly23Ser). Genomic abnormalities were all de novo in our patients. We reviewed the clinical and the genetic data of patients reported in the literature with: loss-of-function variants in CHAMP1 (total 40); chromosome 13q34 deletions ranging from 1.1 to 4 Mb (total 7) and of the unique patient with a missense variant. We could infer that loss-of-function variants in CHAMP1 cause a homogeneous phenotype with severe ID, autism spectrum disorders (ASD) and highly distinctive facial characteristics through a dominant negative effect. CHAMP1 haploinsufficiency results in borderline ID with negligible consequences on the quality of life. Missense variants give rise to a severe epileptic encephalopathy through gain-of-function mechanism, most likely. We tentatively define for the first time distinct categories among the CHAMP1-related disorder on the basis of pathomechanisms.

Whole exome sequencing identifies a rare variant in MAS1 gene in a subject with lethal COVID-19.

COVID-19 may be considered a multifactorial disease caused by the interaction between the virus itself, as the environmental contribute, and the genetic background of the host. SARS-CoV-2 infection occurs through the interaction between the spike protein and ACE2, a receptor in the host cells. Clinically, COVID-19 is characterized by a high heterogeneity in symptomatology ranging from asymptomatic to severe symptoms, and even worsening to death. This variability relies on the host genomic profile and other individual comorbidities. We performed exome analysis in one family displaying a variable spectrum of SARS-CoV-2 infection despite a common exposure. After segregation analysis, we found that the c.446C>T p.(S149L) in MAS1 gene was exclusively present in the individual with severe COVID-19, who died because of pneumonia and multiple thrombotic events. MAS1 encodes a receptor for Ang1-7 in the renin-angiotensin system (RAS) with an anti-inflammatory, anti-fibrotic and anti-angiogenic effect. We hypothesize that downregulation of RAS, due to this rare variant, might impair the protective effect and concur to the clinical severity of the disease. Our results support the protective role of the ACE2/Ang-(1-7)/Mas1 axis and the potential danger of its dysregulation leading to severe COVID-19 disease; if further confirmed, these findings will be useful for management of critically ill patients.

Genetic variants determine intrafamilial variability of SARS-CoV-2 clinical outcomes in 19 Italian families.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in a wide range of outcomes characterized by a high heterogeneity in both symptomatology and susceptibility to the disease. In such a perspective, COVID-19 may be considered as a multifactorial disease featured by the interaction between the environment, which is the virus itself, and the genetic profile of the host. Our analysis aimed at investigating the transmission dynamics of SARS-CoV-2 within families whose members responded in different ways to the infection, although the exposure was common to the entire group and occurred before the availability of any vaccine. The goal was to understand how the genetic background of each subject can influence the viral infection outcome and hence the above-mentioned clinical variability. We performed a segregation analysis in 19 Italian families with a designed custom panel of 42 genes involved in immunity and virus entry and which have also been shown to be related to SARS-CoV-2 host response. We carried out both a familial segregation analysis and a global statistical analysis. In the former we identified eighteen risk variants co-segregating with a COVID-positive status and six variants with a possible protective effect. In addition, sixteen variants showed a trend of association to a severe phenotype. Together with common SNPs, we detected private rare variants that may also provide insight into the observed clinical COVID-19 heterogeneity. The global statistical analysis confirmed statistically significant positive associations between SARS-CoV-2 individual response and some specific gene variants identified in familial analysis. In conclusion our data confirm that the clinical expression of COVID-19 is markedly influenced by the host genetic profile both with a mendelian transmission pattern and a polygenic architecture.