Publications by authors named "Rossella Tricarico"

Tribbles pseudokinases (TRIB1-3) are important signaling modulators involved in several cancers. However, their function in gastric cancer (GC) remains undefined. GC is still a deadly disease since the lack of sensitive and specific biomarkers for early diagnosis and therapy response prediction negatively affects patients' outcome.

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Article Synopsis
  • Colorectal cancer (CRC) is a common and serious cancer in the U.S., affecting about 135,000 people each year and causing around 50,000 deaths.
  • Some people with a genetic disease called autosomal dominant polycystic kidney disease (ADPKD), which affects kidneys, might have a lower chance of getting CRC.
  • Studies using mice show that when the gene PKD1 is missing, it can reduce the risk and growth of CRC, possibly helping us understand how genetics influence this type of cancer.
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Background & Aims: Aberrant DNA methylation is frequent in colorectal cancer (CRC), but underlying mechanisms and pathologic consequences are poorly understood.

Methods: We disrupted active DNA demethylation genes Tet1 and/or Tdg from Apc mice and characterized the methylome and transcriptome of colonic adenomas. Data were compared to human colonic adenocarcinomas (COAD) in The Cancer Genome Atlas.

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Dietary factors can regulate epigenetic processes during life, modulating the intracellular pools of metabolites necessary for epigenetic reactions and regulating the activity of epigenetic enzymes. Their effects are strong during the prenatal life, when epigenetic patterns are written, allowing organogenesis. However, interactions between diet and the epigenome continue throughout life and likely contribute to the onset and progression of various complex diseases.

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Loss of expression or activity of the tumor suppressor PTEN acts similarly to an activating mutation in the oncogene PIK3CA in elevating intracellular levels of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), inducing signaling by AKT and other pro-tumorigenic signaling proteins. Here, we analyze sequence data for 34,129 colorectal cancer (CRC) patients, capturing 3,434 PTEN mutations. We identify specific patterns of PTEN mutation associated with microsatellite stability/instability (MSS/MSI), tumor mutational burden (TMB), patient age, and tumor location.

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Biological sex profoundly conditions organismal development and physiology, imposing wide-ranging effects on cell signaling, metabolism, and immune response. These effects arise from sex-specified differences in hormonal exposure, and from intrinsic genetic and epigenetic differences associated with the presence of an XX versus XY chromosomal complement. In addition, biological sex is now recognized to be a determinant of the incidence, presentation, and therapeutic response of multiple forms of cancer, including cancers not specifically associated with male or female anatomy.

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Mitochondrial dysfunction has consequences not only for cellular energy output but also for cellular signaling pathways. Mitochondrial dysfunction, often based on inherited gene variants, plays a role in devastating human conditions such as mitochondrial neuropathies, myopathies, cardiovascular disorders, and Parkinson and Alzheimer diseases. Of the proteins essential for mitochondrial function, more than 98% are encoded in the cell nucleus, translated in the cytoplasm, sorted based on the presence of encoded mitochondrial targeting sequences (MTSs), and imported to specific mitochondrial sub-compartments based on the integrated activity of a series of mitochondrial translocases, proteinases, and chaperones.

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Melanoma is an aggressive neoplasm with increasing incidence that is classified by the NCI as a recalcitrant cancer, i.e., a cancer with poor prognosis, lacking progress in diagnosis and treatment.

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BRCA1 functions in homologous recombination (HR) both up- and downstream of DNA end resection. However, in cells with 53BP1 gene knockout (KO), BRCA1 is dispensable for the initiation of resection, but whether BRCA1 activity is entirely redundant after end resection is unclear. Here, we found that 53bp1 KO rescued the embryonic viability of a Brca1 mouse model that harbors a stop codon in the coiled-coil domain.

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Article Synopsis
  • - Thymine DNA Glycosylase (TDG) is crucial for repairing DNA mismatches and plays an epigenomic role by removing cytosine derivatives during DNA demethylation, protecting the genome from mutagenesis.
  • - The study analyzed how inactivation of TDG contributes to tumor formation using a mouse model, revealing a significant increase in small intestinal adenomas among test mice compared to controls, particularly in females.
  • - Findings suggest that TDG inactivation is linked to intestinal tumor development and indicates potential sex-specific mechanisms in colorectal cancer protection, as seen in human patient data from the TCGA database.
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How protein-protein interactions regulate and alter histone modifications is a major unanswered question in epigenetics. The histone acetyltransferase p300 binds thymine DNA glycosylase (TDG); utilizing mass spectrometry to measure site-specific changes in histone acetylation, we found that the absence of TDG in mouse embryonic fibroblasts leads to a reduction in the rate of histone acetylation. We demonstrate that TDG interacts with the CH3 domain of p300 to allosterically promote p300 activity to specific lysines on histone H3 (K18 and K23).

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Tumor suppressor genes and their effector pathways have been identified for many dominantly heritable cancers, enabling efforts to intervene early in the course of disease. Our approach on the subject of early intervention was to investigate gene expression patterns of morphologically normal "one-hit" cells before they become hemizygous or homozygous for the inherited mutant gene which is usually required for tumor formation. Here, we studied histologically non-transformed renal epithelial cells from patients with inherited disorders that predispose to renal tumors, including von Hippel-Lindau (VHL) disease and Tuberous Sclerosis (TSC).

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Pathogenicity assessment of DNA variants in disease genes to explain their clinical consequences is an integral component of diagnostic molecular testing. The International Society for Gastrointestinal Hereditary Tumors (InSiGHT) has developed specific criteria for the interpretation of mismatch repair (MMR) gene variants. Here, we performed a systematic investigation of 24 MLH1 and MSH2 variants.

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The DNA glycosylase gene MBD4 safeguards genomic stability at CpG sites and is frequently mutated at coding poly-A tracks in mismatch repair (MMR)-defective colorectal tumors (CRC). Mbd4 biallelic inactivation in mice provided conflicting results as to its role in tumorigenesis. Thus, it is unclear whether MBD4 alterations are only secondary to MMR defects without functional consequences or can contribute to the mutator phenotype.

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Lynch syndrome (LS) is a tumor predisposing condition caused by constitutional defects in genes coding for components of the mismatch repair (MMR) apparatus. While hypermethylation of the promoter of the MMR gene MLH1 occurs in about 15% of colorectal cancer samples, it has also been observed as a constitutional alteration, in the absence of DNA sequence mutations, in a small number of LS patients. In order to obtain further insights on the phenotypic characteristics of MLH1 epimutation carriers, we investigated the somatic and constitutional MLH1 methylation status of 14 unrelated subjects with a suspicion of LS who were negative for MMR gene constitutional mutations and whose tumors did not express the MLH1 protein.

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It is generally believed that cerebellar granule neurons originate exclusively from granule neuron precursors (GNPs) in the external germinal layer (EGL). Here we identified a rare population of neuronal progenitors in mouse developing cerebellum that expresses Nestin. Although Nestin is widely considered a marker for multipotent stem cells, these Nestin-expressing progenitors (NEPs) are committed to the granule neuron lineage.

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MUTYH-associated polyposis (MAP) is an autosomal recessive adenomatous polyposis caused by biallelic germline mutations of the base-excision-repair gene MUTYH. In MAP patients of European origin, the combined allele frequency of the mutations p.Tyr179Cys and p.

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A 37-year-old man was hospitalised because of anaemia and fatigue due to an infiltrating adenocarcinoma of the Treitz angle (duodenum), together with gastric, duodenal and colorectal polyps. After the operation, removal of colorectal lesions revealed the presence of ganglioneuromatosis of the large bowel. Further investigations showed lack of MLH1 protein expression and microsatellite instability in the duodenal neoplasm, while the gene was normally expressed in the polyps.

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MUTYH variants are differently distributed in geographical areas of the world. In MUTYH-associated polyposis (MAP) patients from North-Eastern Italy, c.933+3A>C (IVS10+3A>C), a transversion causing an aberrant splicing process, accounts for nearly 1/5 of all mutations.

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Background: MUTYH-associated polyposis (MAP) is an autosomal recessive form of intestinal polyposis predisposing to colorectal carcinoma. High resolution melting analysis (HRMA) is a mutation scanning method that allows detection of heterozygous sequence changes with high sensitivity, whereas homozygosity for a nucleotide change may not lead to significant curve shape or melting temperature changes compared to homozygous wild-type samples. Therefore, HRMA has been mainly applied to the detection of mutations associated with autosomal dominant or X-linked disorders, while applications to autosomal recessive conditions are less common.

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Adnexal tumors with follicular differentiation in the breast parenchyma are rarely encountered. The authors present a unique case arising in a 64-year-old woman, in whom they observed composite differentiation toward follicular germinative cells of the hair follicle with focal areas of outer root sheath differentiation and pilar-type keratinization. The histogenesis of this tumor is analyzed in light of the peculiar pathological, immunohistochemical, and molecular genetic findings.

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MUTYH-associated polyposis (MAP) is an autosomal recessive condition predisposing to colorectal cancer, caused by constitutional biallelic mutations in the base excision repair (BER) gene MUTYH. Colorectal tumours from MAP patients display an excess of somatic G>T mutations in the APC and KRAS genes due to defective BER function. To date, few extracolonic manifestations have been observed in MAP patients, and the clinical spectrum of this condition is not yet fully established.

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