Relationship between MUTYH, OGG1 and BRCA1 mutations and mRNA expression in breast and ovarian cancer predisposition

Moscatello, Carmelo; Nicola, Marta Di; Veschi, Serena; Gregorio, Patrizia Di; Cianchetti, Ettore; Stuppia, Liborio; Battista, Pasquale; Cama, Alessandro; Curia, Maria Cristina; Aceto, Gitana María

doi:10.3892/mco.2020.2177

Cited by 7 publications

(3 citation statements)

References 46 publications

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“…As shown in Figure 1 A, in HBOC mutated families, PDAC is the second recurrent cancer and happen in 13% of cases, higher than OC. Interestingly, by comparing the prevalence of cancers that recur in mutated and non-mutated HBOC families, statistically significant difference is observed in OC onset ( Table 3 ), confirming that OC patients exhibit a high mutational rate [ 31 ]. Patients with BRCA2 mutations are at increased risk for PDAC onset; it has been reported that loss of BRCA2 function predisposes the pancreas to profound DNA damage that determines a major frequency of invasive neoplasia.…”

Section: Discussionmentioning

confidence: 96%

Pancreatic Cancer with Mutation in BRCA1/2, MLH1, and APC Genes: Phenotype Correlation and Detection of a Novel Germline BRCA2 Mutation

Vietri

Goletti

Caliendo

et al. 2022

Genes

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Pancreatic ductal adenocarcinoma (PDAC) is the seventh leading cause of cancer death worldwide; most of cases are sporadic, however about 5% to 10% report a hereditary predisposition. Several hereditary syndromes have been associated with familial pancreatic cancer (FPC) onset, including hereditary breast and ovarian cancer syndrome (HBOC), Lynch syndrome (LS), Familial atypical multiple mole melanoma (FAMMM), Familial adenomatous polyposis (FAP), Li–Fraumeni syndrome (LFS),Peutz–Jeghers syndrome (PJS), and Hereditary pancreatitis (HP).The aim of this study was to determine the mutational status of a cohort of 56 HBOC families, 7 LS families, 3 FAP and FAMMM families, and 1 LFS family with at least one case of PDAC. Mutation analysis of BRCA1/2, ATM, CHEK2, PALB2, RAD51C, RAD51D, NBN, CDH1, TP53, MLH1, MSH2, MSH6, and PMS2genes, showedmutation in BRCA1/2, MLH1, and APC genes. We founda high mutation rate in patients belong HBOC and LS families, with a percentage of 28.6% in both syndromes and prevalence in HBOC of BRCA2 mutations with one case of double mutation in BRCA2 gene. In FAP family, we found a pathogenic mutation in APC gene in 1/3 families. We observed an early onset of PDAC and a lower survival in PDAC patients belonging to mutated families, while no evidence of possible pancreatic cancer cluster regions was found. Moreover, we identified a novel BRCA2 germline mutation, c.5511delT (p.Phe1837LeufsX3), not reported in any database, that segregated with disease in HBOC patients. Mutational analysis was extended to family membersof mutated patients, both healthy and cancer affected, which revealed 23 unaffected family members that inherited the proband’s mutation. Although correlative by its nature, the presence of a BRCA mutation in PDAC patients may have benefits in terms of optimized treatment and longer outcome.

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Section: Discussionmentioning

confidence: 96%

Pancreatic Cancer with Mutation in BRCA1/2, MLH1, and APC Genes: Phenotype Correlation and Detection of a Novel Germline BRCA2 Mutation

Vietri

Goletti

Caliendo

et al. 2022

Genes

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“…Total RNA was isolated using TriFast (EUROGOLD EuroClone) according to the manufacturer’s instructions. The synthesis of complementary DNA (cDNA) was performed as previously described [ 34 ]. The mRNA levels were evaluated by SYBR Green quantitative real-time PCR (qRT-PCR) analysis using StepOne™ 2.0 (Applied Biosystems, Thermo Fisher Scientific, Waltham, MA, USA).…”

Section: Methodsmentioning

confidence: 99%

Emerging Role of Oxidative Stress on EGFR and OGG1-BER Cross-Regulation: Implications in Thyroid Physiopathology

Moscatello

Marcantonio

Savino

et al. 2022

Cells

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Thyroid diseases have a complex and multifactorial aetiology. Despite the numerous studies on the signals referable to the malignant transition, the molecular mechanisms concerning the role of oxidative stress remain elusive. Based on its strong oxidative power, H2O2 could be responsible for the high level of oxidative DNA damage observed in cancerous thyroid tissue and hyperactivation of mitogen-activated protein kinase (MAPK) and PI3K/Akt, which mediate ErbB signaling. Increased levels of 8-oxoG DNA adducts have been detected in the early stages of thyroid cancer. These DNA lesions are efficiently recognized and removed by the base excision repair (BER) pathway initiated by 8-oxoG glycosylase1 (OGG1). This study investigated the relationships between the EGFR and OGG1-BER pathways and their mutual regulation following oxidative stress stimulus by H2O2 in human thyrocytes. We clarified the modulation of ErbB receptors and their downstream pathways (PI3K/Akt and MAPK/ERK) under oxidative stress (from H2O2) at the level of gene and protein expression, according to the mechanism defined in a human non-pathological cell system, Nthy-ori 3-1. Later, on the basis of the results obtained by gene expression cluster analysis in normal cells, we assessed the dysregulation of the relationships in a model of papillary thyroid cancer with RET/PTC rearrangement (TPC-1). Our observations demonstrated that a H2O2 stress may induce a physiological cross-regulation between ErbB and OGG1-BER pathways in normal thyroid cells (while this is dysregulated in the TPC-1 cells). Gene expression data also delineated that MUTYH gene could play a physiological role in crosstalk between ErbB and BER pathways and this function is instead lost in cancer cells. Overall, our data on OGG1 protein expression suggest that it was physiologically regulated in response to oxidative modulation of ErbB, and that these might be dysregulated in the signaling pathway involving AKT in the progression of thyroid malignancies with RET/PTC rearrangements.

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“…Other genes carry a differential risk depending on the BC immunophenotype: BARD1, RAD51C, and RAD51D mutations are associated with a higher risk of ER-negative BCs, including TNBCs, whereas ATM and CHK2 mutations are associated with a higher risk of ER+ BC. Although germline mutations in BRIP1, MUTYH, or OGG have been reported, their association with BC risk remains unclear [4][5][6]).…”

Section: Germline Mutations Of Additional Dna Damage Response (Ddr)-associated Genesmentioning

confidence: 99%

Recent Advances in Enhancing the Therapeutic Index of PARP Inhibitors in Breast Cancer

Franchet

Hoffmann

2021

Cancers

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As poly-(ADP)-ribose polymerase (PARP) inhibition is synthetic lethal with the deficiency of DNA double-strand (DSB) break repair by homologous recombination (HR), PARP inhibitors (PARPi) are currently used to treat breast cancers with mutated BRCA1/2 HR factors. Unfortunately, the increasingly high rate of PARPi resistance in clinical practice has dented initial hopes. Multiple resistance mechanisms and acquired vulnerabilities revealed in vitro might explain this setback. We describe the mechanisms and vulnerabilities involved, including newly identified modes of regulation of DSB repair that are now being tested in large cohorts of patients and discuss how they could lead to novel treatment strategies to improve the therapeutic index of PARPi.

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Relationship between MUTYH, OGG1 and BRCA1 mutations and mRNA expression in breast and ovarian cancer predisposition

Cited by 7 publications

References 46 publications

Pancreatic Cancer with Mutation in BRCA1/2, MLH1, and APC Genes: Phenotype Correlation and Detection of a Novel Germline BRCA2 Mutation

Pancreatic Cancer with Mutation in BRCA1/2, MLH1, and APC Genes: Phenotype Correlation and Detection of a Novel Germline BRCA2 Mutation

Emerging Role of Oxidative Stress on EGFR and OGG1-BER Cross-Regulation: Implications in Thyroid Physiopathology

Recent Advances in Enhancing the Therapeutic Index of PARP Inhibitors in Breast Cancer

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