Hedgehog/GLI1 Transcriptionally Regulates FANCD2 in Ovarian Tumor Cells: Its Inhibition Induces HR-Deficiency and Synergistic Lethality with PARP Inhibition.

Mani, Chinnadurai; Tripathi, Kaushlendra; Chaudhary, Sandeep; Somasagara, Ranganatha R.; Rocconi, Rodney P.; Crasto, Chiquito J.; Reedy, Mark B.; Athar, Mohammad; Palle, Komaraiah

doi:10.1016/j.neo.2021.06.010

Cited by 10 publications

(4 citation statements)

References 60 publications

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“…A study in Finland supports these findings by showing a significant association of variant (c.2715LJ+LJ1GLJ>LJA) in the FANCD2 gene with breast cancer (Mantere, 2017). Also, studies conducted in the United Kingdom and Poland on ovarian carcinoma samples verified that the risk of recurrence and death are highly associated with the expression level of FANCD2 (Moes-Sosnowska, 2019; Mani, 2021). On the other hand, in the United States, a study conducted on 181 ovarian cancer patients provided evidence of an increased survival rate in patients with FANCD2 mutation (Joshi, 2020).…”

Section: Discussionmentioning

confidence: 90%

Next-generation DNA sequencing identifies mutated FANCD2 Gene as a novel Biomarker for monitoring early disease progression and timely therapeutic interventions in advanced phase Chronic Myeloid Leukemia patients

Alanazi,

Siyal,

Absar

et al. 2023

Preprint

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Chronic Myeloid Leukemia, resulting due to chromosomal aberration t(9;22) through formation of oncogenic BCR-ABL fusion oncogene. Modern BCR-ABL inhibitors, called TKIs, have revolutionized CML treatment. CML has three stages: chronic, accelerated, and blast crisis. TKIs work well in CP-CML, where patients survive as long as the normal population, but they don’t work in AP- and BC-CML. Even with advances in treatment, BC-CML has an average overall survival of less than a year, giving oncologists little time to clinically intervene. Oncologists can delay or prevent CML advancement by detecting patients at risk of disease progression early and making timely treatment decisions, especially with third and fourth generation TKIs. However, no universal molecular biomarkers exist to diagnose CML patient groups at risk of disease progression.A recent study found that all BC-CML patients have mutant FANCD2. Our study was designed to detect mutant FANCD2 in AP-CML (early progression phase) to investigate its potential as a novel biomarker of early CML progression from chronic phase to accelerated phase due to the urgent need for such a biomarker.Our study comprised of 123 CP-CML (control group) and 60 AP-CML patients (as experimental group) from Hayatabad Medical Complex, Peshawar, Pakistan, from Jan 2020 to July 2023. DNA was extracted from the patients and FANCD2 gene was sequenced using Illumina next generation sequencer (NGS) Illumina MiSeq sequencer. NGS analysis revealed a unique splice site mutation in FANCD2 gene (c. 2022-5C>T). This mutation was detected in all CP-CML patients but in none of CP-CML. The mutation was confirmed by Sanger sequencing.FANCD2 is member of Fanconi anemia (FA-) pathway gene involved in DNA repair and genomic instability. Therefore, our studies show that FANCD2 (c. 2022-5C>T) mutation as a very specific molecular biomarker for early CML progression. We recommend to clinical validate this biomarker is prospective clinical trials.

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Section: Discussionmentioning

confidence: 90%

Next-generation DNA sequencing identifies mutated FANCD2 Gene as a novel Biomarker for monitoring early disease progression and timely therapeutic interventions in advanced phase Chronic Myeloid Leukemia patients

Alanazi,

Siyal,

Absar

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…A study conducted in Finland supports these findings by showing a significant association of variant (c.2715 + 1G > A) in the FANCD2 gene with breast cancer [ 59 ]. Also, studies carried out on ovarian carcinoma samples verified that the risk of recurrence and death are highly associated with the expression level of FANCD2 [ 38 , 60 ]. In contrast, a study conducted on 181 ovarian cancer patients provided evidence of an increased survival rate in patients with the FANCD2 mutation [ 61 ].…”

Section: Discussionmentioning

confidence: 99%

Clinical Validation of the Somatic FANCD2 Mutation (c.2022-5C>T) as a Novel Molecular Biomarker for Early Disease Progression in Chronic Myeloid Leukemia: A Case–Control Study

Alanazi,

Siyal,

Basit

et al. 2024

Hematology Reports

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Background: Chronic myeloid leukemia (CML) results from chromosomal translocation t(9;22) leading to the formation of the BCR-ABL fusion oncogene. CML has three stages: the chronic phase (CP), the accelerated phase (AP), and the blast crisis (BC). Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of CML. TKIs work well in CP-CML, and these patients have a survival rate similar to the normal population, but TKIs are less effective in advanced-phase CML. Even with current advances in treatment, BC-CML patients have an average overall survival of less than a year. Early recognition of CML patients at risk of disease progression can help in timely interventions with appropriate TKIs or other therapeutic modalities. Although some markers of disease progression like BCR-ABL kinase domain, ASXL1, and GATA2 mutations are available, no universal and exclusively specific molecular biomarkers exist to early diagnose CML patients at risk of CML progression for timely therapeutic interventions to delay or minimize blast crisis transformation in CML. A recent study found that all BC-CML patients harbored the FANCD2 (c.2022-5C>T) mutation. Therefore, the current study was designed to detect this FANCD2 mutant in AP-CML (early progression phase) and to clinically validate its potential as a novel molecular biomarker of early CML progression from CP to AP. Methods: Our study comprised 123 CP-CML (control group) and 60 AP-CML patients (experimental group) from 2 oncology centers, from January 2020 to July 2023. Mean hemoglobin level, WBC count, platelet count, treatment type, hepatomegaly, splenomegaly, and survival status of AP-CML patients were significantly different from those of CP-CML patients. However, as these clinical parameters cannot help in the early detection of patients at risk of CML progression, there was a need for a clinically validated biomarker of AP-CML. DNA was extracted from the patients’ blood samples, and the FANCD2 gene was sequenced using an Illumina NextSeq500 next-generation sequencer (NGS). Results: The NGS analysis revealed a unique splice-site mutation in the FANCD2 gene (c.2022-5C>T). This mutation was detected in the majority (98.3%) of AP-CML patients but in none of the CP-CML patients or healthy control sequences from genomic databases. The mutation was confirmed by Sanger sequencing. FANCD2 is a member of the Fanconi anemia pathway genes involved in DNA repair and genomic stability, and aberrations of this gene are associated with many cancers. Conclusions: In conclusion, our study shows that the somatic FANCD2 (c.2022-5C>T) mutation is a new molecular biomarker for early CML progression. We recommend further clinical validation of this biomarker in prospective clinical trials.

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“…Mani et al Found that Hedgehog (Hh) / Glioma associated protein 1 (GLI1) was abnormally activated in some (Ovarian carcinosarcoma)OCS and affected the function of RF by regulating the transcription of FANCD2, thereby promoting DNA damage repair. Inducing the down-regulation of Hh / GLI1 can lead to HR repair deficiency, so it is related to improving resistance [ 52 ]. In addition, studies have found that mir-493-5p expressed in BRCA2 mutant cancer cells affects the stability of single-strand annealing (SSA), R-loops, and replication fork, which may lead to PARP inhibitor resistance.…”

Section: Parp Inhibitor Resistancementioning

confidence: 99%

Clinical application of PARP inhibitors in ovarian cancer: from molecular mechanisms to the current status

Cheng

et al. 2023

J Ovarian Res

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As a kind of gynecological tumor, ovarian cancer is not as common as cervical cancer and breast cancer, but its malignant degree is higher. Despite the increasingly mature treatment of ovarian cancer, the five-year survival rate of patients is still less than 50%. Based on the concept of synthetic lethality, poly (ADP- ribose) polymerase (PARP) inhibitors target tumor cells with defects in homologous recombination repair(HRR), the most significant being the target gene Breast cancer susceptibility genes(BRCA). PARP inhibitors capture PARP-1 protein at the site of DNA damage to destroy the original reaction, causing the accumulation of PARP-DNA nucleoprotein complexes, resulting in DNA double-strand breaks(DSBs) and cell death. PARP inhibitors have been approved for the treatment of ovarian cancer for several years and achieved good results. However, with the widespread use of PARP inhibitors, more and more attention has been paid to drug resistance and side effects. Therefore, further research is needed to understand the mechanism of PARP inhibitors, to be familiar with the adverse reactions of the drug, to explore the markers of its efficacy and prognosis, and to deal with its drug resistance. This review elaborates the use of PARP inhibitors in ovarian cancer.

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Hedgehog/GLI1 Transcriptionally Regulates FANCD2 in Ovarian Tumor Cells: Its Inhibition Induces HR-Deficiency and Synergistic Lethality with PARP Inhibition.

Cited by 10 publications

References 60 publications

Next-generation DNA sequencing identifies mutated FANCD2 Gene as a novel Biomarker for monitoring early disease progression and timely therapeutic interventions in advanced phase Chronic Myeloid Leukemia patients

Next-generation DNA sequencing identifies mutated FANCD2 Gene as a novel Biomarker for monitoring early disease progression and timely therapeutic interventions in advanced phase Chronic Myeloid Leukemia patients

Clinical Validation of the Somatic FANCD2 Mutation (c.2022-5C>T) as a Novel Molecular Biomarker for Early Disease Progression in Chronic Myeloid Leukemia: A Case–Control Study

Clinical application of PARP inhibitors in ovarian cancer: from molecular mechanisms to the current status

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