Increased PTEN gene expression in patients with endometrial carcinoma from areas of high risk depleted uranium exposure

Jumaah, Alaa Salah; Al-Haddad, Hawraa Sahib; Mahdi, Liwaa Hussein; Hatem, Emad; Al-Janabi, Asaad; McAllister, Katherine; Yasseen, Akeel A.

doi:10.1186/s13104-019-4756-4

Cited by 6 publications

(4 citation statements)

References 27 publications

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“…EC is the most common gynecologic malignancy in the western world [ 2 , 3 , 34 ], and survival rates are not improving. There is urgent need for strategies to improve outlook for patients with aggressive subtypes and advanced disease.…”

Section: Discussionmentioning

confidence: 99%

The frequency of POLE-mutation in endometrial carcinoma and prognostic implications: a systemic review and meta-analysis

Jumaah

Salim

Al-Haddad

et al. 2020

J Pathol Transl Med

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Endometrial carcinoma (EC) is the most common cancer of the female reproductive system. In the United States, EC was the sixth-cause of cancer-related death in 2018, accounting for 11,350 deaths. The disease affects an estimated 1 out of every 37 and 49 women respectively during their lifetime in the United States and Australia [1,2]. The outlook for 5-year survival after treatment ranges from 74% to 91% [3,4]. EC has been historically classified into estrogen dependent (type I) and estrogenindependent (type II) cancers [4]. Type II tumors are less common, more clinically aggressive, and may have serous, clear cell or undifferentiated histology. In contrast, type I tumors present in 70%-80% of cases, with endometrioid histology and a more favorable outcome. The updated classification of EC identifies four molecular subtypes according to The Cancer Genomic Atlas (TCGA): "POLE-mutated (ultramutated), microsatellite unstable (hypermutated), copy number low (endometrioid), and copy number high (serous-like)" [1]. The POLE-ultramutated subgroup holds great promise for the outlook of EC patients. The tumors have a more favorable outcome, and are usually noted to be of endometrioid type and associated with lymphoid infiltrates [5]. The POLE gene encodes the catalytic subunit of DNA polymerase epsilon, which synthesizes the leading strand of replicating DNA. The epsilon polymerase recognizes and removes mispaired nucleotides using exonuclease activity. This proofreading capacity of epsilon enables high fidelity DNA replication [6]. Mutations can occur in the exonuclease domain of the polymerase,

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Section: Discussionmentioning

confidence: 99%

The frequency of POLE-mutation in endometrial carcinoma and prognostic implications: a systemic review and meta-analysis

Jumaah

Salim

Al-Haddad

et al. 2020

J Pathol Transl Med

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“…CDKN2A gene locus encodes two tumor suppressor proteins p16/INK4A and P14/ARF, which regulate cell cycle by cyclin D inhibition, and its inactivation leads to a tumorigenesis through the PI3K/Akt pathway [ 44 ]. Recent studies provide evidence of PI3K and MAPK pathways' involvement in uranium-induced toxicity [ 45 , 46 ]. In addition, the activation of the NF-κB/IL-6 pathway in response to INK4a/ARF inhibition triggering tumor growth and development has been described recently [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Long-term environmental metal exposure is associated with hypomethylation of CpG sites in NFKB1 and other genes related to oncogenesis

Stepanyan,

Petrackova,

Hakobyan

et al. 2023

Clin Epigenet

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Background Long-term environmental exposure to metals leads to epigenetic changes and may increase risks to human health. The relationship between the type and level of metal exposure and epigenetic changes in subjects exposed to high concentrations of metals in the environment is not yet clear. The aim of our study is to find the possible association of environmental long-term exposure to metals with DNA methylation changes of genes related to immune response and carcinogenesis. We investigated the association of plasma levels of 21 essential and non-essential metals detected by ICP-MS and the methylation level of 654 CpG sites located on NFKB1, CDKN2A, ESR1, APOA5, IGF2 and H19 genes assessed by targeted bisulfite sequencing in a cohort of 40 subjects living near metal mining area and 40 unexposed subjects. Linear regression was conducted to find differentially methylated positions with adjustment for gender, age, BMI class, smoking and metal concentration. Results In the metal-exposed group, five CpGs in the NFKB1 promoter region were hypomethylated compared to unexposed group. Four differentially methylated positions (DMPs) were associated with multiple metals, two of them are located on NFKB1 gene, and one each on CDKN2A gene and ESR1 gene. Two DMPs located on NFKB1 (chr4:102500951, associated with Be) and IGF2 (chr11:2134198, associated with U) are associated with specific metal levels. The methylation status of the seven CpGs located on NFKB1 (3), ESR1 (2) and CDKN2A (2) positively correlated with plasma levels of seven metals (As, Sb, Zn, Ni, U, I and Mn). Conclusions Our study revealed methylation changes in NFKB1, CDKN2A, IGF2 and ESR1 genes in individuals with long-term human exposure to metals. Further studies are needed to clarify the effect of environmental metal exposure on epigenetic mechanisms and pathways involved.

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“…A single study measured the expression of the tumour-suppressor gene, PTEN, in endometrial carcinoma patients living in DU-exposed areas (cases) and unexposed areas (controls) in Southern Iraq. 53 The study found that PTEN gene expression mean fold change was greater among the exposed group (0.139±0.185) than the unexposed group (0.0031±0.0029), but the difference in means was not statistically significant when tumour grade and cancer stage were controlled for (p=0.286 and p=0.98, respectively).…”

Section: Resultsmentioning

confidence: 91%

Weaponised uranium and adverse health outcomes in Iraq: a systematic review

et al. 2021

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BackgroundThe US military first deployed depleted uranium (DU) weapons in Iraq during the Gulf War in 1990 and in the 2003 invasion of Iraq. Research into the health impacts of DU has been mired in debate and controversy. Research funded by the US government has denied the health risks posed by DU to the Iraqi population, while opponents have claimed that DU is responsible for increased rates of birth defects and cancers in Iraq. Others assert that the public health impacts of DU weapons remain uncertain. This systematic review identified, appraised and synthesised all human observational studies assessing adverse health outcomes associated with DU exposure among the Iraqi population. To our knowledge, no systematic review has been conducted on the topic previously.MethodsWe searched 11 electronic databases for human observational studies published between 1990 and 2020 that measured association between exposure to weaponised uranium and health outcomes (including cancer, birth defects, immune system function and mortality) among the Iraqi population. We assessed risk of bias using the Navigation Guide’s risk of bias tool and rated certainty of the evidence using the Grading of Recommendations, Assessment, Development and Evaluations approach (PROSPERO: CRD42018108225).ResultsOur searches identified 2601 records, of which 28 met our inclusion criteria. We identified five additional eligible reports from other sources. Two articles reported the results of multiple relevant studies; our final set included 33 articles reporting on 36 eligible studies. Most studies (n=30, 83%) reported a positive association between uranium exposure and adverse health outcomes. However, we found that the reviewed body of evidence suffers from a high risk of bias.ConclusionThe available evidence suggests possible associations between exposure to depleted uranium and adverse health outcomes among the Iraqi population. More primary research and the release of missing data are needed to design meaningful health and policy interventions in Iraq.

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Increased PTEN gene expression in patients with endometrial carcinoma from areas of high risk depleted uranium exposure

Cited by 6 publications

References 27 publications

The frequency of POLE-mutation in endometrial carcinoma and prognostic implications: a systemic review and meta-analysis

The frequency of POLE-mutation in endometrial carcinoma and prognostic implications: a systemic review and meta-analysis

Long-term environmental metal exposure is associated with hypomethylation of CpG sites in NFKB1 and other genes related to oncogenesis

Weaponised uranium and adverse health outcomes in Iraq: a systematic review

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