The global burden of cancer attributable to risk factors, 2010–19: a systematic analysis for the Global Burden of Disease Study 2019

BACKGROUND: Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. METHODS: The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk–outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. FINDINGS: Globally, in 2019, the risk factors included in this analysis accounted for 4·45 million (95% uncertainty interval 4·01–4·94) deaths and 105 million (95·0–116) DALYs for both sexes combined, representing 44·4% (41·3–48·4) of all cancer deaths and 42·0% (39·1–45·6) of all DALYs. There were 2·88 million (2·60–3·18) risk-attributable cancer deaths in males (50·6% [47·8–54·1] of all male cancer deaths) and 1·58 million (1·36–1·84) risk-attributable cancer deaths in females (36·3% [32·5–41·3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20·4% (12·6–28·4) and DALYs by 16·8% (8·8–25·0), with the greatest percentage increase in metabolic risks (34·7% [27·9–42·8] and 33·3% [25·8–42·0]). INTERPRETATION: The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden

Inhibition of cyclin D1 gene transcription by Brg-1

The evolutionarily conserved SWI-SNF chromatin remodeling complex regulates cellular proliferation. A catalytic subunit, BRG-1, is frequently down regulated, silenced or mutated in malignant cells, however, the mechanism by which BRG-1 may function as a tumor suppressor or block breast cancer cellular proliferation is not understood. The cyclin D1 gene is a collaborative oncogene overexpressed in greater than 50% of human breast cancers. Herein, BRG-1 inhibited DNA synthesis and cyclin D1 expression in human MCF-7 breast cancer epithelial cells. The cyclin D1 promoter AP-1 and CRE sites were required for repression by BRG-1 in promoter assays. BRG-1 deficient cells abolished and siRNA to BRG-1 reduced, formation of the BRG-1 chromatin complex. The endogenous cyclin D1 promoter AP-1 site bound BRG-1. Estradiol treatment of MCF7 cells induced recruitment of BRG-1 to the endogenous hpS2 gene promoter. Estradiol, which induced cyclin D1 abundance, was associated with a reduction in recruitment of the co-repressors HP1α/HDAC1 to the endogenous cyclin D1 promoter AP-1/BRG-1 binding sites. These studies suggest the endogenous cyclin D1 promoter BRG-1 binding site functions as a molecular scaffold in the context of local chromatin upon which coactivators and corepressors are recruited to regulate cyclin D1

Hormonal therapy promotes hormone-resistant phenotype by increasing DNMT activity and expression in prostate cancer models

We hypothesized that hormonal therapy favors the development of the hormone-resistant phenotype through epigenetic mechanisms. Human prostate cancer tissues and in vitro and in vivo models were used to verify this hypothesis. We demonstrated that tumor cells continuously treated with bicalutamide (BCLT) or cultured in androgen-depleted medium progressively acquire higher DNA methyltransferase (DNMT) activity and expression than cells cultured in standard condition. Increased DNMT expression and activity also paralleled the up-regulation of truncated AR isoforms, which favors the development of the hormone-resistant phenotype. After androgen stimulation with 10(-12) m dihydrotestosterone, DNMT activity was significantly reduced in comparison with hormonal therapy. Consistent with these observations, the silencing of DNMT3a and DNMT3b significantly decreased the DNMT activity levels. These findings were also directly correlated with phosphatase and tensin homolog down-regulation and activation of ERK and phosphatidylinositol 3-kinases/AKT8 virus oncogene cellular homolog pathways. The use of a pan-DNMT inhibitor (5-Azacitidine) greatly reduced the development of the hormone-resistant phenotype induced by long-term BCLT treatment, and this finding correlated with low DNMT activity. The regulation of DNMT activity was, in some measure, dependent on the androgen receptor, as small interfering RNA treatment targeting the androgen receptor greatly decreased the modulation of DNMT activity under androgenic and antiandrogenic stimulation. These observations were correlated in vivo in patients, as demonstrated by immunohistochemistry. Patients treated by BCLT before surgery had higher DNMT3a and DNMT3b expression than patients who had not undergone this treatment. Our findings provide evidence of a relationship between the castration-resistant phenotype and DNMT expression and activity in human prostate cancer

The effect of amiodarone on the control of hyperthyroidism by propylthiouracil

CommentLetterSCOPUS: le.jFLWNAinfo:eu-repo/semantics/publishe

p27Kip1 Repression of ErbB2-Induced Mammary Tumor Growth in Transgenic Mice Involves Skp2 and Wnt/β-Cantenin Signaling

The journal Cancer Research is the original source of the material