| 1. |
- Li, Yanni, et al.
(författare)
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Association of Mitochondrial DNA Copy Number and Telomere Length with Prevalent and Incident Cancer and Cancer Mortality in Women : A Prospective Swedish Population-Based Study
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:15
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Tidskriftsartikel (refereegranskat)abstract
- Changes in mitochondrial DNA copy number (mtDNA-CN) and telomere length have, separately, been proposed as risk factors for various cancer types. However, those results are conflicting. Here, mtDNA-CN and relative telomere length were measured in 3225 middle-aged women included in a large population-based prospective cohort. The baseline mtDNA-CN in patients with prevalent breast cancer was significantly higher (12.39 copies/µL) than cancer-free individuals. During an average of 15.2 years of follow-up, 520 patients were diagnosed with cancer. Lower mtDNA-CN was associated with decreased risk of genital organ cancer (hazard ratio (HR), 0.84), and shorter telomere length was associated with increased risk of urinary system cancer (HR, 1.79). Furthermore, mtDNA-CN was inversely associated with all-cause (HR, 1.20) and cancer-specific mortality (HR, 1.21) when considering all cancer types. Surprisingly, shorter telomere length was associated with decreased risk of cancer-specific mortality when considering all cancer types (HR, 0.85). Finally, lower mtDNA-CN and shorter telomere length were associated with increased risk of both all-cause and cancer-specific mortality in genital organ cancer patients. In this study population, we found that mtDNA-CN and telomere length were significantly associated with prevalent and incident cancer and cancer mortality. However, these associations were cancer type specific and need further investigation.
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| 2. |
- Li, Yanni, et al.
(författare)
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Mitochondrial heteroplasmic shifts reveal a positive selection of breast cancer
- 2023
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Ingår i: Journal of Translational Medicine. - 1479-5876. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Breast cancer is, despite screening, not always detected early enough and is together with other tumor types known to shed genetic information in circulation. Unlike single-copy nuclear DNA, mitochondrial DNA (mtDNA) copies range from 100s to 10,000s per cell, thus providing a potentially alternative to identify potential missing cancer information in circulation at an early stage.METHODS: To characterize mitochondrial mutation landscapes in breast cancer, whole mtDNA sequencing and bioinformatics analyses were performed on 86 breast cancer biopsies and 50 available matched baseline cancer-free whole blood samples from the same individuals, selected from a cohort of middle-aged women in Sweden. To determine whether the mutations can be detected in blood plasma prior to cancer diagnosis, we further designed a nested case-control study (n = 663) and validated the shortlisted mutations using droplet digital PCR.RESULTS: We detected different mutation landscapes between biopsies and matched whole blood samples. Compared to whole blood samples, mtDNA from biopsies had higher heteroplasmic mutations in the D-loop region (P = 0.02), RNR2 (P = 0.005), COX1 (P = 0.037) and CYTB (P = 0.006). Furthermore, the germline mtDNA mutations had higher heteroplasmy level than the lost (P = 0.002) and de novo mutations (P = 0.04). The nonsynonymous to synonymous substitution ratio (dN/dS) was higher for the heteroplasmic mutations (P = 7.25 × 10 -12) than that for the homoplasmic mutations, but the de novo (P = 0.06) and lost mutations (P = 0.03) had lower dN/dS than the germline mutations. Interestingly, we found that the critical regions for mitochondrial transcription: MT-HSP1 (odds ratio [OR]: 21.41), MT-TFH (OR: 7.70) and MT-TAS2 (OR: 3.62), had significantly higher heteroplasmic mutations than the rest of the D-loop sub-regions. Finally, we found that the presence of mt.16093T > C mutation increases 67% risk of developing breast cancer. CONCLUSIONS: Our findings show that mitochondrial genetic landscape changes during cancer pathogenesis and positive selection of mtDNA heteroplasmic mutations in breast cancer. Most importantly, the mitochondrial mutations identified in biopsies can be traced back in matched plasma samples and could potentially be used as early breast cancer diagnostic biomarkers.
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| 3. |
- Li, Yanni, et al.
(författare)
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Mitochondrial related genome-wide Mendelian randomization identifies putatively causal genes for multiple cancer types
- 2023
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Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 88
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Mitochondrial dysfunction is a hallmark of cancer. However, it is unclear whether it is a cause of cancer. This two-sample Mendelian randomization (MR) analyses, uses genetic instruments to proxy the exposure of mitochondrial dysfunction and cancer summary statistics as outcomes, allowing for causal inferences.METHODS: Summary statistics from 18 common cancers (2107-491,974 participants), gene expression, DNA methylation and protein expression quantitative trait loci (eQTL, mQTL and pQTL, respectively, 1000-31,684 participants) on individuals of European ancestry, were included. Genetic variants located within or close to the 1136 mitochondrial-related genes (in cis) and robustly associated with the mitochondrial molecular alterations were used as instrumental variables, and their causal associations with cancers were examined using summary-data-based MR (SMR) analyses. An additional five MR methods were used as sensitivity analyses to confirm the casual associations. A Bayesian test for colocalization between mitochondrial molecular QTLs and cancer risk loci was performed to provide insights into the potential regulatory mechanisms of risk variants on cancers.FINDINGS: We identified potential causal relationships between mitochondrial-related genes and breast, prostate, gastric, lung cancer and melanoma by primary SMR analyses. The sensitivity and the colocalization analyses further refined four genes that have causal effects on three types of cancer. We found strong evidence of positive association of FDPS expression level with breast cancer risk (OR per SD, 0.66; 95% CI, 0.49-0.83; P = 9.77 × 10-7), NSUN4 expression level with both breast cancer risk (OR per SD, 1.05; 95% CI, 1.03-1.07; P = 5.24 × 10-6) and prostate cancer risk (OR per SD, 1.06; 95% CI, 1.03-1.09; P = 1.01 × 10-5), NSUN4 methylation level with both breast and prostate cancer risk, and VARS2 methylation level with lung cancer risk.INTERPRETATIONS: This data-driven MR study demonstrated the causal role of mitochondrial dysfunction in multiple cancers. Furthermore, this study identified candidate genes that can be the targets of potential pharmacological agents for cancer prevention.FUNDING: This work was supported by Styrelsen för Allmänna Sjukhusets i Malmö Stiftelse för bekämpande av cancer (20211025).
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| 4. |
- Memon, Ashfaque A, et al.
(författare)
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Association of mitochondrial DNA copy number with prevalent and incident type 2 diabetes in women : A population-based follow-up study
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial dysfunction is an important factor of the aging process and may play a key role in various diseases. Mitochondrial DNA copy number (mtDNA-CN) is an indirect measure of mitochondrial dysfunction and is associated with type 2 diabetes mellitus (T2DM); however, whether mtDNA-CN can predict the risk of developing T2DM is not well-known. We quantified absolute mtDNA-CN in both prevalent and incident T2DM by well-optimized droplet digital PCR (ddPCR) method in a population-based follow-up study of middle aged (50-59 years) Swedish women (n = 2387). The median follow-up period was 17 years. Compared to those who were free of T2DM, mtDNA-CN was significantly lower in both prevalent T2DM and in women who developed T2DM during the follow-up period. Mitochondrial DNA-copy number was also associated with glucose intolerance, systolic blood pressure, smoking status and education. In multivariable Cox regression analysis, lower baseline mtDNA-CN was prospectively associated with a higher risk of T2DM, independent of age, BMI, education, smoking status and physical activity. Moreover, interaction term analysis showed that smoking increased the effect of low mtDNA-CN at baseline on the risk of incident T2DM. Mitochondrial DNA-copy number may be a risk factor of T2DM in women. The clinical usefulness of mtDNA-CN to predict the future risk of T2DM warrants further investigation.
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| 5. |
- Memon, Ashfaque A., et al.
(författare)
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Quantification of mitochondrial DNA copy number in suspected cancer patients by a well optimized ddPCR method
- 2017
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Ingår i: Biomolecular Detection and Quantification. - : Elsevier BV. - 2214-7535. ; 13, s. 32-39
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Tidskriftsartikel (refereegranskat)abstract
- Changes in mitochondrial DNA (mtDNA) content is a useful clinical biomarker for various diseases, however results are controversial as several analytical factors can affect measurement of mtDNA. MtDNA is often quantified by taking ratio between a target mitochondrial gene and a reference nuclear gene (mtDNA/nDNA) using quantitative real time PCR often on two separate experiments. It measures relative levels by using external calibrator which may not be comparable across laboratories. We have developed and optimized a droplet digital PCR (ddPCR) based method for quantification of absolute copy number of both mtDNA and nDNA gene in whole blood. Finally, the role of mtDNA in suspected cancer patients referred to a cancer diagnostic center was investigated.Analytical factors which can result in false quantification of mtDNA have been optimized and both target and reference have been quantified simultaneously with intra- and inter-assay coefficient variances as 3.1% and 4.2% respectively. Quantification of mtDNA show that compared to controls, solid tumors (but not hematologic malignancies) and other diseases had significantly lower copy number of mtDNA. Higher mtDNA (highest quartile) was associated with a significantly lower risk of both solid tumors and other diseases, independent of age and sex. Receiver operating curve demonstrated that mtDNA levels could differentiate controls from patients with solid tumors and other diseases.Quantification of mtDNA by a well optimized ddPCR method showed that its depletion may be a hallmark of general illness and can be used to stratify healthy individuals from patients diagnosed with cancer and other chronic diseases.
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| 6. |
- Memon, Ashfaque A, et al.
(författare)
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Role of IL-8, CRP and epidermal growth factor in depression and anxiety patients treated with mindfulness-based therapy or cognitive behavioral therapy in primary health care
- 2017
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Ingår i: Psychiatry Research. - : Elsevier BV. - 1872-7123 .- 0165-1781. ; 254, s. 311-316
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Tidskriftsartikel (refereegranskat)abstract
- Epidermal growth factor (EGF) and inflammatory markers have been associated with various neuro-psychiatric disorders. However, their role in mild to moderate depression and anxiety patients treated with mindfulness-based group therapy (mindfulness) or cognitive behavioral therapy (CBT) is not known. In this study we analyzed plasma levels of interleukin (IL)-6, IL-8, high sensitivity C-reactive protein (hsCRP) and EGF before (baseline) and after treatment (8 weeks) and investigated their role in response to both arms of the treatment. To cover variety of mental symptoms, treatment response was analyzed by four scales, the Montgomery-Åsberg depression rating scale (MADRS), Hospital anxiety and depression scale- Depression (HADS-D) and anxiety (HADS-A) and patients health questionnaire-9. EGF levels were significantly decreased after both mindfulness and CBT and were associated with treatment response on all scales independent of the use of tranquilizers and antidepressant treatment. Moreover, baseline EGF levels were significantly associated only with baseline scores of anxiety scale. Levels of inflammatory markers analyzed in this study, were not significantly associated with treatment response on any scale. Our findings suggest that improvement in symptoms of depression and anxiety after both mindfulness and CBT is associated with changes in EGF levels but not with the inflammatory markers.
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| 7. |
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| 8. |
- Memon, Ashfaque, et al.
(författare)
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Circulating HER2 is associated with hyperglycaemia and insulin resistance.
- 2015
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Ingår i: Journal of Diabetes. - : Wiley. - 1753-0407 .- 1753-0393. ; 7:3, s. 369-377
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes mellitus (T2DM) and HER2 are associated with cancer although the role of HER2 in T2DM is not well defined. Our aim was to investigate the association between HER2 levels and T2DM and whether that association was different in Swedish people born in Iraq or Sweden.
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| 9. |
- Memon, Ashfaque, et al.
(författare)
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The association between apolipoprotein M and insulin resistance varies with country of birth.
- 2014
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Ingår i: Nutrition Metabolism and Cardiovascular Diseases. - : Elsevier BV. - 1590-3729 .- 0939-4753. ; 24:11, s. 1174-1180
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Tidskriftsartikel (refereegranskat)abstract
- Risk of type 2 diabetes mellitus (T2DM) differs according to ethnicity. Levels of apolipoprotein M (ApoM) have been shown to be decreased in T2DM. However, its role in different ethnicities is not known. We examined the differences in plasma ApoM levels in Swedish residents born in Iraq (Iraqis) and Sweden (Swedes) in relation to T2DM and insulin resistance (IR).
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| 10. |
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