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- 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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| 2. |
- Vats, Sakshi, et al.
(författare)
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Characterization of the Mitochondrial Genetic Landscape in Abdominal Aortic Aneurysm
- 2023
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Ingår i: Journal of the American Heart Association. - 2047-9980. ; 12:8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Abdominal aortic aneurysm (AAA) is a vascular disease with a mortality rate of >80% if ruptured. Mitochondrial dysfunction has been previously implicated in AAA pathogenesis. In this study, we aimed to characterize the mitochondrial genetic landscape in AAA.Methods and Results: Whole mitochondrial genome sequencing and bioinformatics analysis were performed in comorbidity matched 48 cases without AAA and 48 cases with AAA, objectively diagnosed, and selected from a cohort of 65‐year‐old men recruited for a screening program. We identified differential mutational landscapes in men with and without AAA, with errors in mitochondrial DNA replication or repair as potential sources. Heteroplasmic insertions and overall heteroplasmy of structural rearrangements were significantly elevated in AAA cases. Three heteroplasmic variants were associated with risk factors of AAA: leukocyte concentration, plasma glucose, and cholesterol levels, respectively. Interestingly, mutations were more prevalent in regulatory part of the mitochondria, the displacement loop region, in AAA as compared with controls (P value <0.05), especially in the conserved and critical mitochondrial extended termination‐associated sequence region. Moreover, we report a novel 24 bp mitochondrial DNA duplication present exclusively in cases with AAA (4%) and 75% of the unmatched AAA biopsies. Finally, the haplogroup cluster JTU was overrepresented in AAA and significantly associated with a positive family history of AAA (odds ratio, 2.9 [95% CI, 1.1–8.1]).Conclusions: This is the first study investigating the mitochondrial genome in AAA, where important genetic alterations and haplogroups associated with AAA and clinical risk factors were identified. Our findings have the potential to fill in gaps in the missing genetic information on AAA.
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| 4. |
- Taloyan, Marina, et al.
(författare)
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Sexual dysfunction in Assyrian/Syrian immigrants and Swedish-born persons with type 2 diabetes
- 2012
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Ingår i: BMC Research Notes. - : Springer Science and Business Media LLC. - 1756-0500. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Few studies have investigated sexual dysfunction in immigrant patients with type 2 diabetes in Sweden. The aim of this study was to examine the association between ethnicity and sexual dysfunction and to analyze if this association remains after adjusting for explanatory variables including age, marital status, HbA1c, triglycerides, and hypertension. This cross-sectional study was conducted at four primary health care centers in the Swedish town of Sodertalje. A total of 354 persons with type 2 diabetes (173 Assyrians/Syrians and 181 Swedish-born patients) participated in the survey. The main outcome measure was the self-reported presence of sexual dysfunction based on two questions, one regarding loss of ability to have sexual intercourse and the other loss of sexual desire. Response rates were 78% and 86%, respectively. FINDINGS: The total prevalence of loss of ability to have intercourse was 29.5%. In the multivariate models, the odds of loss of ability to have intercourse was significantly higher in the oldest age group (OR = 5.80; 95% CI, 2.33--14.40), in men (OR = 3.33; 95% CI, 1.33--8.30), and in unmarried individuals (OR = 2.40; 95% CI, 1.02--5.70). The odds of reporting loss of sexual desire was higher in Assyrians/Syrians than in Swedish-born patients and increased from 2.00 in the age- and gender-adjusted model to 2.70 in the fully adjusted model when all confounders were taken into account. CONCLUSIONS: Sexual dysfunction appears to be more common in Assyrians/Syrians than in Swedish-born patients. Health care workers should actively ask about sexual function in their patients with type 2 diabetes.
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