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- Figlioli, G, et al.
(författare)
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The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
- 2019
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Ingår i: NPJ breast cancer. - : Springer Science and Business Media LLC. - 2374-4677. ; 5, s. 38-
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.
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| 2. |
- Sator, Lea, et al.
(författare)
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Overdiagnosis of COPD in Subjects With Unobstructed Spirometry A BOLD Analysis
- 2019
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Ingår i: Chest. - : Elsevier BV. - 0012-3692 .- 1931-3543. ; 156:2, s. 277-288
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There are several reports on underdiagnosis of COPD, while little is known about COPD overdiagnosis and overtreatment. We describe the overdiagnosis and the prevalence of spirometrically defined false positive COPD, as well as their relationship with overtreatment across 23 population samples in 20 countries participating in the BOLD Study between 2003 and 2012.METHODS: A false positive diagnosis of COPD was considered when participants reported a doctor's diagnosis of COPD, but postbronchodilator spirometry was unobstructed (FEV1/FVC > LLN). Additional analyses were performed using the fixed ratio criterion (FEV1/FVC < 0.7).RESULTS: Among 16,177 participants, 919 (5.7%) reported a previous medical diagnosis of COPD. Postbronchodilator spirometry was unobstructed in 569 subjects (61.9%): false positive COPD. A similar rate of overdiagnosis was seen when using the fixed ratio criterion (55.3%). In a subgroup analysis excluding participants who reported a diagnosis of "chronic bronchitis" or "emphysema" (n = 220), 37.7% had no airflow limitation. The site-specific prevalence of false positive COPD varied greatly, from 1.9% in low- to middle-income countries to 4.9% in high-income countries. In multivariate analysis, overdiagnosis was more common among women, and was associated with higher education; former and current smoking; the presence of wheeze, cough, and phlegm; and concomitant medical diagnosis of asthma or heart disease. Among the subjects with false positive COPD, 45.7% reported current use of respiratory medication. Excluding patients with reported asthma, 34.4% of those with normal spirometry still used a respiratory medication.CONCLUSIONS: False positive COPD is frequent. This might expose nonobstructed subjects to possible adverse effects of respiratory medication.
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