| 1. |
- Escala-Garcia, Maria, et al.
(författare)
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A network analysis to identify mediators of germline-driven differences in breast cancer prognosis
- 2020
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies similar to 7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.
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| 2. |
- Nilsson, Markus, et al.
(författare)
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Mapping prostatic microscopic anisotropy using linear and spherical b-tensor encoding : A preliminary study
- 2021
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Ingår i: Magnetic Resonance in Medicine. - : Wiley. - 0740-3194 .- 1522-2594. ; 86:4, s. 2025-2033
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Tensor-valued diffusion encoding provides more specific information than conventional diffusion-weighted imaging (DWI), but has mainly been applied in neuroimaging studies. This study aimed to assess its potential for the imaging of prostate cancer (PCa). Methods: Seventeen patients with histologically proven PCa were enrolled. DWI of the prostate was performed with linear and spherical tensor encoding using a maximal b-value of 1.5 ms/µm2 and a voxel size of 3 × 3 × 4 mm3. The gamma-distribution model was used to estimate the mean diffusivity (MD), the isotropic kurtosis (MKI), and the anisotropic kurtosis (MKA). Regions of interest were placed in MR-defined cancerous tissues, as well as in apparently healthy tissues in the peripheral and transitional zones (PZs and TZs). Results: DWI with linear and spherical encoding yielded different image contrasts at high b-values, which enabled the estimation of MKA and MKI. Compared with healthy tissue (PZs and TZs combined) the cancers displayed a significantly lower MD (P <.05), higher MKI (P < 10−5), and lower MKA (P <.05). Compared with the TZ, tissue in the PZ showed lower MD (P < 10−3) and higher MKA (P < 10−3). No significant differences were found between cancers of different Gleason scores, possibly because of the limited sample size. Conclusion: Tensor-valued diffusion encoding enabled mapping of MKA and MKI in the prostate. The elevated MKI in PCa compared with normal tissues suggests an elevated heterogeneity in the cancers. Increased in-plane resolution could improve tumor delineation in future studies.
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| 3. |
- Poikonen-Saksela, Paula, et al.
(författare)
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Leukocyte nadir as a predictive factor for efficacy of adjuvant chemotherapy in breast cancer. Results from the prospective trial SBG 2000-1
- 2020
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Ingår i: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 59:7, s. 825-832
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Tidskriftsartikel (refereegranskat)abstract
- Background: Retrospective studies have suggested that chemotherapy-induced leukopenia is associated with improved recurrence-free or overall survival. The SBG 2000-1 trial was designed to verify the favorable prognosis associated with chemotherapy-induced leukopenia in early breast cancer. Patients not experiencing chemotherapy-induced leukopenia were randomized into standard dosed or individually escalated chemotherapy doses based on the grade of leukopenia after a first standard dose.Patients and methods: 1452 women in Sweden and Denmark with operable node-positive or high-risk node-negative breast cancer aged 18-60 years were recruited to participate in this trial. Participants received a first FEC cycle at standard doses (600/60/600 mg/m(2)). Patients (n = 1052) with nadir leukopenia grade 0-2 after the first cycle were randomized between either 6 standard FEC or 6 tailored FEC courses with doses of epirubicin and cyclophosphamide escalated during courses 2 and 3 and thereafter aimed at achieving grade 3 leukopenia. Patients with nadir leukopenia grade 3-4 after the first course continued treatment with standard FEC. Results of the randomized comparison has been published previously. The present study focuses on chemotherapy-induced leukopenia as a covariable with outcome in randomized and non-randomized patients. The prognostic value of leukopenia after course 3, was studied in a Cox model adjusted for cumulative doses of epirubicin and cyclophosphamide. The association of chemotherapy-induced leukopenia with prognosis was a preplanned secondary endpoint for this trial.Results: The eight-year distant disease-free survival was 73%, 77%, 78% and 83% for patients with leucocyte nadir grade 0, 1, 2 and 3-4, respectively. Higher degree of leukopenia was highly significantly associated to improved distant disease-free survival (HR 0.84, 95% CI 0.74-0.96, p = .008) and overall survival (HR 0.87 (0.76-0.99, p = .032).Conclusion: This prospective study confirms that chemotherapy-induced leukopenia is a covariable with outcome in primary breast cancer, even after adjustment for chemotherapy doses.
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| 4. |
- Svensson, Johan, 1964, et al.
(författare)
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Cerebrospinal Fluid Sulfatide Levels Lack Diagnostic Utility in the Subcortical Small Vessel Type of Dementia.
- 2021
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 82:2, s. 781-790
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Tidskriftsartikel (refereegranskat)abstract
- Sulfatides (STs) in cerebrospinal fluid (CSF), as well as magnetic resonance imaging (MRI)-detected white matter hyperintensities (WMHs), may reflect demyelination. Here, we investigated the diagnostic utility of CSF ST levels in the subcortical small vessel type of dementia (SSVD), which is characterized by the presence of brain WMHs.To study the diagnostic utility of CSF ST levels in SSVD.This was a mono-center, cross-sectional study of SSVD (n=16), Alzheimer's disease (n=40), mixed dementia (n=27), and healthy controls (n=33). Totally, 20 ST species were measured in CSF by liquid chromatography-mass spectrometry (LC-MS/MS).CSF total ST levels, as well as CSF levels of hydroxylated and nonhydroxylated ST species, did not differ across the study groups. In contrast, CSF neurofilament light chain (NFL) levels separated the patient groups from the controls. CSF total ST level correlated with CSF/serum albumin ratio in the total study population (r=0.64, p< 0.001) and in all individual study groups. Furthermore, CSF total ST level correlated positively with MRI-estimated WMH volume in the total study population (r=0.30, p< 0.05), but it did not correlate with CSF NFL level.Although there was some relation between CSF total ST level and WMH volume, CSF ST levels were unaltered in all dementia groups compared to the controls. This suggests that CSF total ST level is a poor biomarker of demyelination in SSVD. Further studies are needed to investigate the mechanisms underlying the marked correlation between CSF total ST level and CSF/serum albumin ratio.
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| 5. |
- Wendt, Camilla, et al.
(författare)
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A search for modifying genetic factors in CHEK2:c.1100delC breast cancer patients
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- The risk of breast cancer associated with CHEK2:c.1100delC is 2-threefold but higher in carriers with a family history of breast cancer than without, suggesting that other genetic loci in combination with CHEK2:c.1100delC confer an increased risk in a polygenic model. Part of the excess familial risk has been associated with common low-penetrance variants. This study aimed to identify genetic loci that modify CHEK2:c.1100delC-associated breast cancer risk by searching for candidate risk alleles that are overrepresented in CHEK2:c.1100delC carriers with breast cancer compared with controls. We performed whole-exome sequencing in 28 breast cancer cases with germline CHEK2:c.1100delC, 28 familial breast cancer cases and 70 controls. Candidate alleles were selected for validation in larger cohorts. One recessive synonymous variant, rs16897117, was suggested, but no overrepresentation of homozygous CHEK2:c.1100delC carriers was found in the following validation. Furthermore, 11 non-synonymous candidate alleles were suggested for further testing, but no significant difference in allele frequency could be detected in the validation in CHEK2:c.1100delC cases compared with familial breast cancer, sporadic breast cancer and controls. With this method, we found no support for a CHEK2:c.1100delC-specific genetic modifier. Further studies of CHEK2:c.1100delC genetic modifiers are warranted to improve risk assessment in clinical practice.
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| 6. |
- Wennstig, Anna-Karin, et al.
(författare)
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Long-term risk of ischemic heart disease after adjuvant radiotherapy in breast cancer : results from a large populationbased cohort
- 2020
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Ingår i: Breast Cancer Research. - London : BioMed Central. - 1465-5411 .- 1465-542X. ; 22:10
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Adjuvant radiotherapy (RT) for breast cancer (BC) has been associated with an increased risk of ischemic heart disease (IHD). We examined the incidence of IHD in a large population-based cohort of women with BC.METHODS: The Breast Cancer DataBase Sweden (BCBaSe) includes all women diagnosed with BC from 1992 to 2012 (n = 60,217) and age-matched women without a history of BC (n = 300,791) in three Swedish health care regions. Information on comorbidity, educational level, and incidence of IHD was obtained through linkage with population-based registries. The risk of IHD was estimated by Cox proportional hazard regression analyses and cumulative incidence by the Kaplan-Meier method.RESULTS: Women with BC had a lower risk of IHD compared to women without BC with a hazard ratio (HR) of 0.91 (95% CI 0.88-0.95). When women with left-sided BC were compared to right-sided BC, an increased HR for IHD of 1.09 (95% CI 1.01-1.17) was seen. In women receiving RT, a HR of 1.18 (95% CI 1.06-1.31) was seen in left-sided compared to right-sided BC, and the HRs increased with more extensive lymph node involvement and with the addition of systemic therapy. The cumulative IHD incidence was increased in women receiving left-sided RT compared to right-sided RT, starting from the first years after RT and sustained with longer follow-up.CONCLUSIONS: Women given RT for left-sided BC during 1992 to 2012 had an increased risk of IHD compared to women treated for right-sided BC. These women were treated in the era of three-dimensional conformal RT (3DCRT), and the results emphasize the importance of further developing and implementing RT techniques that lower the cardiac doses, without compromising the beneficial effects of RT.
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| 7. |
- Wennstig, Anna-Karin, 1973-
(författare)
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Long-term side effects of radiotherapy in breast cancer : studies in ischemic heart disease and lung cancer
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Breast cancer (BC) is the most common cancer in women worldwide. Due to early detection and advances in adjuvant therapies, most women diagnosed with early BC will be cured of their disease, and issues of survivorship are of great importance. Adjuvant radiotherapy (RT) in BC is well established and significantly reduces local recurrences and BC mortality. Still, it usually involves some accidental irradiation to the heart and lungs, which may lead to long-term side effects, mainly ischemic heart disease (IHD) and lung cancer (LC). The overall aim with this thesis was to study IHD and radiation-induced LC in women receiving RT for BC from the early 1990s until recently.In paper I and paper II a cohort of women (n=182) receiving computed tomography (CT)-based RT (3DCRT) for BC during 1992 to 2012, who subsequently were referred to a coronary angiography and treated for coronary stenosis, was studied. Paper I was a reproducibility study with the aim to examine the inter-observer variation in delineation of the coronary arteries (CAs) in CT scans used for 3DCRT planning. All patients treated at one of the participating RT departments (n=32), were selected from the larger cohort, and the CAs were delineated in the patients’ CT-scans by three oncologists independently, with a validated CT-based heart atlas as guideline. Spatial difference between the different delineations, and variance in radiation dose was calculated. The median distance between the centers of the arteries was 2-8 mm for the right coronary artery (RCA), and 1-4 mm for the left main coronary artery (LMCA) and the left anterior descending artery (LAD). The intraclass correlation coefficient (ICC) was derived to quantify the variance in estimated doses. The ICC for mean doses varied from 0.76 to 0.98 for LMCA-LAD, and from 0.73 to 0.92 for RCA, indicating that variation in radiation doses was mainly due to interpatient variation. In conclusion, the study showed high consistency in contouring the CAs in the patients’ planning CTs, in particular the LMCA-LAD. In paper II, the aim was to examine the relationship between radiation dose to the CAs and subsequent coronary stenosis that required a coronary intervention at this location. The CAs were delineated and divided into segments in the 182 patients’ planning-CTs and doses were recalculated based on the dose distribution of the original RT plans. The location of the CA stenosis was identified from the Swedish Coronary Angiography and Angioplasty Register (SCAAR). Mean doses to the heart and the LAD were substantially higher in women receiving left-sided RT compared to right-sided RT. Segment-wise analyses were performed to assess the risk of developing a coronary stenosis that required an intervention at a certain radiation dose. Segments receiving radiation doses < 1 Gray (Gy) were used as reference. The main finding was a five-fold increase in risk of a clinically relevant coronary stenosis in the mid LAD at mean doses over 20 Gy, compared to doses of 0-1 Gy (odds ratio 5.23; 95 % CI (confidence interval) 2.01-13.6). There were iv too few events to calculate increase in risk per Gy. Still, the result of this study supports that the radiation dose to the LAD should be considered at RT planning and kept as low as possible.In paper III and IV, the BcBaSe cohort was used to examine risk of IHD, and radiation-induced LC after adjuvant RT for BC. The BCBaSe consists of 68089 women diagnosed with BC during 1992 to 2012, and 340352 age-matched women without BC diagnosis. In paper III, Cox regression analyses were performed to estimate risk of IHD, by comparing women with BC to women without BC diagnosis, and by comparing left-sided BC to right-sided BC. Kaplan-Meier analysis was performed to assess cumulative incidence of IHD. Women with BC had a lower risk of IHD compared to women without BC diagnosis at follow-up (hazard ratio (HR) 0.91; 95 % CI 0.88-0.95). Women irradiated for left-sided BC had a higher risk of IHD compared to women irradiated for right-sided BC (HR 1.18; 95 % CI 1.06-1.31). The HRs increased with more extensive lymph node involvement and with addition of systemic therapy. The cumulative IHD incidence was increased in women receiving left-sided RT compared to rightsided RT, starting from the first years after RT and sustained with longer followup. In paper IV, Kaplan-Meier analyses were performed to assess cumulative incidence of LC and LC-specific survival. Cox regression analyses were performed to estimate risk of LC after adjuvant RT for BC, comparing women with BC to women without BC diagnosis. Women with BC receiving RT had a higher cumulative incidence of LC compared both to women with BC not receiving RT and women without BC. This became apparent 5 years after RT and increased with longer follow-up. Women with BC receiving RT had a higher risk of LC compared to women without BC diagnosis (HR 2.35; 95 % CI 1.54-3.59). LCspecific survival was significantly higher in women with a prior BC compared to women without a prior BC diagnosis. In paper III and paper IV information on individual dosimetry data was not available. Most women likely received 3DCRT given with tangential fields and were treated before breathing adaption techniques were implemented in Sweden. The results of these studies emphasize the importance of further development and implementing of RT techniques and regimens that lower the cardiac and lung doses.In conclusion, we found that radiation doses to the LAD remained high in women receiving 3DCRT for BC between 1992 and 2012, and were associated with an increased risk of clinically relevant CA stenosis. Delineating the LAD was feasible and the results of these studies support that the LAD radiation dose should be considered in RT treatment planning. The register-based studies confirmed that the risk of IHD was significantly increased in women receiving left-sided RT and that the risk of LC after BC RT was significantly increased in this large cohort of women with BC.
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| 8. |
- Wennstig, Anna-Karin, 1973-, et al.
(författare)
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Risk of primary lung cancer after adjuvant radiotherapy in breast cancer : a large population-based study
- 2021
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Ingår i: npj Breast Cancer. - : Springer Nature. - 2374-4677. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Adjuvant radiotherapy (RT) for breast cancer (BC) has been associated with an increased risk of later radiation-induced lung cancer (LC). We examined the risk of primary LC in a population-based cohort of 52300 women treated for BC during 1992 to 2012, and 253796 age-matched women without BC. Cumulative incidence of LC was calculated by the Kaplan–Meier method, and the risk of LC after BC treatment was estimated by Cox proportional hazards regression analyses. Women with BC receiving RT had a higher cumulative incidence of LC compared to women with BC not receiving RT and women without BC. This became apparent 5 years after RT and increased with longer follow-up. Women with BC receiving RT had a Hazard ratio of 1.59 (95% confidence interval 1.37–1.84) for LC compared to women without BC. RT techniques that lower the incidental lung doses, e.g breathing adaption techniques, may lower this risk.
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| 9. |
- Yang, Xin, et al.
(författare)
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Cancer risks associated with germline PALB2 pathogenic variants : An international study of 524 families
- 2020
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Ingår i: Journal of Clinical Oncology. - 0732-183X. ; 38:7, s. 674-685
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10-76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10-3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10-3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 3 1022). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age (P for trend = 2.0 × 10-3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies (P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.
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