| 61. |
- Mueller, Stefanie H., et al.
(author)
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Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry
- 2023
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In: Genome Medicine. - : BioMed Central (BMC). - 1756-994X. ; 15
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Journal article (peer-reviewed)abstract
- Background: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes.Methods: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry.Results: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 x 10(-6)) and AC058822.1 (P = 1.47 x 10(-4)), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C.Conclusions: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 x 10(-5)), demonstrating the importance of diversifying study cohorts.
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| 62. |
- Mälarstig, Anders, et al.
(author)
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Evaluation of circulating plasma proteins in breast cancer using Mendelian randomisation
- 2023
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Journal article (peer-reviewed)abstract
- Biomarkers for early detection of breast cancer may complement population screening approaches to enable earlier and more precise treatment. The blood proteome is an important source for biomarker discovery but so far, few proteins have been identified with breast cancer risk. Here, we measure 2929 unique proteins in plasma from 598 women selected from the Karolinska Mammography Project to explore the association between protein levels, clinical characteristics, and gene variants, and to identify proteins with a causal role in breast cancer. We present 812 cis-acting protein quantitative trait loci for 737 proteins which are used as instruments in Mendelian randomisation analyses of breast cancer risk. Of those, we present five proteins (CD160, DNPH1, LAYN, LRRC37A2 and TLR1) that show a potential causal role in breast cancer risk with confirmatory results in independent cohorts. Our study suggests that these proteins should be further explored as biomarkers and potential drug targets in breast cancer.
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| 63. |
- Numan Hellquist, Barbro, et al.
(author)
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Effectiveness of population-based service screening with mammography for women ages 40 to 49 years with a high or low risk of breast cancer : socioeconomic status, parity, and age at birth of first child
- 2015
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In: Cancer. - : Wiley. - 0008-543X .- 1097-0142. ; 121:2, s. 251-258
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Journal article (peer-reviewed)abstract
- BACKGROUND: Invitation to mammography screening of women aged 40 to 49 years is a matter of debate in many countries and a cost-effective alternative in countries without screening among women aged 40 to 49 years could be inviting those at higher risk. The relative effectiveness of mammography screening was estimated for subgroups based on the breast cancer risk factors parity, age at time of birth of first child, and socioeconomic status (SES).METHODS: The SCReening of Young Women (SCRY) database consists of all women aged 40 to 49 years in Sweden between 1986 and 2005 and was split into a study and control group. The study group consisted of women residing in areas in which women aged 40 to 49 years were invited to screening and the control group of women in areas in which women aged 40 to 49 years were not invited to screening. Rate ratio (RR) estimates were calculated for 2 exposures: invitation and attendance.RESULTS: There were striking similarities noted in the RR pattern for women invited to and attending screening and no statistically significant difference or trend in the RR was noted by risk group. The RR estimates increased by increasing parity for parity of 0 to 2 and ranged from 0.55 (95% confidence interval [95% CI], 0.38-0.79) to 0.79 (95% CI, 0.65-0.95) for attending women. The RR for women with high SES was lower than that for women with low SES (RR, 0.72 [95% CI, 0.60-0.86] and RR, 0.79 [95% CI, 0.63-0.99], respectively). For women aged 20 to 24 years at the time of the birth of their first child, the RR was 0.73 (95% CI, 0.58-0.91) and estimates for other ages were similar.CONCLUSIONS: There was no statistically significant difference noted in the relative effectiveness of mammography screening by parity, age at the time of birth of the first child, or SES. Cancer 2014.
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| 64. |
- Numan Hellquist, Barbro, et al.
(author)
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Effectiveness of population-based service screening with mammography for women ages 40 to 49 years with high and low risk of breast cancer : socioeconomic status, parity and age at birth of first child
-
Other publication (other academic/artistic)abstract
- Background Whether women in age 40-49 years should be invited to mammography screening or not is debated in many countries and a cost-effective alternative in countries with no screening in age 40-49 years could be selective screening i.e. inviting women at higher risk. In the current study relative effectiveness of mammography screening was estimated for subgroups based on the breast cancer risk factors parity, age at birth of first child and socioeconomic status (SES).Methods The SCReening of Young women (SCRY) database consist of all women in age 40-49 years in Sweden in 1986-2005 and is split into a study and control group. The study group consists of women in areas where women age 40-49 years were invited to screening and the control group of women in areas where women 40-49 years were not. Rate ratio (RR) estimates were calculated for risk groups. Two exposures were considered; invitation to mammography screening and attendance.Results There were striking similarities in the RR pattern for women invited to and attending in screening for all three risk factors and there was no statistically significant difference or trend in the RR by risk group. The RR estimates increased by increasing parity for parity 0 to 2 and ranged from 0.55 (95% CI 0.38-0.79) to 0.79 (95% CI 0.65-0.95) for women attending screening. The RR for white collar workers (low SES) was lower than for blue collar workers (high SES), 0.72 (95% CI 0.60-0.86) and 0.79 (95% CI 0.63-0.99) respectively for attending. For women 20-24 years at birth of first child RR was estimated at 0.73 (95% CI 0.58-0.91) for attending and estimates for other ages were similar.Conclusion There was no statistically significant difference in relative effectiveness of mammography screening by parity, age at birth of first child or socio-economic status.
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| 65. |
- Rantalainen, Mattias, et al.
(author)
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Sequencing-based breast cancer diagnostics as an alternative to routine biomarkers
- 2016
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In: Scientific Reports. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 2045-2322.
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Journal article (peer-reviewed)abstract
- Sequencing-based breast cancer diagnostics have the potential to replace routine biomarkers and provide molecular characterization that enable personalized precision medicine. Here we investigate the concordance between sequencing-based and routine diagnostic biomarkers and to what extent tumor sequencing contributes clinically actionable information. We applied DNA- and RNA-sequencing to characterize tumors from 307 breast cancer patients with replication in up to 739 patients. We developed models to predict status of routine biomarkers (ER, HER2,Ki-67, histological grade) from sequencing data. Non-routine biomarkers, including mutations in BRCA1, BRCA2 and ERBB2(HER2), and additional clinically actionable somatic alterations were also investigated. Concordance with routine diagnostic biomarkers was high for ER status (AUC = 0.95;AUC(replication) = 0.97) and HER2 status (AUC = 0.97;AUC(replication) = 0.92). The transcriptomic grade model enabled classification of histological grade 1 and histological grade 3 tumors with high accuracy (AUC = 0.98;AUC(replication) = 0.94). Clinically actionable mutations in BRCA1, BRCA2 and ERBB2(HER2) were detected in 5.5% of patients, while 53% had genomic alterations matching ongoing or concluded breast cancer studies. Sequencing-based molecular profiling can be applied as an alternative to histopathology to determine ER and HER2 status, in addition to providing improved tumor grading and clinically actionable mutations and molecular subtypes. Our results suggest that sequencing-based breast cancer diagnostics in a near future can replace routine biomarkers
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| 66. |
- Ruoqing, Chen, 1985-
(author)
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Parental cancer and children’s well-being : understanding the potential role of psychological stress
- 2017
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Doctoral thesis (other academic/artistic)abstract
- Early life stress has a major influence on one’s health through the life course. During childhood, early experience may not only affect the normal brain development, but also influence the susceptibility to mental and physical disorders. A cancer diagnosis in a parent may cause substantial distress in the children, who may have to confront and adapt to short- and long-term changes in their lives and subsequently experience a higher risk of physical and psychosocial problems. Therefore, the first aim of this thesis was to examine whether parental cancer is associated with physical and mental health problems in the affected children using data from the Swedish national registers. Further, to explore the potential mechanism determining the impact of stress on children’ health, we focused on the brain development in childhood and investigated the association between stress biomarkers and brain morphology, using data from a Dutch population-based cohort.In Study I, we assessed the association between parental cancer and risk of injury in a large representative sample of Swedish children. We found that parental cancer was associated with a higher risk of hospital contacts for injury, particularly during the first year after the cancer diagnosis and when the parent experienced a psychiatric illness after the cancer diagnosis. The risk increment reduced during the second and third years and became null afterwards.Given the observed higher risk of adverse physical health in terms of injury, we further investigated the influence of parental cancer on adverse mental health in terms of psychiatric disorders among children. In Study II, we constructed a matched cohort, and separately examined the associations between parental cancer diagnosed during pregnancy or after birth and clinical diagnoses of psychiatric disorders or use of prescribed psychiatric medications. Paternal but not maternal cancer during pregnancy appeared to be associated with a higher risk of psychiatric disorders, primary among girls. Parental cancer after birth conferred a higher risk of clinical diagnoses of psychiatric disorders, particularly stress reaction and adjustment disorders. The affected children also experienced a higher risk of use of prescribed psychiatric medications, particularly anxiolytics. The latter associations were most pronounced for parental cancer with poor expected survival and for parental death after cancer diagnosis.In Study III, we focused on other domains of mental and physical health affected by parental cancer. We examined the associations of parental cancer with intellectual performance, stress resilience, and physical fitness among boys that underwent the compulsory military conscription examination during early adulthood. We observed positive associations of parental cancer with low stress resilience and low physical fitness, with stronger associations noted for parental cancer with poor expected survival and for a loss of parent through death after cancer diagnosis. No overall association was observed between parental cancer and intellectual performance, but the parental cancer with poor expected survival or resulting in a death of the parent was associated with a higher risk of low intellectual performance.
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| 67. |
- Salmela, Elina, et al.
(author)
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Swedish population substructure revealed by genome-wide single nucleotide polymorphism data
- 2011
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:2, s. e16747-
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Journal article (peer-reviewed)abstract
- The use of genome-wide single nucleotide polymorphism (SNP) data has recently proven useful in the study of human population structure. We have studied the internal genetic structure of the Swedish population using more than 350,000 SNPs from 1525 Swedes from all over the country genotyped on the Illumina HumanHap550 array. We have also compared them to 3212 worldwide reference samples, including Finns, northern Germans, British and Russians, based on the more than 29,000 SNPs that overlap between the Illumina and Affymetrix 250K Sty arrays. The Swedes--especially southern Swedes--were genetically close to the Germans and British, while their genetic distance to Finns was substantially longer. The overall structure within Sweden appeared clinal, and the substructure in the southern and middle parts was subtle. In contrast, the northern part of Sweden, Norrland, exhibited pronounced genetic differences both within the area and relative to the rest of the country. These distinctive genetic features of Norrland probably result mainly from isolation by distance and genetic drift caused by low population density. The internal structure within Sweden (F(ST) = 0.0005 between provinces) was stronger than that in many Central European populations, although smaller than what has been observed for instance in Finland; importantly, it is of the magnitude that may hamper association studies with a moderate number of markers if cases and controls are not properly matched geographically. Overall, our results underline the potential of genome-wide data in analyzing substructure in populations that might otherwise appear relatively homogeneous, such as the Swedes.
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| 68. |
- Sandberg, Maria E. C., et al.
(author)
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Influence of radiotherapy for the first tumor on aggressiveness of contralateral breast cancer
- 2013
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 132:10, s. 2388-2394
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Journal article (peer-reviewed)abstract
- We aimed to investigate if characteristics of contralateral breast cancer (CBC) are influenced by adjuvant radiotherapy for the first breast cancer. Using information from population-based registers and medical records, we analyzed two cohorts comprising all women with CBC diagnosed >3 months after their first cancer (809 patients in Stockholm 19762005 and 750 patients in South Sweden 19772005). We used Poisson regression to calculate risk of distant metastasis after CBC, comparing patients treated and not treated with radiotherapy for the first cancer. Logistic regression was used to estimate odds ratio (OR) of more aggressive tumor characteristics in the second cancer, compared to the first. For patients with CBC in Stockholm with <5 years between the cancers radiotherapy for the first cancer conferred a nearly doubled risk of distant metastasis [incidence rate ratio (IRR) = 1.91; 95% confidence interval (CI): 1.272.88], compared to those not treated with radiotherapy. This was replicated in the South Swedish cohort [IRR = 2.12 (95% CI: 1.403.23)]. In Stockholm, we found an increased odds that, following radiotherapy, a second cancer was of more advanced TNM-stage [OR 2.16 (95% CI 1.134.11)] and higher histological grade [OR = 2.00 (95% CI 1.083.72)] compared to the first, for patients with CBC with <5 years between the cancers. No effect on any of the investigated outcomes was seen for patients diagnosed with CBC >5 years from the first cancer. In conclusion, patients diagnosed with CBC within 5 years had worse prognosis and more aggressive tumor characteristics of the second cancer, if they had received radiotherapy for their first cancer, compared to no radiotherapy.
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| 69. |
- Sartor, Hanna, et al.
(author)
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The association of single nucleotide polymorphisms (SNPs) with breast density and breast cancer survival : the Malmö Diet and Cancer Study
- 2020
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In: Acta Radiologica. - : SAGE Publications. - 0284-1851 .- 1600-0455. ; 61:10, s. 1326-1334
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Journal article (peer-reviewed)abstract
- Background: Genetic factors are important in determining breast density, and heritable factors account for 60% of the variation. Certain single nucleotide polymorphisms (SNPs) are associated with density and risk of breast cancer but the association with prognosis is not clear. Purpose: To investigate associations between selected SNPs and breast cancer survival in the Malmö Diet and Cancer Study (MDCS). Material and Methods: A total of 724 unrelated women with breast cancer and registered radiological and pathological data were identified in MDCS 1991–2007, with genotyping available for 672 women. Associations among 15 SNPs, density, and breast cancer-specific survival were analyzed using logistic/Cox regression, adjusted for factors affecting density and survival. Variants significantly associated with either density or survival were validated in a large independent breast cancer cohort (LIBRO-1). Results: Minor homozygotes of SNPs rs9383589, CCDC170 and rs6557161, ESR1 were associated with high breast density (adjusted odds ratio [AOR] 8.97, 95% confidence interval [CI] 1.35–59.57; AOR 2.08, 95% CI 1.19–3.65, respectively) and poorer breast cancer survival (adjusted hazard ratio [HRadj] 6.46, 95% CI 1.95–21.39; HRadj 2.30, 95% CI 1.33–3.96, respectively) compared to major homozygotes. For SNP rs3757318, ESR1, minor homozygotes (HRadj 7.46, 95% CI 2.28–24.45) were associated with poorer survival. We confirmed that rs6557161, ESR1 was significantly associated with both density and survival in the LIBRO-1 study. Conclusion: These findings support a shared genetic basis for density and breast cancer survival. The SNP significantly associated with both density and survival in both cohorts may be of interest in future research investigating polygenic risk scores for breast cancer risk and screening stratification purposes.
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| 70. |
- Shen, Qing, et al.
(author)
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Psychiatric disorders and cardiovascular diseases during the diagnostic workup of potential breast cancer : a population-based cohort study in Skåne, Sweden
- 2019
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In: Breast Cancer Research. - : BioMed Central. - 1465-5411 .- 1465-542X. ; 21:1
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Journal article (peer-reviewed)abstract
- BACKGROUND: An increasing number of women are evaluated for potential breast cancer and may experience mental distress during evaluation. We aim to assess the risks of psychiatric disorders and cardiovascular diseases during the diagnostic workup of potential breast cancer.METHODS: All women with a new diagnosis of unspecified lump in breast (N = 15,714), benign tumor or breast cancer in situ (N = 4435), or breast cancer (N = 8512) during 2005-2014 in Skåne, Sweden, were considered as exposed to a breast diagnostic workup. We used multivariable Poisson regression to compare rates of psychiatric disorders and cardiovascular diseases during the 6 weeks before the date of diagnosis of these women with the corresponding rates of women not undergoing such workup. The commonest waiting time for breast cancer patients was 6 weeks during the study period. A within-individual comparison was performed to control for potential unmeasured time-stationary confounders.RESULTS: Compared to the reference, we found a higher rate of psychiatric disorders during the 6 weeks before diagnosis of benign tumor or breast cancer in situ (incidence rate ratio [IRR], 1.3; 95% confidence interval [CI], 1.1 to 1.5) and breast cancer (IRR, 1.4; 95% CI, 1.2 to 1.6). A higher rate was also noted for cardiovascular diseases (IRR, 1.3; 95% CI, 1.1 to 1.6 for benign tumor or breast cancer in situ, and IRR, 1.9; 95% CI, 1.8 to 2.0 for breast cancer). The rate increases for breast cancer were greater comparing a diagnostic workup due to symptoms to a workup due to screening. Little rate increase of neither psychiatric disorders nor cardiovascular diseases was noted during the 6 weeks before the diagnosis of unspecified lump in breast. The within-individual comparison largely confirmed these findings.CONCLUSIONS: Women with benign and malignant breast tumor had increased rates of psychiatric disorders and cardiovascular diseases during the waiting for a final diagnosis.
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