| 1. |
|
|
| 2. |
|
|
| 3. |
- Dahlgren, Malin
(författare)
-
Breast Cancer Biomarkers with Clinical Relevance Identified by Massively-parallel DNA and RNA Sequencing
- 2021
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Women have a 10% lifetime risk of developing breast cancer, and the disease has surpassed lung cancer as the most frequently diagnosed type of cancer in the world. Breast cancer originates in the epithelial cells of the mammary gland and tumor cells have undergone a series of genetic and phenotypic changes that confer tumor promoting properties.Genomic rearrangement is a common phenomenon in cancer, involving breakage and dysfunctional repair of chromosomes. With the aim to characterize such variants and their progression from primary to metastatic disease, we performed whole-genome sequencing of paired primary tumors and metastases (study I) and paired contralateral breast cancers (CBC) (study II). Metastasis rearrangement profiles bore a remarkable resemblance to the respective primary tumors (median 89% shared), indicating that the rearrangements were early events in tumor development, remaining stable throughout progression. Our study on CBC (study II) subsequently allowed us to identify 1 in 10 tumor pairs that likely represented metastatic spread rather than a new primary tumor (76% of rearrangements shared). One of the risk factors for breast cancer is high exposure to estrogens; signaling via estrogen receptor (ER) α is considered the most important driver for the 75% of tumors expressing this marker. Mutations in the gene for ERα are known to be common in endocrine therapy-refractory breast cancer and confer resistance to standard anti-hormonal treatment. In study III, we interrogated RNA-seq data from 3217 primary breast tumors from the SCAN-B initiative and found that 1% of tumors were positive for one of the mutations at surgery. For those patients that received adjuvant endocrine therapy, the mutations were associated to worse overall and relapse-free survival. In study IV, we further explored the SCAN-B dataset to investigate the phenotypic properties and prognosis associated to high expression of the much less well studied ERβ. We discovered that this receptor was not abundantly expressed, with 1/3 of tumors entirely negative. Further, we saw that patients with high levels of ERβ mRNA had slightly improved overall survival and that the expression of ERβ was associated to expression of genes involved in immune cell activation.In summary, we have employed sequencing technology to study breast cancer patient material to identify and assess the validity of genomic and transcriptomic changes that may both be of value as potential biomarkers, and in elucidating biological mechanisms that drive or suppress breast cancer progression.
|
|
| 4. |
- Dahlgren, Malin, et al.
(författare)
-
CITED1 as a marker of favourable outcome in anti-endocrine treated, estrogen-receptor positive, lymph-node negative breast cancer.
- 2023
-
Ingår i: BMC Research Notes. - 1756-0500. ; 16:1
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate CITED1 as a potential biomarker of anti-endocrine response and breast cancer recurrence, given its previously determined role in mediating estrogen-dependant transcription. The study is a continuation of earlier work establishing the role of CITED1 in mammary gland development.Results: CITED1 mRNA is associated with estrogen-receptor positivity and selectively expressed in the GOBO dataset of cell lines and tumours representing the luminal-molecular subtype. In patients treated with tamoxifen, higher CITED1 correlated with better outcome, suggesting a role in anti-estrogen response. The effect was particularly evident in the subset of estrogen-receptor positive, lymph-node negative (ER+/LN-) patients although noticeable divergence of the groups was apparent only after five years. Tissue microarray (TMA) analysis further validated the association of CITED1 protein, by immunohistochemistry, with favourable outcome in ER+, tamoxifen-treated patients. Although we also found a favourable response to anti-endocrine treatment in a larger TCGA dataset, the tamoxifen-specific effect was not replicated. Finally, MCF7 cells overexpressing CITED1 showed selective amplification of AREG but not TGFα suggesting that maintenance of specific ERα-CITED1 mediated transcription is important for the long-term response to anti-endocrine therapy. These findings together confirm the proposed mechanism of action of CITED1 and support its potential use as a prognostic biomarker.
|
|
| 5. |
- Dahlgren, Malin, et al.
(författare)
-
Preexisting Somatic Mutations of Estrogen Receptor Alpha (ESR1) in Early-Stage Primary Breast Cancer
- 2021
-
Ingår i: JNCI Cancer Spectrum. - : Oxford University Press (OUP). - 2515-5091. ; 5:2
-
Tidskriftsartikel (refereegranskat)abstract
- More than three-quarters of primary breast cancers are positive for estrogen receptor alpha (ER; encoded by the gene ESR1), the most important factor for directing anti-estrogenic endocrine therapy (ET). Recently, mutations in ESR1 were identified as acquired mechanisms of resistance to ET, found in 12% to 55% of metastatic breast cancers treated previously with ET. We analyzed 3217 population-based invasive primary (nonmetastatic) breast cancers (within the SCAN-B study, ClinicalTrials.gov NCT02306096), sampled from initial diagnosis prior to any treatment, for the presence of ESR1 mutations using RNA sequencing. Mutations were verified by droplet digital polymerase chain reaction on tumor and normal DNA. Patient outcomes were analyzed using Kaplan-Meier estimation and a series of 2-factor Cox regression multivariable analyses. We identified ESR1 resistance mutations in 30 tumors (0.9%), of which 29 were ER positive (1.1%). In ET-treated disease, presence of ESR1 mutation was associated with poor relapse-free survival and overall survival (2-sided log-rank test P < .001 and P = .008, respectively), with hazard ratios of 3.00 (95% confidence interval = 1.56 to 5.88) and 2.51 (95% confidence interval = 1.24 to 5.07), respectively, which remained statistically significant when adjusted for other prognostic factors. These population-based results indicate that ESR1 mutations at diagnosis of primary breast cancer occur in about 1% of women and identify for the first time in the adjuvant setting that such preexisting mutations are associated to eventual resistance to standard hormone therapy. If replicated, tumor ESR1 screening should be considered in ER-positive primary breast cancer, and for patients with mutated disease, ER degraders such as fulvestrant or other therapeutic options may be considered as more appropriate.
|
|
| 6. |
- Dalal, Hina, et al.
(författare)
-
Clinical associations of ESR2 (estrogen receptor beta) expression across thousands of primary breast tumors
- 2022
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12, s. 1-12
-
Tidskriftsartikel (refereegranskat)abstract
- Estrogen receptor alpha (ERα, encoded by ESR1) is a well-characterized transcription factor expressed in more than 75% of breast tumors and is the key biomarker to direct endocrine therapies. On the other hand, much less is known about estrogen receptor beta (ERβ, encoded by ESR2) and its importance in cancer. Previous studies had some disagreement, however most reports suggested a more favorable prognosis for patients with high ESR2 expression. To add further clarity to ESR2 in breast cancer, we interrogated a large population-based cohort of primary breast tumors (n = 3207) from the SCAN-B study. RNA-seq shows ESR2 is expressed at low levels overall with a slight inverse correlation to ESR1 expression (Spearman R = -0.18, p = 2.2e-16), and highest ESR2 expression in the basal- and normal-like PAM50 subtypes. ESR2-high tumors had favorable overall survival (p = 0.006), particularly in subgroups receiving endocrine therapy (p = 0.03) and in triple-negative breast cancer (p = 0.01). These results were generally robust in multivariable analyses accounting for patient age, tumor size, node status, and grade. Gene modules consistent with immune response were associated to ESR2-high tumors. Taken together, our results indicate that ESR2 is generally expressed at low levels in breast cancer but associated with improved overall survival and may be related to immune response modulation.
|
|
| 7. |
|
|
| 8. |
- Nilsson, Malin, 1973-
(författare)
-
Att förklara människan : Diskurser i populärvetenskapliga TV-program
- 2009
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The principle aim of the study is to describe, analyze and problemize the ways in which television science documentaries (within a public service context) discursively represent scientific theories, research results and conclusions about the origins of human nature and the causes of human behavior. The study covers 25 programs broadcasted by SVT and UR during a period of four years,2002-2005 , and 12 additional programs are used as a basis for discussion. Most of the programs included in the study are productions purchased mainly from BBC Science. Thus, managing editors, producers and presenters were interviewed for the purpose of illuminating quality judgements and purchasing criteria. A five stage-model of critical discourse analysis has inspired the method which emphasizes the network of communicative practices in which the media text and representation are embedded. That includes media genre, production and narrative conventions as well as the wider historical, social and political/ideological context and discourse practices of which the issues represented are a part. The critical discourse analysis has been complemented by ideas about different documentary modes of representation or basic ways of organizing documentary texts in relation to certain recurrent features or conventions. In the analysis these modes have been applied to understand the degree of transparency and editorial presence and visibility in the science documentaries. The importance of the discourses presented is related to their more applied meanings. When certain descriptions, explanations and understandings of alleged human “basics” gain priority, it may affect the possibilities to define and handle very concrete social issues in a way that is inconsistent with this fundamental perspective. Thus, the ideological function of the science documentaries (as public service-program and educational media) deserves serious attention.
|
|
| 9. |
- Olbers, Torsten, 1964, et al.
(författare)
-
Two-year outcome of laparoscopic Roux-en-Y gastric bypass in adolescents with severe obesity: results from a Swedish Nationwide Study (AMOS)
- 2012
-
Ingår i: International Journal of Obesity. - : Springer Science and Business Media LLC. - 1476-5497 .- 0307-0565. ; 36:11, s. 1388-1395
-
Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: The prevalence of obesity among adolescents has increased and we lack effective treatments. OBJECTIVE: To determine if gastric bypass is safe and effective for an unselected cohort of adolescents with morbid obesity in specialized health care. DESIGN, SETTING AND PATIENTS: Intervention study for 81 adolescents (13-18 years) with a body mass index (BMI) range 36-69 kg m(-2) undergoing laparoscopic gastric bypass surgery in a university hospital setting in Sweden between April 2006 and May 2009. For weight change comparisons, we identified an adult group undergoing gastric bypass surgery (n = 81) and an adolescent group (n = 81) receiving conventional care. MAIN OUTCOME MEASUREMENTS: Two-year outcome regarding BMI in all groups, and metabolic risk factors and quality of life in the adolescent surgery group. RESULTS: Two-year follow-up rate was 100% in both surgery groups and 73% in the adolescent comparison group. In adolescents undergoing surgery, BMI was 45.5 +/- 6.1 (mean +/- s.d.) at baseline and 30.2 (confidence interval 29.1-31.3) after 2 years (P<0.001) corresponding to a 32% weight loss and a 76% loss of excess BMI. The 2-year weight loss was 31% in adult surgery patients, whereas 3% weight gain was seen in conventionally treated adolescents. At baseline, hyperinsulinemia (>20 m Ul(-1)) was present in 70% of the adolescent surgery patients, which was reduced to 0% at 1 year and 3% at 2 years. Other cardiovascular risk factors were also improved. Two-thirds of adolescents undergoing surgery had a history of psychopathology. Nevertheless, the treatment was generally well tolerated and, overall, quality of life increased significantly. Adverse events were seen in 33% of patients. CONCLUSIONS: Adolescents with severe obesity demonstrated similar weight loss as adults following gastric bypass surgery yet demonstrating high prevalence of psychopathology at baseline. There were associated benefits for health and quality of life. Surgical and psychological challenges during follow-up require careful attention. International Journal of Obesity (2012) 36, 1388-1395; doi:10.1038/ijo.2012.160; published online 25 September 2012
|
|
| 10. |
- Olsson, Eleonor, et al.
(författare)
-
Serial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease.
- 2015
-
Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4684 .- 1757-4676. ; 7:8, s. 1034-1047
-
Tidskriftsartikel (refereegranskat)abstract
- Metastatic breast cancer is usually diagnosed after becoming symptomatic, at which point it is rarely curable. Cell-free circulating tumor DNA (ctDNA) contains tumor-specific chromosomal rearrangements that may be interrogated in blood plasma. We evaluated serial monitoring of ctDNA for earlier detection of metastasis in a retrospective study of 20 patients diagnosed with primary breast cancer and long follow-up. Using an approach combining low-coverage whole-genome sequencing of primary tumors and quantification of tumor-specific rearrangements in plasma by droplet digital PCR, we identify for the first time that ctDNA monitoring is highly accurate for postsurgical discrimination between patients with (93%) and without (100%) eventual clinically detected recurrence. ctDNA-based detection preceded clinical detection of metastasis in 86% of patients with an average lead time of 11 months (range 0-37 months), whereas patients with long-term disease-free survival had undetectable ctDNA postoperatively. ctDNA quantity was predictive of poor survival. These findings establish the rationale for larger validation studies in early breast cancer to evaluate ctDNA as a monitoring tool for early metastasis detection, therapy modification, and to aid in avoidance of overtreatment.
|
|
