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Sökning: WFRF:(Brueffer Christian)

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11.
  • Chapman, Lesley M, et al. (författare)
  • SVCurator: A Crowdsourcing app to visualize evidence of structural variants for the human genome
  • 2019
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • A high quality benchmark for small variants encompassing 88 to 90% of the reference genome has been developed for seven Genome in a Bottle (GIAB) reference samples. However a reliable benchmark for large indels and structural variants (SVs) is yet to be defined. In this study, we manually curated 1235 SVs which can ultimately be used to evaluate SV callers ortrain machine learning models. We developed a crowdsourcing app - SVCurator - to help curators manually review large indels and SVs within the human genome, and report their genotype and size accuracy.SVCurator is a Python Flask-based web platform that displays images from short, long, and linked read sequencing data from the GIAB Ashkenazi Jewish Trio son [NIST RM 8391/HG002]. We asked curators to assign labels describing SV type (deletion or insertion), size accuracy, and genotype for 1235 putative insertions and deletions sampled from different size bins between 20 and 892,149 bp. The crowdsourced results were highly concordant with 37 out ofthe 61 curators having at least 78% concordance with a set of ‘expert’ curators, where there was 93% concordance amongst ‘expert’ curators. This produced high confidence labels for 935 events. When compared to the heuristic-based draft benchmark SV callset from GIAB, the SVCurator crowdsourced labels were 94.5% concordant with the benchmark set. We found that curators can successfully evaluate putative SVs when given evidence from multiple sequencing technologies.
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13.
  • 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.
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14.
  • 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.
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16.
  • Dobilas, Arturas, et al. (författare)
  • Preoperative circulating tumor DNA level is associated to poor overall survival in patients with ovarian cancer
  • 2022
  • Ingår i: International Journal of Gynecological Cancer. - 1048-891X. ; 32:Suppl 2, s. 405-405
  • Konferensbidrag (refereegranskat)abstract
    • Introduction/BackgroundCirculating tumor DNA (ctDNA), which is shed from tumor cells into the blood, is a promising minimal-invasive method for cancer diagnostics and monitoring. The aim of this study was to evaluate preoperative ctDNA levels in the plasma of patients with ovarian cancer and correlate the levels to clinico-pathological parameters and patient outcome.MethodologyTumor DNA was extracted from ovarian tumor tissue from 41 patients. Targeted sequencing using a panel of 127 genes recurrently mutated in cancer was performed to identify candidate somatic mutations in the tumor DNA. SAGAsafe digital PCR (dPCR) assays targeting the candidate mutations were used to measure ctDNA levels in patient plasma samples, obtained prior to surgery, to evaluate ctDNA levels in terms of mutant copy number/mL and variant allele frequency.ResultsSomatic mutations were found in 24 tumors, of which seven were from patients with borderline, and 17 with invasive cancer diagnosis. TP53 was the most frequently mutated gene. Fifteen of 24 patients had detectable ctDNA levels in pre-operative plasma. Plasma ctDNA mutant concentration increased with higher stage (p_trend
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17.
  • Dobilas, Arturas, et al. (författare)
  • Preoperative ctDNA Levels Are Associated With Poor Overall Survival in Patients With Ovarian Cancer
  • 2023
  • Ingår i: Cancer Genomics & Proteomics. - 1790-6245. ; 20:6 suppl, s. 763-770
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND/AIM: Circulating tumor DNA (ctDNA), which is shed from cancer cells into the bloodstream, offers a potential minimally invasive approach for cancer diagnosis and monitoring. This research aimed to assess the preoperative ctDNA levels in ovarian tumors patients' plasma and establish correlations with clinicopathological parameters and patient prognosis.PATIENTS AND METHODS: Tumor DNA was extracted from ovarian tumor tissue from 41 patients. Targeted sequencing using a panel of 127 genes recurrently mutated in cancer was performed to identify candidate somatic mutations in the tumor DNA. SAGAsafe digital PCR (dPCR) assays targeting the candidate mutations were used to measure ctDNA levels in patient plasma samples, obtained prior to surgery, to evaluate ctDNA levels in terms of mutant copy number/ml and variant allele frequency.RESULTS: Somatic mutations were found in 24 tumor samples, 17 of which were from ovarian cancer patients. The most frequently mutated gene was TP53. Preoperative plasma ctDNA levels were detected in 14 of the 24 patients. With higher stage, plasma ctDNA mutant concentration increased (p for trend <0.001). The overall survival of cancer patients with more than 10 ctDNA mutant copies/ml in plasma was significantly worse (p=0.008).CONCLUSION: Pre-operative ctDNA measurement in ovarian cancer patients' plasma holds promise as a predictive biomarker for tumor staging and prognosis.
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18.
  • Förnvik, Daniel, et al. (författare)
  • Detection of circulating tumor cells and circulating tumor DNA before and after mammographic breast compression in a cohort of breast cancer patients scheduled for neoadjuvant treatment
  • 2019
  • Ingår i: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 1573-7217 .- 0167-6806. ; 177:2, s. 447-455
  • Tidskriftsartikel (refereegranskat)abstract
    • PurposeIt is not known if mammographic breast compression of a primary tumor causes shedding of tumor cells into the circulatory system. Little is known about how the detection of circulating biomarkers such as circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) is affected by breast compression intervention.MethodsCTCs and ctDNA were analyzed in blood samples collected before and after breast compression in 31 patients with primary breast cancer scheduled for neoadjuvant therapy. All patients had a central venous access to allow administration of intravenous neoadjuvant chemotherapy, which enabled blood collection from superior vena cava, draining the breasts, in addition to sampling from a peripheral vein.ResultsCTC and ctDNA positivity was seen in 26% and 65% of the patients, respectively. There was a significant increase of ctDNA after breast compression in central blood (p = 0.01), not observed in peripheral testing. No increase related with breast compression was observed for CTC. ctDNA positivity was associated with older age (p = 0.05), and ctDNA increase after breast compression was associated with high Ki67 proliferating tumors (p = 0.04). CTCs were more abundant in central compared to peripheral blood samples (p = 0.04).ConclusionsThere was no significant release of CTCs after mammographic breast compression but more CTCs were present in central compared to peripheral blood. No significant difference between central and peripheral levels of ctDNA was observed. The small average increase in ctDNA after breast compression is unlikely to be clinically relevant. The results give support for mammography as a safe procedure from the point of view of CTC and ctDNA shedding to the blood circulation. The results may have implications for the standardization of sampling procedures for circulating tumor markers.
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19.
  • Grüning, Björn, et al. (författare)
  • Bioconda: A sustainable and comprehensive software distribution for the life sciences
  • 2017
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • We present Bioconda (https://bioconda.github.io), a distribution of bioinformatics software for the lightweight, multi-platform and language-agnostic package manager Conda. Currently, Bioconda offers a collection of over 3000 software packages, which is continuously maintained, updated, and extended by a growing global community of more than 200 contributors. Bioconda improves analysis reproducibility by allowing users to define isolated environments with defined software versions, all of which are easily installed and managed without administrative privileges.
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20.
  • Loman, Niklas, et al. (författare)
  • Abstract P2-02-09: Breast cancer subtype distribution and circulating tumor DNA in response to neoadjuvant chemotherapy: Experiences from a preoperative cohort within SCAN-B
  • 2018
  • Ingår i: Cancer research. Supplement. - 1538-7445. ; 78:4
  • Konferensbidrag (refereegranskat)abstract
    • Introduction: Preoperative chemotherapy in early breast cancer increases the rate of breast preservation and provides prognostic information. In the case of residual disease, a change in subtypes may be observed. Sensitive and reproducible biomarkers predicting treatment response early during the treatment course are needed in order to better exploit the potential benefit of an individualized preoperative treatment.Material and Methods: In an ongoing prospective study within the population-based SCAN-B project (NCT02306096), patients undergoing preoperative chemotherapy for early or locally recurrent breast cancer have been treated with iv Epirubicin and Cyclophosphamide q3w x 3 in sequence with either Docetaxel q3w x 3 or Paclitaxel q1w x 9 with a preoperative intent. HER2-positive cases also received HER2-directed treatment. At baseline, patients were staged using sentinel node biopsy for clinically node-negative patients and CT scan for cytologically confirmed node-positive cases. A clinical core needle biopsy as well as tissue from the surgical specimen was collected for determination of conventional biomarkers including ER, PgR, HER2 and Ki67. Tumor biopsies for biomolecule-extraction and RNA-sequencing were taken using ultrasound guidance and collected fresh in RNAlater at baseline, after 2 treatment cycles, as well as at surgery. Blood plasma samples were collected at baseline, after one-, three-, and six- 3w treatment cycles, and post-surgery. Using RNA-sequencing data, somatic mutations were identified in the tumor biopsies and personalized analyses for circulating tumor DNA (ctDNA) were performed. A pathological complete remission (pCR) was defined as the complete disappearance of invasive breast cancer in the breast and axilla at time of definitive surgery. Subtyping was performed using modified St Gallen criteria (2013).Results: Thus far, 45 patients aged 24-74 years have been included, of which 34 (76 %) were clinical stage 2 and 11 (24%) were stage 3. The subtype distribution at baseline was five Luminal A-like (11 %), 21 Luminal B-like (HER2 negative) (47 %), 8 HER2-positive (18 %) and 11 Triple-negative (ductal) (24 %). The rates of pCR in 38 operated cases to date were 0/3 Luminal A-like, 3/19 Luminal B-like (HER2 negative), 2/8 HER2-positive, and 4/7 Triple-negative (overall 24 % pCR rate). One patient did not undergo surgery due to clinically progressive disease. In 25 cases with evaluable residual disease at surgery, there was a shift in the subtype in 13 (52 %), the majority of which represented a transition from Luminal B to Luminal A. No Triple-negative cases underwent a change in subtype during treatment. Results of the ctDNA analyses will be presented at the meeting.Discussion: We have established an infrastructure allowing for an extensive evaluation of preoperative chemotherapy in early breast cancer. The goal is to develop methods to refine response-guided treatment in early breast cancer using molecular responses in the tumor as well as in the blood circulation. The patients continue to be prospectively monitored with iterative ctDNA analyses during follow-up.
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  • Resultat 11-20 av 34

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