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Sökning: WFRF:(Chen Yilun)

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  • Brueffer, Christian, et al. (författare)
  • Abstract P4-09-03: On the development and clinical value of RNA-sequencing-based classifiers for prediction of the five conventional breast cancer biomarkers: A report from the population-based multicenter SCAN-B study
  • 2018
  • Ingår i: San Antonio Breast Cancer Symposium, 2017,San Antonio, United States,2017-12-05 - 2017-12-09. - American Association for Cancer Research Inc..
  • Konferensbidrag (refereegranskat)abstract
    • Background:In early breast cancer, five histopathological biomarkers are part of current clinical routines and used for determining prognosis and treatment: estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (ERBB2/HER2), Ki67, and Nottingham histological grade (NHG). We aimed to develop classifiers for these biomarkers based on tumor mRNA-sequencing (RNA-seq), compare classification performance to conventional histopathology, and test whether RNA-seq-based predictors could add value for patient risk-stratification.Patients and Methods:In total, 3678 breast tumors were studied. For 405 breast tumors in the training cohort, a comprehensive histopathological biomarker evaluation was performed by three pathology readings to estimate inter-pathologist variability on the original diagnostic slides as well as on repeat immunostains for this study, and the consensus biomarker status for all five conventional biomarkers was determined. Whole transcriptome gene expression profiling was performed by RNA-sequencing on the Illumina platform. Using RNA-seq-derived tumor gene expression data as input, single-gene classifiers (SGC) and multi-gene classifiers (MGC) were trained on the consensus pathology biomarker labels. The trained classifiers were tested on an independent prospective population-based series of 3273 primary breast cancer cases from the multicenter SCAN-B study with median 41 months follow-up (ClinicalTrials.gov identifier NCT02306096), and classifications were evaluated by agreement statistics and by Kaplan-Meier and Cox regression survival analyses.Results:For the histopathological evaluation, pathologist evaluation concordance was high for ER, PgR, and HER2 (average kappa values of .920, .891, and .899, respectively), but moderate for Ki67 and NHG (.734 and .581). Classification concordance between RNA-seq classifiers and histopathology for the independent 3273-cohort was similar to that within histopathology assessments, with SGCs slightly outperforming MGCs. Importantly, patients with discordant results, classified as hormone responsive (HoR+) by histopathology but non-hormone responsive by MGC, presented with significantly inferior overall survival compared to patients with concordant results. These results extended to patients with no adjuvant systemic therapy (hazard ratio, HR, 4.54; 95% confidence interval, CI, 1.42-14.5), endocrine therapy alone (HR 3.46; 95% CI, 2.01-5.95), or receiving chemotherapy (HR 2.57; 95% CI 1.13-5.86). For HoR+ cases receiving endocrine therapy alone, the MGC HoR classifier remained significant after multivariable adjustment (HR 3.14; 95% CI, 1.75-5.65).Conclusions:RNA-seq-based classifiers for the five key early breast cancer biomarkers were generally equivalent to conventional histopathology with regards to classification error rate. However, when benchmarked using overall survival, our RNA-seq classifiers provided added clinical value in particular for cases that are determined by histopathology to be hormone-responsive but by RNA-seq appear hormone-insensitive and have a significantly poorer outcome when treated with endocrine therapy alone
3.
  • Brueffer, Christian, et al. (författare)
  • Clinical Value of RNA Sequencing–Based Classifiers for Prediction of the Five Conventional Breast Cancer Biomarkers: A Report From the Population-Based Multicenter Sweden Cancerome Analysis Network—Breast Initiative
  • 2018
  • Ingår i: JCO Precision Oncology. - American Society of Clinical Oncology. - 2473-4284. ; 2, s. 1-18
  • Tidskriftsartikel (refereegranskat)abstract
    • PurposeIn early breast cancer (BC), five conventional biomarkers—estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), Ki67, and Nottingham histologic grade (NHG)—are used to determine prognosis and treatment. We aimed to develop classifiers for these biomarkers that were based on tumor mRNA sequencing (RNA-seq), compare classification performance, and test whether such predictors could add value for risk stratification.MethodsIn total, 3,678 patients with BC were studied. For 405 tumors, a comprehensive multi-rater histopathologic evaluation was performed. Using RNA-seq data, single-gene classifiers and multigene classifiers (MGCs) were trained on consensus histopathology labels. Trained classifiers were tested on a prospective population-based series of 3,273 BCs that included a median follow-up of 52 months (Sweden Cancerome Analysis Network—Breast [SCAN-B], ClinicalTrials.gov identifier: NCT02306096), and results were evaluated by agreement statistics and Kaplan-Meier and Cox survival analyses.ResultsPathologist concordance was high for ER, PgR, and HER2 (average κ, 0.920, 0.891, and 0.899, respectively) but moderate for Ki67 and NHG (average κ, 0.734 and 0.581). Concordance between RNA-seq classifiers and histopathology for the independent cohort of 3,273 was similar to interpathologist concordance. Patients with discordant classifications, predicted as hormone responsive by histopathology but non–hormone responsive by MGC, had significantly inferior overall survival compared with patients who had concordant results. This extended to patients who received no adjuvant therapy (hazard ratio [HR], 3.19; 95% CI, 1.19 to 8.57), or endocrine therapy alone (HR, 2.64; 95% CI, 1.55 to 4.51). For cases identified as hormone responsive by histopathology and who received endocrine therapy alone, the MGC hormone-responsive classifier remained significant after multivariable adjustment (HR, 2.45; 95% CI, 1.39 to 4.34).ConclusionClassification error rates for RNA-seq–based classifiers for the five key BC biomarkers generally were equivalent to conventional histopathology. However, RNA-seq classifiers provided added clinical value in particular for tumors determined by histopathology to be hormone responsive but by RNA-seq to be hormone insensitive.
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  • Chen, Yilun, et al. (författare)
  • Identification and use of personalized genomic markers for monitoring circulating tumor DNA
  • 2018
  • Ingår i: Methods in Molecular Biology. - Humana Press. - 1064-3745. ; 1768, s. 303-322
  • Bokkapitel (refereegranskat)abstract
    • Digital PCR techniques are ideally suited for accurately quantifying trace amounts of target DNA sequences, such as tumor-derived mutant DNA that is present in the blood circulation of patients with cancer. Here, we describe an approach marrying low-coverage whole-genome sequencing of tumor tissues, to enumerate chromosomal rearrangement breakpoints, together with droplet digital PCR (ddPCR)-based personalized rearrangement assays to cost-effectively monitor circulating tumor DNA levels at multiple time-points during the clinical course. The method is generally applicable to essentially any cancer patient, as all cancers harbor unstable genomes, and may have uses for measuring minimal residual disease, response to therapy, and early detection of metastasis.
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  • Chen, Yilun, et al. (författare)
  • PTEN and NEDD4 in Human Breast Carcinoma.
  • 2016
  • Ingår i: Pathology and Oncology Research. - Springer. - 1532-2807. ; 22:1, s. 41-47
  • Tidskriftsartikel (refereegranskat)abstract
    • PTEN is an important tumor suppressor gene that antagonizes the oncogenic PI3K/AKT signaling pathway and has functions in the nucleus for maintaining genome integrity. Although PTEN inactivation by mutation is infrequent in breast cancer, transcript and protein levels are deficient in >25 % of cases. The E3 ubiquitin ligase NEDD4 (also known as NEDD4-1) has been reported to negatively regulate PTEN protein levels through poly-ubiquitination and proteolysis in carcinomas of the prostate, lung, and bladder, but its effect on PTEN in the breast has not been studied extensively. To investigate whether NEDD4 contributes to low PTEN levels in human breast cancer, we analyzed the expression of these proteins by immunohistochemistry across a large Swedish cohort of breast tumor specimens, and their transcript expression levels by microarrays. For both NEDD4 and PTEN, their transcript expression was significantly correlated to their protein expression. However, comparing NEDD4 expression to PTEN expression, either no association or a positive correlation was observed at the protein and transcript levels. This unexpected observation was further corroborated in two independent breast cancer cohorts from The Netherlands Cancer Institute and The Cancer Genome Atlas. Our results suggest that NEDD4 is not responsible for the frequent down-regulation of the PTEN protein in human breast carcinoma.
8.
  • 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. - 1573-7217. ; 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.
9.
  • 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: San Antonio Breast Cancer Symposium, 2017,San Antonio, United States,2017-12-05 - 2017-12-09. - American Association for Cancer Research Inc..
  • 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.
10.
  • Olsson, Eleonor, et al. (författare)
  • Mutation Screening of 1,237 Cancer Genes across Six Model Cell Lines of Basal-Like Breast Cancer.
  • 2015
  • Ingår i: PLoS ONE. - Public Library of Science. - 1932-6203. ; 10:12
  • Tidskriftsartikel (refereegranskat)abstract
    • Basal-like breast cancer is an aggressive subtype generally characterized as poor prognosis and lacking the expression of the three most important clinical biomarkers, estrogen receptor, progesterone receptor, and HER2. Cell lines serve as useful model systems to study cancer biology in vitro and in vivo. We performed mutational profiling of six basal-like breast cancer cell lines (HCC38, HCC1143, HCC1187, HCC1395, HCC1954, and HCC1937) and their matched normal lymphocyte DNA using targeted capture and next-generation sequencing of 1,237 cancer-associated genes, including all exons, UTRs and upstream flanking regions. In total, 658 somatic variants were identified, of which 378 were non-silent (average 63 per cell line, range 37-146) and 315 were novel (not present in the Catalogue of Somatic Mutations in Cancer database; COSMIC). 125 novel mutations were confirmed by Sanger sequencing (59 exonic, 48 3'UTR and 10 5'UTR, 1 splicing), with a validation rate of 94% of high confidence variants. Of 36 mutations previously reported for these cell lines but not detected in our exome data, 36% could not be detected by Sanger sequencing. The base replacements C/G>A/T, C/G>G/C, C/G>T/A and A/T>G/C were significantly more frequent in the coding regions compared to the non-coding regions (OR 3.2, 95% CI 2.0-5.3, P<0.0001; OR 4.3, 95% CI 2.9-6.6, P<0.0001; OR 2.4, 95% CI 1.8-3.1, P<0.0001; OR 1.8, 95% CI 1.2-2.7, P = 0.024, respectively). The single nucleotide variants within the context of T[C]T/A[G]A and T[C]A/T[G]A were more frequent in the coding than in the non-coding regions (OR 3.7, 95% CI 2.2-6.1, P<0.0001; OR 3.8, 95% CI 2.0-7.2, P = 0.001, respectively). Copy number estimations were derived from the targeted regions and correlated well to Affymetrix SNP array copy number data (Pearson correlation 0.82 to 0.96 for all compared cell lines; P<0.0001). These mutation calls across 1,237 cancer-associated genes and identification of novel variants will aid in the design and interpretation of biological experiments using these six basal-like breast cancer cell lines.
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