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| 4. |
- Kroeze, Leonie I., et al.
(author)
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Evaluation of a Hybrid Capture-Based Pan-Cancer Panel for Analysis of Treatment Stratifying Oncogenic Aberrations and Processes
- 2020
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In: Journal of Molecular Diagnostics. - : Elsevier. - 1525-1578 .- 1943-7811. ; 22:6, s. 757-769
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Journal article (peer-reviewed)abstract
- Stratification of patients for targeted and immune-based therapies requires extensive genomic profiling that enables sensitive detection of clinically relevant variants and interrogation of biomarkers, such as tumor mutational burden (TMB) and microsatellite instability (MSI). Detection of single and multiple nucleotide variants, copy number variants, MSI, and TMB was evaluated using a commercially available next-generation sequencing panel containing 523 cancer-related genes (1.94 megabases). Analysis of formalin-fixed, paraffin-embedded tissue sections and cytologic material from 45 tumor samples showed that all previously known MSI-positive samples (n = 7), amplifications (n = 9), and pathogenic variants (n = 59) could be detected. TMB and MSI scores showed high intralaboratory and interlaboratory reproducibility (eight samples tested in 11 laboratories). For reliable TMB analysis, 20 ng DNA was shown to be sufficient, even for relatively poor-quality samples. A minimum of 20% neoplastic cells was required to minimize variations in TMB values induced by chromosomal instability or tumor heterogeneity. Subsequent analysis of 58 consecutive lung cancer samples in a diagnostic setting was successful and revealed sufficient somatic mutations to generate mutational signatures in 14 cases. In conclusion, the 523-gene assay can be applied for evaluation of multiple DNA-based biomarkers relevant for treatment selection.
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| 5. |
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| 6. |
- Tacon, Lyndal J., et al.
(author)
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The glucocorticoid receptor is overexpressed in malignant adrenocortical tumors
- 2009
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In: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 94:11, s. 4591-4599
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Journal article (peer-reviewed)abstract
- CONTEXT: Adrenocortical carcinoma (ACC) is a rare tumor with a poor prognosis. The Weiss score is the most widely accepted method for distinguishing an ACC from an adrenocortical adenoma (ACA); however, in borderline cases, accurate diagnosis remains problematic. We recently discovered that the glucocorticoid receptor (GR) gene NR3C1 is significantly up-regulated in ACCs compared with ACAs in global gene expression studies. OBJECTIVE: Our objective was to study GR expression in adrenocortical tumors (ACTs) and to assess its utility as an adjunct to the Weiss score. DESIGN: Microarray analysis, real-time quantitative RT-PCR (qPCR), immunohistochemistry, Western blot, and direct sequencing were performed. RESULTS: Analysis of 28 ACTs by microarray and 49 ACTs by qPCR found NR3C1 expression to be up-regulated in ACCs compared with ACAs (P < 0.001). Western blotting and RT-PCR confirmed the presence of the GRalpha isoform in ACCs, and no mutations were detected on direct sequencing. Immunohistochemistry for GR in an overlapping cohort of ACTs demonstrated strongly positive nuclear staining in 31 of 33 ACCs (94%), with negative staining in 40 of 41 ACAs (98%) (P < 0.001). This finding was validated in an external cohort of ACTs, such that 14 of 18 ACCs (78%) demonstrated positive nuclear staining whereas 32 of 33 ACAs (94%) were negative (P < 0.001). CONCLUSIONS: The immunohistochemical finding of nuclear GR staining identified ACCs with high diagnostic accuracy. We propose that GR immunohistochemistry may complement the Weiss score in the diagnosis of ACC in cases that display borderline histology. The possibility that GR is transcriptionally active in these tumors, and may therefore be a therapeutic target, requires further study.
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| 8. |
- de Jager, Vincent D., et al.
(author)
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Developments in predictive biomarker testing and targeted therapy in advanced stage non-small cell lung cancer and their application across European countries
- 2024
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In: The Lancet Regional Health. - : Elsevier. - 2666-7762. ; 38
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Research review (peer-reviewed)abstract
- In the past two decades, the treatment of metastatic non-small cell lung cancer (NSCLC), has undergone significant changes due to the introduction of targeted therapies and immunotherapy. These advancements have led to the need for predictive molecular tests to identify patients eligible for targeted therapy. This review provides an overview of the development and current application of targeted therapies and predictive biomarker testing in European patients with advanced stage NSCLC. Using data from eleven European countries, we conclude that recommendations for predictive testing are incorporated in national guidelines across Europe, although there are differences in their comprehensiveness. Moreover, the availability of recently EMA-approved targeted therapies varies between European countries. Unfortunately, routine assessment of national/regional molecular testing rates is limited. As a result, it remains uncertain which proportion of patients with metastatic NSCLC in Europe receive adequate predictive biomarker testing. Lastly, Molecular Tumor Boards (MTBs) for discussion of molecular test results are widely implemented, but national guidelines for their composition and functioning are lacking. The establishment of MTB guidelines can provide a framework for interpreting rare or complex mutations, facilitating appropriate treatment decision-making, and ensuring quality control.
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| 9. |
- Elfving, Hedvig, et al.
(author)
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Evaluation of NTRK immunohistochemistry as a screening method for NTRK gene fusion detection in non-small cell lung cancer
- 2021
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In: Lung Cancer. - : Elsevier. - 0169-5002 .- 1872-8332. ; 151, s. 53-59
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Journal article (peer-reviewed)abstract
- Purpose: The small molecule inhibitors larotrectinib and entrectinib have recently been approved as cancer agnostic drugs in patients with tumours harbouring a rearrangement of the neurotrophic tropomyosin receptor kinase (NTRK). These oncogenic fusions are estimated to occur in 0.1-3 % of non-small cell lung cancers (NSCLC). Although molecular techniques are most reliable for fusion detection, immunohistochemical analysis is considered valuable for screening. Therefore, we evaluated the newly introduced diagnostic immunohistochemical assay (clone EPR17341) on a representative NSCLC cohort.Methods: Cancer tissue from 688 clinically and molecularly extensively annotated NSCLC patients were comprised on tissue microarrays and stained with the pan-TRK antibody clone EPR17341. Positive cases were further analysed with the TruSight Tumor 170 RNA assay (Illumina). Selected cases were also tested with a NanoString NTRK fusion assay. For 199 cases, NTRK RNA expression data were available from previous RNA sequencing analysis.Results: Altogether, staining patterns for 617 NSCLC cases were evaluable. Of these, four cases (0.6 %) demonstrated a strong diffuse cytoplasmic and membranous staining, and seven cases a moderate staining (1.1 %). NanoString or TST170-analysis could not confirm an NTRK fusion in any of the IHC positive cases, or any of the cases with high mRNA levels. In the four cases with strong staining intensity in the tissue microarray, whole section staining revealed marked heterogeneity of NTRK protein expression.Conclusion: The presence of NTRK fusion genes in non-small cell lung cancer is exceedingly rare. The use of the immunohistochemical NTRK assay will result in a small number of false positive cases. This should be considered when the assay is applied as a screening tool in clinical diagnostics.
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| 10. |
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| 11. |
- Jager, Vincent D. de, et al.
(author)
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Advancements in Non-Small Cell Lung Cancer Developments in predictive biomarker testing and targeted therapy in advanced stage non-small cell lung cancer and their application across European countries
- 2024
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In: LANCET REGIONAL HEALTH-EUROPE. - 2666-7762. ; 38
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Journal article (peer-reviewed)abstract
- In the past two decades, the treatment of metastatic non -small cell lung cancer (NSCLC), has undergone significant changes due to the introduction of targeted therapies and immunotherapy. These advancements have led to the need for predictive molecular tests to identify patients eligible for targeted therapy. This review provides an overview of the development and current application of targeted therapies and predictive biomarker testing in European patients with advanced stage NSCLC. Using data from eleven European countries, we conclude that recommendations for predictive testing are incorporated in national guidelines across Europe, although there are differences in their comprehensiveness. Moreover, the availability of recently EMA-approved targeted therapies varies between European countries. Unfortunately, routine assessment of national/regional molecular testing rates is limited. As a result, it remains uncertain which proportion of patients with metastatic NSCLC in Europe receive adequate predictive biomarker testing. Lastly, Molecular Tumor Boards (MTBs) for discussion of molecular test results are widely implemented, but national guidelines for their composition and functioning are lacking. The establishment of MTB guidelines can provide a framework for interpreting rare or complex mutations, facilitating appropriate treatment decision -making, and ensuring quality control.
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| 15. |
- Nesti, Cedric, et al.
(author)
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Hemicolectomy versus appendectomy for patients with appendiceal neuroendocrine tumours 1-2 cm in size : a retrospective, Europe-wide, pooled cohort study
- 2023
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In: The Lancet Oncology. - : Elsevier. - 1470-2045 .- 1474-5488. ; 24:2, s. 187-194
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Journal article (peer-reviewed)abstract
- BackgroundAwareness of the potential global overtreatment of patients with appendiceal neuroendocrine tumours (NETs) of 1–2 cm in size by performing oncological resections is increasing, but the rarity of this tumour has impeded clear recommendations to date. We aimed to assess the malignant potential of appendiceal NETs of 1–2 cm in size in patients with or without right-sided hemicolectomy.MethodsIn this retrospective cohort study, we pooled data from 40 hospitals in 15 European countries for patients of any age and Eastern Cooperative Oncology Group performance status with a histopathologically confirmed appendiceal NET of 1–2 cm in size who had a complete resection of the primary tumour between Jan 1, 2000, and Dec 31, 2010. Patients either had an appendectomy only or an appendectomy with oncological right-sided hemicolectomy or ileocecal resection. Predefined primary outcomes were the frequency of distant metastases and tumour-related mortality. Secondary outcomes included the frequency of regional lymph node metastases, the association between regional lymph node metastases and histopathological risk factors, and overall survival with or without right-sided hemicolectomy. Cox proportional hazards regression was used to estimate the relative all-cause mortality hazard associated with right-sided hemicolectomy compared with appendectomy alone. This study is registered with ClinicalTrials.gov, NCT03852693.Findings282 patients with suspected appendiceal tumours were identified, of whom 278 with an appendiceal NET of 1–2 cm in size were included. 163 (59%) had an appendectomy and 115 (41%) had a right-sided hemicolectomy, 110 (40%) were men, 168 (60%) were women, and mean age at initial surgery was 36·0 years (SD 18·2). Median follow-up was 13·0 years (IQR 11·0–15·6). After centralised histopathological review, appendiceal NETs were classified as a possible or probable primary tumour in two (1%) of 278 patients with distant peritoneal metastases and in two (1%) 278 patients with distant metastases in the liver. All metastases were diagnosed synchronously with no tumour-related deaths during follow-up. Regional lymph node metastases were found in 22 (20%) of 112 patients with right-sided hemicolectomy with available data. On the basis of histopathological risk factors, we estimated that 12·8% (95% CI 6·5 –21·1) of patients undergoing appendectomy probably had residual regional lymph node metastases. Overall survival was similar between patients with appendectomy and right-sided hemicolectomy (adjusted hazard ratio 0·88 [95% CI 0·36–2·17]; p=0·71).InterpretationThis study provides evidence that right-sided hemicolectomy is not indicated after complete resection of an appendiceal NET of 1–2 cm in size by appendectomy, that regional lymph node metastases of appendiceal NETs are clinically irrelevant, and that an additional postoperative exclusion of metastases and histopathological evaluation of risk factors is not supported by the presented results. These findings should inform consensus best practice guidelines for this patient cohort.
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| 16. |
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| 18. |
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| 19. |
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| 20. |
- Biswas, Dhruva, et al.
(author)
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A clonal expression biomarker associates with lung cancer mortality
- 2019
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In: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 25:10, s. 1540-1548
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Journal article (peer-reviewed)abstract
- An aim of molecular biomarkers is to stratify patients with cancer into disease subtypes predictive of outcome, improving diagnostic precision beyond clinical descriptors such as tumor stage(1). Transcriptomic intratumor heterogeneity (RNA-ITH) has been shown to confound existing expression-based biomarkers across multiple cancer types(2-6). Here, we analyze multi-region whole-exome and RNA sequencing data for 156 tumor regions from 48 patients enrolled in the TRACERx study to explore and control for RNA-ITH in non-small cell lung cancer. We find that chromosomal instability is a major driver of RNA-ITH, and existing prognostic gene expression signatures are vulnerable to tumor sampling bias. To address this, we identify genes expressed homogeneously within individual tumors that encode expression modules of cancer cell proliferation and are often driven by DNA copy-number gains selected early in tumor evolution. Clonal transcriptomic biomarkers overcome tumor sampling bias, associate with survival independent of clinicopathological risk factors, and may provide a general strategy to refine biomarker design across cancer types.
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| 21. |
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| 22. |
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| 23. |
- de Jager, Vincent D., et al.
(author)
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Future perspective for the application of predictive biomarkertesting in advanced stage non-small cell lung cance
- 2024
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In: LANCET REGIONAL HEALTH-EUROPE. - 2666-7762. ; 38
-
Journal article (peer-reviewed)abstract
- For patients with advanced stage non-small cell lung cancer (NSCLC), treatment strategies have changed significantly due to the introduction of targeted therapies and immunotherapy. In the last few years, we have seen an explosive growth of newly introduced targeted therapies in oncology and this development is expected to continue in the future. Besides primary targetable aberrations, emerging diagnostic biomarkers also include relevant co-occurring mutations and resistance mechanisms involved in disease progression, that have impact on optimal treatment management. Toaccommodate testing of pending biomarkers, it is necessary to establish routine large-panel next-generationsequencing (NGS) for all patients with advanced stage NSCLC. For cost-effectiveness and accessibility, it is recommended to implement predictive molecular testing using large-panel NGS in a dedicated, centralized expert laboratory within a regional oncology network. The central molecular testing center should host a regional Molecular Tumor Board and function as a hub for interpretation of rare and complex testing results and clinical decision-making. Copyright (c) 2024 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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| 24. |
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| 25. |
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| 26. |
- Edsjö, A., et al.
(author)
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Molecular pathology - the key to precision oncology
- 2021
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In: Läkartidningen. - 1652-7518. ; 118
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Journal article (peer-reviewed)abstract
- Rapidly expanding knowledge of the molecular landscape of cancers has resulted in the implementation of an increasing number of specific therapies targeted at tumors with specific molecular aberrations. In response to this development, new tools for predictive testing for molecular targets need to be implemented in routine health care. To achieve robust future molecular diagnostic pathology, and equal opportunity for patients to qualify for targeted therapy, the national working group for Solid Tumors in the initiative Genomic Medicine Sweden (GMS) aims to implement regional and national platforms for comprehensive genomic tumor profiling and linked analysis pipelines. Novel IT-infrastrucutures and recruitment of bioinformaticians and molecular biologists to hospital labotatories are paramount. The infrastructure will allow wider inclusion into clinical trials and supplement the national cancer registries with molecular »real world data« for research and evaluation of implemented cancer therapies and diagnostic procedures.
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| 27. |
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| 28. |
- Evren, Elza, et al.
(author)
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Distinct developmental pathways from blood monocytes generate human lung macrophage diversity
- 2021
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In: Immunity. - : Elsevier. - 1074-7613 .- 1097-4180. ; 51, s. 35-35
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Journal article (peer-reviewed)abstract
- The study of human macrophages and their ontogeny is an important unresolved issue. Here, we use a humanized mouse model expressing human cytokines to dissect the development of lung macrophages from human hematopoiesis in vivo. Human CD34+ hematopoietic stem and progenitor cells (HSPCs) generated three macrophage populations, occupying separate anatomical niches in the lung. Intravascular cell labeling, cell transplantation, and fate-mapping studies established that classical CD14+ blood monocytes derived from HSPCs migrated into lung tissue and gave rise to human interstitial and alveolar macrophages. In contrast, non-classical CD16+ blood monocytes preferentially generated macrophages resident in the lung vasculature (pulmonary intravascular macrophages). Finally, single-cell RNA sequencing defined intermediate differentiation stages in human lung macrophage development from blood monocytes. This study identifies distinct developmental pathways from circulating monocytes to lung macrophages and reveals how cellular origin contributes to human macrophage identity, diversity, and localization in vivo.
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| 29. |
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| 30. |
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| 31. |
- Larsson, Erik, et al.
(author)
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Expression of the endogenous retrovirus ERV3 (HERV-R) during induced monocytic differentiation in the U-937 cell line
- 1996
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In: International Journal of Cancer. - 0020-7136 .- 1097-0215. ; 67:3, s. 451-456
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Journal article (peer-reviewed)abstract
- ERV3 (HERV-R) is a complete human endogenous retrovirus located on the long arm of chromosome 7. LTR-env-gene-spliced mRNA of 9 and 3.5 Kb is widely expressed in human tissues and cells, but gag-pol mRNA has not been found. Further, the env gp70 gene contains an open reading frame throughout its length and its expression has recently been detected as a full-length protein. The highest expression of ERV3 detected so far is in placenta and the lowest in cytotrophoblasts and choriocarcinoma cell lines. In this report we have studied ERV3 mRNA and protein expression in the human monoblastic cell line U-937 during differentiation into monocytes/macrophages. Differentiation of U-937 cells was induced by 1,25a-dihydroxyvitamin D3 (vitD3), retinoic acid (RA), gamma interferon (IFN-gamma) and phorbol-myristate-acetate (PMA-TPA). The expression of ERV3 env mRNA was found to be differentiation-associated, with high expression detected in the late stages of monocytic development. Using TPA, the expression of ERV3 env was detected as 9- and 3.5-kb transcripts by Northern blotting, as mRNA by in situ hybridization and as a cytoplasmic 65-kDa protein by immunofluorescence and Western blots. Low levels of basal expression were found, with up-regulation of both message and protein at 24 to 48 hr after addition of TPA. Induction with vitD3, IFN-gamma and RA produced higher levels of mRNA at earlier time points. It is concluded that the U-937 cell line represents an excellent model system for further studies to study the relationship between ERV3 expression and cellular differentiation.
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| 32. |
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| 33. |
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| 34. |
- Moens, Lotte N. J., et al.
(author)
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HaloPlex Targeted Resequencing for Mutation Detection in Clinical Formalin-Fixed, Paraffin-Embedded Tumor Samples
- 2015
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In: Journal of Molecular Diagnostics. - : Elsevier BV. - 1525-1578 .- 1943-7811. ; 17:6, s. 729-739
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Journal article (peer-reviewed)abstract
- In recent years, the advent of massively parallel next-generation sequencing technologies has enabled substantial advances in the study of human diseases. Combined with targeted DNA enrichment methods, high sequence coverage can be obtained for different genes simultaneously at a reduced cost per sample, creating unique opportunities for clinical cancer diagnostics. However, the formalin-fixed, paraffin-embedded (FFPE) process of tissue samples, routinely used in pathology departments, results in DNA fragmentation and nucleotide modifications that introduce a number of technical challenges for downstream biomotecular analyses. We evaluated the HaloPlex target enrichment system for somatic mutation detection in 80 tissue fractions derived from 20 clinical cancer cases with paired tumor and normal tissue available in both FFPE and fresh-frozen format. Several modifications to the standard method were introduced, including a reduced target fragment Length and two strand capturing. We found that FFPE material can be used for HaloPlex-based target enrichment and next-generation sequencing, even when starting from small amounts of DNA. By specifically capturing both strands for each target fragment, we were able to reduce the number of false-positive errors caused by FFPE-induced artifacts and Lower the detection limit for somatic mutations. We believe that the HaloPlex method presented here will be broadly applicable as a tool for somatic mutation detection in clinical cancer settings.
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| 35. |
- Norén-Nyström, Ulrika, et al.
(author)
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Bone marrow fibrosis in childhood acute lymphoblastic leukemia correlates to biological factors, treatment response and outcome
- 2008
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In: Leukemia. - Baltimore : Williams & Wilkins. - 0887-6924 .- 1476-5551. ; 22:3, s. 504-510
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Journal article (peer-reviewed)abstract
- We retrospectively evaluated reticulin fiber density (RFD) in 166 diagnostic bone marrow (BM) biopsies and 62 biopsies obtained at treatment day 29 from children with acute lymphoblastic leukemia (ALL). Patients with B-cell precursor (BCP)-ALL showed higher RFD as compared to patients with T-cell ALL (P<0.001). RFD correlated negatively with white blood cell count (P=0.008) in BCP-ALL patients. Patients with high-hyperdiploid ALL (51-61 chromosomes), no high-risk criteria and low RFD showed a favorable outcome when compared to similar patients with high RFD (P=0.002). In BCP-ALL patients, RFD at diagnosis correlated to the levels of minimal residual disease (MRD) analyzed by flow cytometry on treatment day 29 (P=0.001). Accordingly, patients with MRD > or = 10(-4) presented higher RFD at diagnosis compared to patients with MRD < 10(-4) (P=0.003). BCP-ALL patients with low RFD at diagnosis and a rapid reduction of RFD on day 29 had a favorable outcome compared to patients with the same baseline RFD level at diagnosis but a slow RFD reduction (P=0.041). To our knowledge, these findings are novel and may indicate BM fibrosis as a new valuable prognostic marker in childhood ALL. Expanded use of BM biopsy both at diagnosis and during follow-up is suggested.
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| 36. |
- Rao, Shuan, et al.
(author)
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RANK rewires energy homeostasis in lung cancer cells and drives primary lung cancer
- 2017
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In: Genes & Development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 31:20, s. 2099-2112
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Journal article (peer-reviewed)abstract
- Lung cancer is the leading cause of cancer deaths. Besides smoking, epidemiological studies have linked female sex hormones to lung cancer in women; however, the underlying mechanisms remain unclear. Here we report that the receptor activator of nuclear factor-kB (RANK), the key regulator of osteoclastogenesis, is frequently expressed in primary lung tumors, an active RANK pathway correlates with decreased survival, and pharmacologic RANK inhibition reduces tumor growth in patient-derived lung cancer xenografts. Clonal genetic inactivation of KRas(G12D) in mouse lung epithelial cells markedly impairs the progression of KRas(G12D)-driven lung cancer, resulting in a significant survival advantage. Mechanistically, RANK rewires energy homeostasis in human and murine lung cancer cells and promotes expansion of lung cancer stem-like cells, which is blocked by inhibiting mitochondrial respiration. Our data also indicate survival differences in KRas(G12D)-driven lung cancer between male and female mice, and we show that female sex hormones can promote lung cancer progression via the RANK pathway. These data uncover a direct role for RANK in lung cancer and may explain why female sex hormones accelerate lung cancer development. Inhibition of RANK using the approved drug denosumab may be a therapeutic drug candidate for primary lung cancer.
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| 37. |
- Rennel, Emma, et al.
(author)
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Endocan is a VEGF-A and PI3K regulated gene with increased expression in human renal cancer
- 2007
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In: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 313:7, s. 1285-1294
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Journal article (peer-reviewed)abstract
- An in vitro model of VEGF-A-induced angiogenesis was used to generate transcription profiles of human microvascular endothelial cells. Microarray analysis showed increased transcription of genes known to regulate angiogenesis, but also genes that previously have not been firmly associated with angiogenesis such as endocan, pinin, plakophilin, phosphodiesterase 4B and gelsolin. Increased endocan mRNA levels in response to VEGF-A in endothelial cells and in human renal cancer have previously been reported. We now show increased endocan protein levels in VEGF-A treated endothelial cells and in human renal clear cell carcinoma. Increased protein expression was observed both in tumor cells and in a subset of tumor vessels, while expression in normal kidney tissue was low. VEGF-A seemed to be a specific inducer of endocan transcription since FGF-2, PDGF-BB, HGF/SF and EGF did not alter expression levels. Inhibition of PI3K with LY294002 caused a 12-fold increase in endocan transcription suggesting a repressive function of PI3K. In contrast inhibition of Src or MEK, which are signaling pathways activated by VEGF-A, did not influence basal or VEGF-A-induced endocan levels. In conclusion our study shows that, among angiogenic growth factors, VEGF-A is a specific inducer of endocan transcription which is translated into increased protein levels in VEGF-A treated endothelial cells. Increased endocan protein expression in human renal cancer suggests a role in tumor growth.
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| 38. |
- Salomonsson, A., et al.
(author)
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A Nation-Wide Population-Based Mapping of Targetable Alterations in Smoking-Independent Lung Cancer
- 2018
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In: Journal of Thoracic Oncology. - : Elsevier. - 1556-0864 .- 1556-1380. ; 13:10, s. S431-S432
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Journal article (other academic/artistic)abstract
- Background: Smoking is by far the most important cause of lung cancer. However, lung cancer among never-smokers is common and increasing [1]. A smoking-independent subgroup of lung adenocarcinoma with certain molecular and clinical features exists [2-3]. Therefore, as 1st project within the Swedish Molecular Initiative against Lung cancer (SMIL) we aim to characterize never-smoking lung cancer for etiological, diagnostic and therapeutic purposes.Method: Through the Swedish National Lung Cancer Registry [1], we identified all individuals who underwent surgery for lung cancer in Sweden 2005-2014 and who were registered as never-smokers (n=540). At each study site (n=6), clinical data were reviewed by a thoracic oncologist/pulmonologist through patients' medical charts and archived tumor tissues were retrieved and reviewed by a thoracic pathologist. For subsequent studies, we extracted DNA and RNA (using the Qiagen AllPrep kit for FFPE tissue) and constructed tissue microarrays. As a first pre-planned analysis, we performed fusion gene mapping using an RNA-based NanoString nCounter Elements assay, as previously described [4].Result: In the first 212 (out of 540) analyzed samples, we detected 17 fusions involving ALK, 8 involving RET, and 2 involving NRG1. In addition, MET exon 14 skipping was found in 17 samples. In total, these findings involved 21% of analyzed cases. Additional results from further studies on the cohort will be presented.Conclusion: SMIL is an ongoing nation-wide molecular research collaboration on lung cancer where we currently collect one of the largest never-smoking lung tumor cohorts worldwide. From the first pre-planned analyses, we conclude that, in a population-based cohort of early stage lung cancer from never-smokers, druggable oncogenic fusions are frequent.
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| 39. |
- Salomonsson, Annette, et al.
(author)
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Comprehensive analysis of RNA binding motif protein 3 (RBM3) in non-small cell lung cancer
- 2020
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In: Cancer Medicine. - : Blackwell Publishing Ltd. - 2045-7634. ; 9:15, s. 5609-5619
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Journal article (peer-reviewed)abstract
- Aims High expression of the RNA-binding motif protein 3 (RBM3) correlates with improved prognosis in several major types of cancer. The aim of the present study was to examine the prognostic value of RBM3 protein and mRNA expression in non-small cell lung cancer (NSCLC).Methods and results Immunohistochemical expression of RBM3 was evaluated in surgically treated NSCLC from two independent patient populations (n = 213 and n = 306). Staining patterns were correlated with clinicopathological parameters, overall survival (OS), and recurrence-free interval (RFI). Cases with high nuclear RBM3 protein expression had a prolonged 5-year OS in both cohorts when analyzing adenocarcinomas separately (P = .02 and P = .01). RBM3 remained an independent prognostic factor for OS in multivariable analysis of cohort I (HR 0.44, 95% CI 0.21-0.90) and for RFI in cohort II (HR 0.38, 95% CI 0.22-0.74). In squamous cell carcinoma, there was instead an insignificant association to poor prognosis. Also, the expression levels of RBM3 mRNA were investigated in 2087 lung adenocarcinomas and 899 squamous cell carcinomas assembled from 13 and 8 public gene expression microarray datasets, respectively. The RBM3 mRNA levels were not clearly associated with patient outcome in either adenocarcinomas or squamous cell carcinomas.Conclusions The results from this study support that high protein expression of RBM3 is linked to improved outcome in lung adenocarcinoma.
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