| 1. |
- Fredriksson, Simon, et al.
(författare)
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Multiplexed proximity ligation assays to profile putative plasma biomarkers relevant to pancreatic and ovarian cancer
- 2008
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 54:3, s. 582-589
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Sensitive methods are needed for biomarker discovery and validation. We tested one promising technology, multiplex proximity ligation assay (PLA), in a pilot study profiling plasma biomarkers in pancreatic and ovarian cancer. METHODS: We used 4 panels of 6- and 7-plex PLAs to detect biomarkers, with each assay consuming 1 mu L plasma and using either matched monoclonal antibody pairs or single batches of polyclonal antibody. Protein analytes were converted to unique DNA arnplicons by proximity ligation and subsequently detected by quantitative PCR. We profiled 18 pancreatic cancer cases and 19 controls and 19 ovarian cancer cases and 20 controls for the following proteins: a disintegrin and metalloprotease 8, CA-125, CA 19-9, carboxypeptidase A1, carcinoembryonic antigen, connective tissue growth factor, epidermal growth factor receptor, epithelial cell adhesion molecule, Her2, galectin-1, insulin-like growth factor 2, interleukin-1 alpha, interleukin-7, mesothelin, macrophage migration inhibitory factor, osteopontin, secretory leukocyte peptidase inhibitor, tumor necrosis factor a, vascular endothelial growth factor, and chitinase 3-like 1. Probes for CA-125 were present in 3 of the multiplex panels. We measured plasma concentrations of the CA-125-mesothelin complex by use of a triple-specific PLA with 2 ligation events among 3 probes. RESULTS: The assays displayed consistent measurements of CA-125 independent of which other markers were simultaneously detected and showed good correlation with Luminex data. In comparison to literature reports, we achieved expected results for other putative markers. CONCLUSION: Multiplex PLA using either matched monoclonal antibodies or single batches of polyclonal. antibody should prove useful for identifying and validating sets of putative disease biomarkers and finding. multimarker panels.
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| 2. |
- George, Julie, et al.
(författare)
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Comprehensive genomic profiles of small cell lung cancer
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 524:7563, s. 47-U73
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Tidskriftsartikel (refereegranskat)abstract
- We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Dex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.
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| 3. |
- Khadse, Anand, et al.
(författare)
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Prognostic Significance of the Loss of Heterozygosity of KRAS in Early-Stage Lung Adenocarcinoma
- 2022
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Ingår i: Frontiers in Oncology. - : Frontiers Media S.A.. - 2234-943X. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Lung cancer is a common disease with a poor prognosis. Genomic alterations involving the KRAS gene are common in lung carcinomas, although much is unknown about how different mutations, deletions, and expressions influence the disease course. The first approval of a KRAS-directed inhibitor was recently approved by the FDA. Mutations in the KRAS gene have been associated with poor prognosis for lung adenocarcinomas, but implications of the loss of heterozygosity (LOH) of KRAS have not been investigated. In this study, we have assessed the LOH of KRAS in early-stage lung adenocarcinoma by analyzing DNA copy number profiles and have investigated the effect on patient outcome in association with mRNA expression and somatic hotspot mutations. KRAS mutation was present in 36% of cases and was associated with elevated mRNA expression. LOH in KRAS was associated with a favorable prognosis, more prominently in KRAS mutated than in wild-type patients. The presence of both LOH and mutation in KRAS conferred a better prognosis than KRAS mutation alone. For wild-type tumors, no difference in prognosis was observed between patients with and without LOH in KRAS. Our study indicates that LOH in KRAS is an independent prognostic factor that may refine the existing prognostic groups of lung adenocarcinomas.
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| 4. |
- Kvarnbrink, Samuel, 1981-
(författare)
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LRIG1 in lung cancer : prognostic effects and mechanistic studies
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Lung cancer is the leading cause of cancer-related death worldwide as well as in Sweden. Non-small cell lung cancer (NSCLC) is the predominant form, which is largely subdivided into adenocarcinomas and squamous cell carcinomas. A small minority of NSCLC cases that present with localized small tumors are curable with surgery alone, but adjuvant chemotherapy is recommended in most cases that are treated with surgery, even though it only increases the chance of cure by less than 5%. Therefore, additional biomarkers are needed to guide the clinical decision making in early-stage disease.The leucine-rich repeats and immunoglobulin-like (LRIG) family of proteins consists of three paralogous transmembrane proteins that are involved in the regulation of growth factor signaling. Of these proteins, LRIG1 is the most studied and it interacts with a wide variety of growth factor receptors and related proteins, including the epidermal growth factor (EGFR) and several others. High levels of LRIG1 have been associated with better survival in a multitude of malignant diseases, including (but not limited to) breast cancer, bladder cancer, cervical cancer, glioma and melanoma. The aim of this thesis was to investigate whether LRIG1 was a prognostic factor in NSCLC as well, and to further characterize the biological role of LRIG proteins in this disease.To investigate the prognostic impact of LRIG proteins in NSCLC, we stained a tissue microarray (TMA) containing tumor samples from 347 surgically treated early-stage NSCLC patients for LRIG1, LRIG2 and LRIG3. LRIG1 high-expressing adenocarcinoma cases had a large and statistically significant survival benefit of 33 months compared to negative cases. Similarly, an in silico analysis of a large gene expression dataset from the Oncomine database showed that high LRIG1 mRNA expression was linked to better survival as well. Differences in survival persisted even when adjusting for known prognostic factors, meaning that LRIG1 was an independent positive prognostic marker for survival in NSCLC.A yeast two-hybrid screen was performed to search for proteins interacting with a conserved cytosolic peptide shared between all three mammalian LRIG proteins. This screen yielded hits for the paralogous proteins LIM domain only protein 7 (LMO7) and LIM and calponin homology domains-containing protein 1 (LIMCH1). LRIG1 and LRIG3 were both found to physically interact with LMO7 and LIMCH1 as assessed through immunoprecipitation techniques on overexpressed proteins. For LMO7, this could also be confirmed at endogenous protein levels using the proximity ligation assay. The 347 samples in the previously mentioned TMA were stained for LMO7. In our survival analysis, we observed no significant survival differences when looking at LMO7 alone, but the survival benefit observed for high LRIG1 was found to be limited to the subgroup that also was negative for LMO7. This means that the observed physical interaction between LRIG1 and LMO7 appears to translate to differences in patient survival.To investigate possible mechanisms underlying the observed association between high LRIG1 expression and a favorable patient survival, a panel of NSCLC cell lines was modified to overexpress LRIG1. Broadly, LRIG1 overexpression resulted in minor decreases in cellular proliferation rates and no effects on chemosensitivity or radiosensitivity. Looking across the panel of NSCLC cell lines, no clear pattern was observed regarding the effects of LRIG1 overexpression on cellular motility. However, LRIG1 overexpression significantly decreased the clonogenic potential in most cell lines. The only cell line in the panel, H1299, that formed hematogenous disseminated disease in immunodeficient mice was used to establish a mixed-population primary tumor of tagged LRIG1 overexpressing cells and control cells. The LRIG1 transduced cells were was found to be enriched in the injected primary tumor, but no significant changes in their relative abundance was observed between the metastatic sites and their corresponding primary tumors.In summary, we found that LRIG1 was an independent positive prognostic factor in early-stage NSCLC. We identified LMO7 and LIMCH1 as interaction partners for LRIG proteins and showed that the interaction between LMO7 and LRIG1 had implications for the clinical outcome in NSCLC. Furthermore, our mechanistic studies on the effects of LRIG1 overexpression on NSCLC cells suggested that the survival benefit conferred by high LRIG1 expression may be due to differences in metastatic potential. Taken together, the findings in this thesis suggest an important biological role for LRIG proteins in NSCLC.
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| 5. |
- Lehtiö, Janne, et al.
(författare)
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Proteogenomics of non-small cell lung cancer reveals molecular subtypes associated with specific therapeutic targets and immune-evasion mechanisms
- 2021
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Ingår i: Nature Cancer. - : Springer Science and Business Media LLC. - 2662-1347. ; 2:11, s. 1224-1242
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Tidskriftsartikel (refereegranskat)abstract
- Despite major advancements in lung cancer treatment, long-term survival is still rare and a deeper understanding of molecular phenotypes would allow the identification of specific cancer dependencies and immune-evasion mechanisms. Here we performed in-depth mass-spectrometry-based proteogenomic analysis of 141 tumors representing all major histologies of non-small cell lung cancer (NSCLC). We identified six distinct proteome subtypes with striking differences in immune cell composition and subtype-specific expression of immune checkpoints. Unexpectedly, high neoantigen burden was linked to global hypomethylation and complex neoantigens mapped to genomic regions, such as endogenous retroviral elements and introns, in immune-cold subtypes. Further, we linked immune evasion with LAG-3 via STK11 mutation-dependent HNF1A activation and FGL1 expression. Finally, we develop a data-independent acquisition mass-spectrometry-based NSCLC subtype classification method, validate it in an independent cohort of 208 NSCLC cases and demonstrate its clinical utility by analyzing an additional cohort of 84 late-stage NSCLC biopsy samples.
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| 6. |
- Yu, Hui, et al.
(författare)
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Programmed Cell Death Ligand 1 Expression in Resected Non-Small Cell Lung Cancer
- 2021
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Ingår i: Clinical Lung Cancer. - : Elsevier. - 1525-7304 .- 1938-0690. ; 22:4, s. 555-562
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Tidskriftsartikel (refereegranskat)abstract
- Background: Recently, anti-programmed cell death 1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) immunotherapies have yielded promising outcomes for patients with advanced non-small cell lung cancer (NSCLC) and led to great interest in applying these agents to treat resectable early-stage NSCLC. The objective of our study was to evaluate PD-L1 protein expression in resectable early-stage NSCLC specimens from a large Northern European cohort, examine the relationship to clinical characteristics, and demonstrate the prognostic role in resected NSCLC.Material and Methods: A large cohort of 875 NSCLC tumors consisted of 337 patients from Sweden and 538 patients from Norway was studied. All the patients had undergone pulmonary resection, and most patients had had early-stage NSCLC. PD-L1 protein expression was assessed by immunohistochemistry using the Dako PD-L1 22C3 pharmDx kit. The tumor proportion score for PD-L1 protein expression was compared with comprehensive demographic and clinicopathologic data.Results: The overall prevalence of PD-L1 protein expression in the resectable NSCLC cohort was 9.5% at a tumor proportion score cutoff of ≥ 50%. Stage I NSCLC had lower PD-L1 expression compared with that of the other stages (P = .0012). PD-L1 expression correlated with wild-type EGFR gene expression (P = .0156) and mutated KRAS gene expression (P = .0004). No significant association was found between PD-L1 expression and mortality after multivariable adjustment for clinical characteristics, although the survival curves showed PD-L1 expression significantly correlated with a poor prognosis in the total NSCLC cohort and in the adenocarcinoma subgroup.Conclusion: PD-L1 expression in the present large cohort of resectable NSCLC was relatively low compared with data from clinical trials of advanced NSCLC. PD-L1 expression correlated positively with tumor stage, wild-type EGFR, and KRAS mutation. PD-L1 expression was not found as an independent prognostic factor in the present study. These findings could be important in the future when evaluating the role of anti-PD-1/PD-L1 immunotherapy in the setting of neoadjuvant or adjuvant trials for early-stage resectable NSCLC.
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