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| 6. |
- Ekman, S., et al.
(författare)
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Treatment (Tx) patterns and overall survival (OS) in patients (pts) with NSCLC in Sweden : A SCAN-LEAF study analysis from the I-O Optimise initiative
- 2019
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Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534. ; 30:Suppl 2, s. 17-17
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Konferensbidrag (refereegranskat)abstract
- Background: As part of I-O Optimise, a multinational research platform providing real-world insights into the management of lung cancers, the SCAN-LEAF study aims to describe the epidemiology, clinical care and outcomes for pts with NSCLC in Scandinavia. We report initial Tx and OS for pts with NSCLC prior to the availability of immunotherapies in Sweden. Methods: The analysis includes all adult pts diagnosed with NSCLC at Uppsala and Karolinska (Stockholm) University Hospitals from 2012 to 2015 (follow-up to Dec 2016). Electronic medical record data were extracted using Pygargus CXP software and linked with national registries. Bespoke rule-based algorithms were applied to describe Tx patterns; Kaplan–Meier methods were used to estimate OS. Results: 2779 pts were diagnosed with incident NSCLC (median age, 70 yrs [range: 22–96; 14.2% ≥80]; male, 48.5%; histology: non-squamous (NSQ), 70.9%, squamous (SQ), 17.7%, other, 11.4%; stage distribution: I, 19.3%; II, 7.7%; IIIA, 12.3%; IIIB, 7.2%; IV, 51.2%). Initial Tx (≤6 months from diagnosis) by stage and yr of diagnosis is shown in the table. Median OS (months) for NSQ and SQ pts: not reached and 52.8 in stage I, 43.2 and 23.6 in stage II, 26.7 and 20.4 in stage IIIA, 12.5 and 12.9 in stage IIIB, and 7.6 and 6.1 in stage IV, respectively. Among stage IIIB–IV pts, 60.7% (NSQ) and 53.5% (SQ) had ≥1 line of systemic anti-cancer therapy (SACT); median OS was 12.2 (NSQ) and 10.4 (SQ) months in pts on SACT, and 3.1 (NSQ) and 3.7 (SQ) months in pts not on SACT. Ongoing analyses will assess factors associated with SACT receipt in stage IIIB–IV pts. Conclusions: Swedish pts with NSCLC had a high burden of disease, with most diagnosed at stage IV and a median OS of 1 yr in late-stage pts receiving SACT. There is also scope for improved prognosis in pts diagnosed at early stages, particularly in SQ pts. Future analyses will assess the potential impact of recent improvements in diagnostics and therapeutics on Tx patterns and OS in Swedish NSCLC pts.
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| 7. |
- 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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| 9. |
- Oskarsdottir, G. N., et al.
(författare)
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Lobectomy for non-small cell lung carcinoma : a nationwide study of short- and long-term survival
- 2017
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Ingår i: Acta Oncologica. - 0284-186X. ; 56, s. 936-942
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Lobectomy is the standard curative treatment for non-small cell carcinoma (NSCLC) of the lung. Most studies on lobectomy have focused on short-term outcome and 30-day mortality. The aim of this study was to determine both short-term and long-term surgical outcome in all patients who underwent lobectomy for NSCLC in Iceland over a 24-year period. Material and methods: The study involved 489 consecutive patients with NSCLC who underwent lobectomy with curative intent in Iceland, 1991–2014. Patient demographics, pTNM stage, rate of perioperative complications, and 30-day mortality were registered. Overall survival was analyzed with the Kaplan?Meier method. The Cox proportional hazards model was used to evaluate factors that were prognostic of overall mortality. To study trends in survival, the study period was divided into six 4-year periods. The median follow-up time was 42 months and no patients were lost to follow-up. Results: The average age of the patients was 67 years and 53.8% were female. The pTNM disease stage was IA in 148 patients (30.0%), IB in 125 patients (25.4%), IIA in 96 patients (19.5%), and IIB in 50 patients (10.1%), but 74 (15.0%) were found to be stage IIIA, most often diagnosed perioperatively. The total rate of major complications was 4.7%. Thirty-day mortality was 0.6% (three patients). One- and 5-year overall survival was 85.0% and 49.2%, respectively, with 3-year survival improving from 48.3% to 72.8% between the periods 1991–1994 and 2011–2014 (p = .0004). Advanced TNM stage and age were independent negative prognostic factors for all-cause mortality, and later calendar year and free surgical margins were independent predictors of improved survival. Conclusions: The short-term outcome of lobectomy for NSCLC in this population-based study was excellent, as reflected in the low 30-day mortality and low rate of major complications. The long-term survival was acceptable and the overall 3-year survival had improved significantly during the study period.
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| 13. |
- Sørensen, J. B., et al.
(författare)
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Evolution of overall survival (OS) in patients (pts) with incident NSCLC in Denmark and Sweden : A SCAN-LEAF study analysis from the I-O Optimise initiative
- 2019
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Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534. ; 30:Suppl 2, s. 16-17
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Konferensbidrag (refereegranskat)abstract
- Background: As part of I-O Optimise, a multinational research platform providing real-world insights into the management of lung cancers, the SCAN-LEAF study aims to describe the epidemiology, clinical care, and outcomes for pts with NSCLC in Scandinavia. Here, we report temporal OS trends among pts diagnosed with incident NSCLC from 2005 to 2015 in Denmark and Sweden. Methods: The SCAN-LEAF Danish and Swedish cohorts were established by linking respective national registries and include all adult pts diagnosed with incident NSCLC from Jan 2005 to Dec 2015 (follow-up to Dec 2016). The Kaplan–Meier method was used to estimate OS at 1, 3, and 5 yrs by histology (non-squamous cell [NSQ] or squamous cell [SQ]), TNM stage, and yr of diagnosis; changes in OS over time were assessed using the Cochrane–Armitage test. Results: 31,939 pts in Denmark and 30,067 pts in Sweden were diagnosed with NSCLC from 2005 to 2015. Most were diagnosed at stage IV (51.6% and 48.4%, respectively) and had NSQ histology (54.4% and 60.4%). Statistically significant trends (P < 0.05) for improved OS accompanied by an absolute OS rate increase of > 5% over the analysis period were seen for NSQ pts at 1 yr for all stages in both countries (Table); at 3 yrs for stages I–IIIB in Denmark (P ≤ 0.027), and stages I–II (P ≤ 0.0013) in Sweden; and at 5 yrs for stages I–II (P ≤ 0.026) in both countries. For SQ pts, this was seen only at 1 yr for stage IIIA in Denmark and stage I in Sweden (Table), and at 5 yrs for stage IIIA in Denmark (p = 0.02). Conclusions: Despite some improvements between 2005 and 2015, mainly in the short-term survival of pts with early-stage NSCLC, long-term OS rates for pts with late-stage disease did not change significantly and remained low. Even in pts with early-stage disease, OS outcomes were suboptimal, with a particular unmet need in the SQ population. Future analyses including data after 2015 will evaluate the potential impact on OS of increased use of new TKIs and immune checkpoint inhibitors.
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| 14. |
- Edlund, Karolina, et al.
(författare)
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CD99 is a novel prognostic stromal marker in non-small cell lung cancer
- 2012
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 131:10, s. 2264-2273
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Tidskriftsartikel (refereegranskat)abstract
- The complex interaction between cancer cells and the microenvironment plays an essential role in all stages of tumourigenesis. Despite the significance of this interplay, alterations in protein composition underlying tumourstroma interactions are largely unknown. The aim of this study was to identify stromal proteins with clinical relevance in non-small cell lung cancer (NSCLC). A list encompassing 203 stromal candidate genes was compiled based on gene expression array data and available literature. The protein expression of these genes in human NSCLC was screened using the Human Protein Atlas. Twelve proteins were selected that showed a differential stromal staining pattern (BGN, CD99, DCN, EMILIN1, FBN1, PDGFRB, PDLIM5, POSTN, SPARC, TAGLN, TNC and VCAN). The corresponding antibodies were applied on tissue microarrays, including 190 NSCLC samples, and stromal staining was correlated with clinical parameters. Higher stromal expression of CD99 was associated with better prognosis in the univariate (p = 0.037) and multivariate (p = 0.039) analysis. The association was independent from the proportion of tumour stroma, the fraction of inflammatory cells and clinical and pathological parameters like stage, performance status and tumour histology. The prognostic impact of stromal CD99 protein expression was confirmed in an independent cohort of 240 NSCLC patients (p = 0.008). Furthermore, double-staining confocal fluorescence microscopy showed that CD99 was expressed in stromal lymphocytes as well as in cancer-associated fibroblasts. Based on a comprehensive screening strategy the membrane protein CD99 was identified as a novel stromal factor with clinical relevance. The results support the concept that stromal properties have an important impact on tumour progression.
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| 15. |
- Ericson, K, et al.
(författare)
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Defective mismatch-repair in patients with multiple primary tumours including colorectal cancer
- 2003
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Ingår i: European Journal of Cancer. - 1879-0852. ; 39:2, s. 8-240
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Tidskriftsartikel (refereegranskat)abstract
- Individuals with an inherited predisposition to cancer development are at an increased risk of developing multiple tumours. Hereditary non-polyposis colorectal cancer (HNPCC) is one of the most common hereditary cancer syndromes and is estimated to account for approximately 2% of colorectal cancers. However, HNPCC individuals are at an increased risk of developing other tumour types such as cancers of the endometrium, urothelium and small intestine. We have utilised a population-based regional cancer registry to identify all patients with double primary colorectal cancers and at least one additional malignancy and characterised the tumour spectrum in this patient group. We subsequently selected those 47 individuals who had developed at least four malignancies, including two colorectal cancers, for studies of the tumour characteristics associated with HNPCC. In total, these individuals developed 209 tumours, 156 of which were successfully retrieved. Microsatellite instability (MSI), a phenomenon caused by defective mismatch-repair (MMR), was identified in 63/154 (41%) evaluable tumours with a MSI-high pattern in 59 and a MSI-low pattern in four tumours. All tumours were immunohistochemically stained for the MMR proteins MLH1 and MSH2, with loss of expression in 55/63 (87%) MSI tumours and in 2/89 (2%) microsatellite stable (MSS) tumours. This loss affected MLH1 in 24 tumours and MSH2 in 33 tumours. A concordant loss of expression for the same MMR protein in several tumours from the same individual, a pattern that strongly suggests an underlying germline MMR gene mutation, was found in 17/45 (38%) patients and affected MLH1 in 8 patients and MSH2 in 9 patients. We conclude that the development of multiple primary tumours, including synchronous or metachronous colorectal cancers, is associated with an increased frequency of MSI and loss of immunohistochemical expression of MLH1 and MSH2.
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| 17. |
- Planck, M, et al.
(författare)
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hMLH1, hMSH2 and hMSH6 mutations in hereditary non-polyposis colorectal cancer families from southern Sweden
- 1999
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Ingår i: International Journal of Cancer. - 0020-7136. ; 83:2, s. 197-202
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Tidskriftsartikel (refereegranskat)abstract
- We have screened 17 Southern Sweden individuals/families with suspected hereditary non-polyposis colorectal cancer (HNPCC) for mutations in the DNA-mismatch repair genes hMLH1, hMSH2 and hMSH6 using denaturing gradient gel electrophoresis, protein truncation test and direct DNA sequencing. The families were selected on the basis of a family history of HNPCC-related tumors or the occurrence of metachronous colorectal cancer/endometrial cancer at young age in an individual with a weak family history of cancer. Furthermore, we required that tumor tissue from at least one individual in the family had to display microsatellite instability. We identified germ-line mutations in 9 individuals from 8 families. Five families had mutations in hMLH1, 4 of which were splice site mutations, 2 had frameshift mutations in hMSH2 and 1 patient with metachronous endometrial and rectal cancer but with a weak family history of cancer had a nonsense mutation in hMSH6. Our results present novel germ-line DNA-repair gene mutations, one of these in hMSH6, and demonstrate the diversified mutation spectrum in Sweden, where no founder mutation has so far been identified.
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| 18. |
- Planck, M, et al.
(författare)
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Somatic frameshift alterations in mononucleotide repeat-containing genes in different tumor types from an HNPCC family with germline MSH2 mutation
- 2000
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Ingår i: Genes, Chromosomes and Cancer. - 1045-2257. ; 29:1, s. 33-39
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Tidskriftsartikel (refereegranskat)abstract
- Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by a germline mutation in one of several DNA repair genes, which in the tumors is reflected as microsatellite instability (MSI). MSI+ tumors have been found to carry somatic frameshift mutations in mononucleotide repeats within the coding regions of several genes involved in growth control, apoptosis, and DNA repair, e.g., TGFBRII, BAX, IGFIIR, TCF4, MSH3, and MSH6. We have studied the occurrence of somatic frameshift alterations in these mononucleotide repeat-containing genes in 24 tumors (15 colorectal cancers, 1 colon adenoma, 4 endometrial cancers, 1 ovarian cancer, 1 gastric cancer, 1 urothelial cancer, and 1 duodenal cancer) from 14 individuals in an HNPCC family with germline hMSH2 mutation. Such somatic frameshift mutations occurred at a variable frequency; the long mononucleotide repeats that characterize intronic MSI markers were mutated in the majority of tumors, 13 of the tumors displayed alterations in the (A)(10) tract of TGFBII, eight tumors (all of gastrointestinal origin) had alterations in the (A)(9) repeat of TCF4, and one to five tumors had somatic frameshift alterations in the shorter mononucleotide repeats of IGFIIR, BAX, MSH3, and MSH6. Thus, longer mononucleotide repeats were more frequently affected by somatic frameshift mutations. The pattern of alterations varied between the tumors from different family members as well as between different tumors from the same individual. To what extent this variable pattern depends on the widespread mismatch repair deficiency induced by the underlying MSH2 mutation, or represents alternative ways whereby the tumors can achieve a tumorigenic phenotype, is unknown. We suggest, however, that the accumulation of somatic frameshifts, rather than the specific loci in which these occur, drives the development of the tumorigenic phenotype in HNPCC.
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| 20. |
- Salomonsson, A., et al.
(författare)
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A Nation-Wide Population-Based Mapping of Targetable Alterations in Smoking-Independent Lung Cancer
- 2018
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Ingår i: Journal of Thoracic Oncology. - : Elsevier. - 1556-0864 .- 1556-1380. ; 13:10, s. S431-S432
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)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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| 23. |
- Isaksson, Sofi, et al.
(författare)
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Pre-operative plasma cell-free circulating tumor DNA and serum protein tumor markers as predictors of lung adenocarcinoma recurrence
- 2019
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Ingår i: Acta Oncologica. - 0284-186X. ; 58:8, s. 1079-1086
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Tidskriftsartikel (refereegranskat)abstract
- Background: Lung cancer patients have a risk of recurrence even after curatively intended surgery. Cell-free circulating tumor DNA (ctDNA) and circulating tumor marker measurements are easily accessible through peripheral blood and could potentially identify patients with worse prognosis. The aim of this study was to examine ctDNA in pre-operative plasma and the role of tumor markers in pre-operative serum for their predictive potential on risk of tumor recurrence. Methods: Mutation analysis by 26-gene targeted sequencing was performed on 157 lung adenocarcinomas (ACs) from patients surgically treated at the Lund University Hospital 2005–2014. Of these, 58 tumors from patients in stages I–IIIA (34 stage I, 14 stage II and 10 stage III) with mutation(s) in EGFR, BRAF or KRAS were included. ctDNA from corresponding plasma (median 1.5 ml, range 1–1.6) was analyzed for one tumor-specific mutation in either of these three oncogenes using ultrasensitive IBSAFE droplet digital PCR (ddPCR). The tumor markers cancer antigen 125 (CA 125) and carbohydrate antigen 19-9 (CA 19-9) were analyzed in corresponding serum with electrochemiluminiscence immunoassay. Results: 6/7 patients with ctDNA and 19/51 without detected ctDNA were diagnosed with recurrence (log-rank test p =.001). 8/10 patients with positive serum tumor markers and 17/47 without tumor markers were diagnosed with recurrence (log-rank test, p =.0002). Fifteen patients had positive ctDNA and/or tumor markers, 12 of these had recurrence (log-rank test, p <.0001). Conclusion: A combination of tumor markers and ctDNA single mutation detection in low-volume pre-operative blood samples is a promising prognostic test. Prediction of recurrent disease in surgically treated early stage lung cancer can likely be further improved by using larger volumes of blood.
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| 24. |
- Malmros, Karina, et al.
(författare)
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Diagnostic gastrointestinal markers in primary lung cancer and pulmonary metastases
- 2023
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Ingår i: Virchows Archiv. - 0945-6317.
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Tidskriftsartikel (refereegranskat)abstract
- Histopathological diagnosis of pulmonary tumors is essential for treatment decisions. The distinction between primary lung adenocarcinoma and pulmonary metastasis from the gastrointestinal (GI) tract may be difficult. Therefore, we compared the diagnostic value of several immunohistochemical markers in pulmonary tumors. Tissue microarrays from 629 resected primary lung cancers and 422 resected pulmonary epithelial metastases from various sites (whereof 275 colorectal cancer) were investigated for the immunohistochemical expression of CDH17, GPA33, MUC2, MUC6, SATB2, and SMAD4, for comparison with CDX2, CK20, CK7, and TTF-1. The most sensitive markers for GI origin were GPA33 (positive in 98%, 60%, and 100% of pulmonary metastases from colorectal cancer, pancreatic cancer, and other GI adenocarcinomas, respectively), CDX2 (99/40/100%), and CDH17 (99/0/100%). In comparison, SATB2 and CK20 showed higher specificity, with expression in 5% and 10% of mucinous primary lung adenocarcinomas and both in 0% of TTF-1-negative non-mucinous primary lung adenocarcinomas (25–50% and 5–16%, respectively, for GPA33/CDX2/CDH17). MUC2 was negative in all primary lung cancers, but positive only in less than half of pulmonary metastases from mucinous adenocarcinomas from other organs. Combining six GI markers did not perfectly separate primary lung cancers from pulmonary metastases including subgroups such as mucinous adenocarcinomas or CK7-positive GI tract metastases. This comprehensive comparison suggests that CDH17, GPA33, and SATB2 may be used as equivalent alternatives to CDX2 and CK20. However, no single or combination of markers can categorically distinguish primary lung cancers from metastatic GI tract cancer.
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| 26. |
- Planck, M, et al.
(författare)
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Increased cancer risk in offspring of women with colorectal carcinoma : a Swedish register-based cohort study
- 2000
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Ingår i: Cancer. - 0008-543X. ; 89:4, s. 9-741
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Colorectal carcinoma is one of the most common malignancies in the Western population, and a considerable proportion of colorectal carcinomas are estimated to have a familial background.METHODS: Individuals whose mothers were diagnosed with colon carcinoma or rectal carcinoma from 1958 to 1993, a total of 1. 48 million person-years, constituted the cohort of this Swedish population-based register study. The children were born during the period 1941-1993, and the cancer incidence was observed during the period 1961-1993, with the expected national Swedish incidence used as a reference.RESULTS: A significantly increased risk of colon carcinoma, rectal carcinoma, and non-Hodgkin lymphoma was observed in the cohort. The cancer risk was more pronounced in children whose mothers were age < 50 years at the time of diagnosis or had developed metachronous colorectal carcinoma. Whereas colon carcinoma in the proband implied an increased risk for both colon tumors and rectal tumors, the offspring of women who were diagnosed with rectal carcinoma were at increased risk of developing rectal carcinoma, but no significantly altered risk of colon carcinoma was observed. In the cohort, the cumulative risk for colorectal carcinoma before age 50 years was increased about 3.0 times compared with the general population.CONCLUSIONS: This report shows a significant familial aggregation of colorectal carcinoma, demonstrates possible differences in hereditary pattern between colon carcinoma and rectal carcinoma, and confirms that younger age at the time of diagnosis or the occurrence of metachronous tumors indicate familial carcinoma.
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| 27. |
- Salomonsson, Annette, et al.
(författare)
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Comprehensive analysis of RNA binding motif protein 3 (RBM3) in non-small cell lung cancer
- 2020
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Ingår i: Cancer Medicine. - : Blackwell Publishing Ltd. - 2045-7634. ; 9:15, s. 5609-5619
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Tidskriftsartikel (refereegranskat)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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| 28. |
- Shahida, B., et al.
(författare)
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Simvastatin downregulates adipogenesis in 3T3-l1 preadipocytes and orbital fibroblasts from graves’ ophthalmopathy patients
- 2019
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Ingår i: Endocrine Connections. - 2049-3614. ; 8:9, s. 1230-1239
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Tidskriftsartikel (refereegranskat)abstract
- Background: Smoking is a strong risk factor for the development of Graves’ ophthalmopathy (GO). Immediate early genes (IEGs) are overexpressed in patients with active GO compared to healthy controls. The aim of this study was to study the effects of tobacco smoking and simvastatin on preadipocytes and orbital fibroblasts (OFs) in the adipogenic process. Methods: Cigarette smoke extract (CSE) was generated by a validated pump system. Mouse 3T3-L1 preadipocytes or OFs were exposed to 10% CSE with or without simvastatin. Gene expression was studied in preadipocytes and OFs exposed to CSE with or without simvastatin and compared to unexposed cells or cells treated with a differentiation cocktail. Results: In 3T3-L1 preadipocytes, Cyr61, Ptgs2, Egr1 and Zfp36 expression levels were two-fold higher in cells exposed to CSE than in unexposed cells. Simvastatin downregulated the expression of these genes (1.6-fold, 5.5-fold, 3.3-fold, 1.4-fold, respectively). CSE alone could not stimulate preadipocytes to differentiate. Scd1, Ppar-γ and adipogenesis were downregulated in simvastatin-treated preadipocytes compared to nontreated preadipocytes 18-, 35- and 1.7-fold, respectively. In OFs, similar effects of CSE were seen on the expression of CYR61 (1.4-fold) and PTGS2 (3-fold). Simvastatin downregulated adipogenesis, PPAR-γ (2-fold) and SCD (27-fold) expression in OFs. Conclusion: CSE upregulated early adipogenic genes in both mouse 3T3-L1 preadipocytes and human OFs but did not by itself induce adipogenesis. Simvastatin inhibited the expression of both early and late adipogenic genes and adipogenesis in preadipocytes and human OFs. The effect of simvastatin should be investigated in a clinical trial of patients with GO.
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| 29. |
- Shen, Sipeng, et al.
(författare)
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A multi-omic study reveals BTG2 as a reliable prognostic marker for early-stage non-small cell lung cancer
- 2018
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Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 12:6, s. 913-924
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Tidskriftsartikel (refereegranskat)abstract
- B-cell translocation gene 2 (BTG2) is a tumour suppressor protein known to be downregulated in several types of cancer. In this study, we investigated a potential role for BTG2 in early-stage non-small cell lung cancer (NSCLC) survival. We analysed BTG2 methylation data from 1230 early-stage NSCLC patients from five international cohorts, as well as gene expression data from 3038 lung cancer cases from multiple cohorts. Three CpG probes (cg01798157, cg06373167, cg23371584) that detected BTG2 hypermethylation in tumour tissues were associated with lower overall survival. The prognostic model based on methylation could distinguish patient survival in the four cohorts [hazard ratio (HR) range, 1.51-2.21] and the independent validation set (HR = 1.85). In the expression analysis, BTG2 expression was positively correlated with survival in each cohort (HR range, 0.28-0.68), which we confirmed with meta-analysis (HR = 0.61, 95% CI 0.54-0.68). The three CpG probes were all negatively correlated with BTG2 expression. Importantly, an integrative model of BTG2 methylation, expression and clinical information showed better predictive ability in the training set and validation set. In conclusion, the methylation and integrated prognostic signatures based on BTG2 are stable and reliable biomarkers for early-stage NSCLC. They may have new applications for appropriate clinical adjuvant trials and personalized treatments in the future.
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| 30. |
- Staaf, Johan, et al.
(författare)
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Diagnostic Value of Insulinoma-Associated Protein 1 (INSM1) and Comparison With Established Neuroendocrine Markers in Pulmonary Cancers : A Comprehensive Study and Review of the Literature
- 2020
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Ingår i: Archives of Pathology & Laboratory Medicine. - 0003-9985 .- 1543-2165. ; 144:9, s. 1075-1085
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Forskningsöversikt (refereegranskat)abstract
- Context.—The diagnostic distinction of pulmonary neuroendocrine (NE) tumors from non–small cell lung carcinomas (NSCLCs) is clinically relevant for prognostication and treatment. Diagnosis is based on morphology and immunohistochemical staining.Objective.—To determine the diagnostic value of insulinoma-associated protein 1 (INSM1), in comparison with established NE markers, in pulmonary tumors.Design.—Fifty-four pulmonary NE tumors and 632 NSCLCs were stained for INSM1, CD56, chromogranin A, and synaptophysin. In a subset, gene expression data were available for analysis. Also, 419 metastases to the lungs were stained for INSM1. A literature search identified 39 additional studies with data on NE markers in lung cancers from the last 15 years. Seven of these included data on INSM1.Results.—A positive INSM1 staining was seen in 39 of 54 NE tumors (72%) and 6 of 623 NSCLCs (1%). The corresponding numbers were 47 of 54 (87%) and 14 of 626 (2%) for CD56, 30 of 54 (56%) and 6 of 629 (1%) for chromogranin A, and 46 of 54 (85%) and 49 of 630 (8%) for synaptophysin, respectively. Analysis of literature data revealed that CD56 and INSM1 were the best markers for identification of high-grade NE pulmonary tumors when considering both sensitivity and specificity, while synaptophysin also showed good sensitivity. INSM1 gene expression was clearly associated with NE histology.Conclusions.—The solid data of both our and previous studies confirm the diagnostic value of INSM1 as a NE marker in pulmonary pathology. The combination of CD56 with INSM1 and/or synaptophysin should be the first-hand choice to confirm pulmonary high-grade NE tumors. INSM1 gene expression could be used to predict NE tumor histology.
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| 31. |
- Staaf, Johan, et al.
(författare)
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Diagnostic value of insulinoma-associated protein 1 (INSM1) and comparison with established neuroendocrine markers in pulmonary cancers
- 2020
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Ingår i: Archives of Pathology and Laboratory Medicine. - 0003-9985. ; 144:9, s. 1075-1085
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Tidskriftsartikel (refereegranskat)abstract
- Context.-The diagnostic distinction of pulmonary neuroendocrine (NE) tumors from non-small cell lung carcinomas (NSCLCs) is clinically relevant for prognostication and treatment. Diagnosis is based on morphology and immunohistochemical staining. Objective.-To determine the diagnostic value of insulinoma-associated protein 1 (INSM1), in comparison with established NE markers, in pulmonary tumors. Design.-Fifty-four pulmonary NE tumors and 632 NSCLCs were stained for INSM1, CD56, chromogranin A, and synaptophysin. In a subset, gene expression data were available for analysis. Also, 419 metastases to the lungs were stained for INSM1. A literature search identified 39 additional studies with data on NE markers in lung cancers from the last 15 years. Seven of these included data on INSM1. Results.-A positive INSM1 staining was seen in 39 of 54 NE tumors (72%) and 6 of 623 NSCLCs (1%). The corresponding numbers were 47 of 54 (87%) and 14 of 626 (2%) for CD56, 30 of 54 (56%) and 6 of 629 (1%) for chromogranin A, and 46 of 54 (85%) and 49 of 630 (8%) for synaptophysin, respectively. Analysis of literature data revealed that CD56 and INSM1 were the best markers for identification of high-grade NE pulmonary tumors when considering both sensitivity and specificity, while synaptophysin also showed good sensitivity. INSM1 gene expression was clearly associated with NE histology. Conclusions.-The solid data of both our and previous studies confirm the diagnostic value of INSM1 as a NE marker in pulmonary pathology. The combination of CD56 with INSM1 and/or synaptophysin should be the first-hand choice to confirm pulmonary high-grade NE tumors. INSM1 gene expression could be used to predict NE tumor histology.
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| 32. |
- Wei, Yongyue, et al.
(författare)
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Epigenetic modifications inlysine demethylases associate with survival of early-stage NSCLC
- 2018
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Ingår i: Clinical Epigenetics. - : Springer Science and Business Media LLC. - 1868-7075 .- 1868-7083. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: KDMlysine demethylase family members are related to lung cancer clinical outcomes and are potential biomarkers for chemotherapeutics. However, little is known about epigenetic alterations inKDMgenes and their roles in lung cancer survival.Methods: Tumor tissue samples of 1230 early-stage non-small cell lung cancer (NSCLC) patients were collected from the five independent cohorts. The 393 methylation sites inKDMgenes were extracted from epigenome-wide datasets and analyzed by weighted random forest (Ranger) in discovery phase and validation dataset, respectively. The variable importance scores (VIS) for the sites in top 5% of both discovery and validation sets were carried forward for Cox regression to further evaluate the association with patient's overall survival. TCGA transcriptomic data were used to evaluate the correlation with the corresponding DNA methylation.Results: DNA methylation at sites cg11637544 inKDM2Aand cg26662347 inKDM1Awere in the top 5% of VIS in both discovery phase and validation for squamous cell carcinomas (SCC), which were also significantly associated with SCC survival (HRcg11637544 = 1.32, 95%CI, 1.16-1.50,P = 1.1 × 10-4;HRcg26662347 = 1.88, 95%CI, 1.37-2.60,P = 3.7 × 10-3), and correlated with corresponding gene expression (cg11637544 forKDM2A,P = 1.3 × 10-10; cg26662347 forKDM1A P = 1.5 × 10-5). In addition, by using flexible criteria for Ranger analysis followed by survival classification tree analysis, we identified four clusters for adenocarcinomas and five clusters for squamous cell carcinomas which showed a considerable difference of clinical outcomes with statistical significance.Conclusions: These findings highlight the association between somatic DNA methylation inKDMgenes and early-stage NSCLC patient survival, which may reveal potential epigenetic therapeutic targets.
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