| 21. |
- Gram, Inger T, et al.
(författare)
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Cigarette smoking and risk of histological subtypes of epithelial ovarian cancer in the EPIC cohort study
- 2012
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 130:9, s. 2204-2210
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Tidskriftsartikel (refereegranskat)abstract
- New data regarding a positive association between smoking and risk of epithelial ovarian cancer (EOC), especially the mucinous tumor type, has started to emerge. The purpose of this study was to examine the association between different measures of smoking exposures and subtypes of EOC in a large cohort of women from 10 European countries. The European Prospective Investigation into Cancer and Nutrition (EPIC) cohort is a multicenter prospective study initiated in 1992. The questionnaires included data about dietary, lifestyle, and health factors. Information about cigarette smoking was collected from individuals in all participating countries. We used Cox proportional hazard regression models to estimate hazard ratio (HR) of EOC overall and serous, mucinous, and endometroid histological subtypes, with 95% confidence intervals (CIs) associated with different measures of smoking exposures adjusting for confounding variables. Altogether 836 incident EOC cases were identified among 326,831 women. The tumors were classified as 400 serous, 83 mucinous, 80 endometroid, 35 clear cell, and 238 unspecified. Compared with never smokers, current smokers had a significantly increased risk for mucinous tumors [HR = 1.85 (95% CI 1.08-3.16)] and those smoking more than 10 cigarettes per day had a doubling in risk [HR = 2.25(95% CI 1.26-4.03)] as did those who had smoked less than 15 pack-years of cigarettes [HR = 2.18 (95% CI 1.07-4.43)]. The results from the EPIC study add further evidence that smoking increases risk of mucinous ovarian cancer and support the notion that the effect of smoking varies according to histological subtype.
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| 22. |
- Grinberg, Marianna, et al.
(författare)
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Reaching the limits of prognostication in non-small cell lung cancer : an optimized biomarker panel fails to outperform clinical parameters.
- 2017
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Ingår i: Modern Pathology. - : Elsevier BV. - 0893-3952 .- 1530-0285. ; 30:7, s. 964-977
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Tidskriftsartikel (refereegranskat)abstract
- Numerous protein biomarkers have been analyzed to improve prognostication in non-small cell lung cancer, but have not yet demonstrated sufficient value to be introduced into clinical practice. Here, we aimed to develop and validate a prognostic model for surgically resected non-small cell lung cancer. A biomarker panel was selected based on (1) prognostic association in published literature, (2) prognostic association in gene expression data sets, (3) availability of reliable antibodies, and (4) representation of diverse biological processes. The five selected proteins (MKI67, EZH2, SLC2A1, CADM1, and NKX2-1 alias TTF1) were analyzed by immunohistochemistry on tissue microarrays including tissue from 326 non-small cell lung cancer patients. One score was obtained for each tumor and each protein. The scores were combined, with or without the inclusion of clinical parameters, and the best prognostic model was defined according to the corresponding concordance index (C-index). The best-performing model was subsequently validated in an independent cohort consisting of tissue from 345 non-small cell lung cancer patients. The model based only on protein expression did not perform better compared to clinicopathological parameters, whereas combining protein expression with clinicopathological data resulted in a slightly better prognostic performance (C-index: all non-small cell lung cancer 0.63 vs 0.64; adenocarcinoma: 0.66 vs 0.70, squamous cell carcinoma: 0.57 vs 0.56). However, this modest effect did not translate into a significantly improved accuracy of survival prediction. The combination of a prognostic biomarker panel with clinicopathological parameters did not improve survival prediction in non-small cell lung cancer, questioning the potential of immunohistochemistry-based assessment of protein biomarkers for prognostication in clinical practice.Modern Pathology advance online publication, 10 March 2017; doi:10.1038/modpathol.2017.14.
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| 23. |
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| 24. |
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| 25. |
- Karlsson, Anna K, et al.
(författare)
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Mutational and gene fusion analyses of primary large cell and large cell neuroendocrine lung cancer.
- 2015
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Ingår i: Oncotarget. - 1949-2553. ; 6:26, s. 22028-22037
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Tidskriftsartikel (refereegranskat)abstract
- Large cell carcinoma with or without neuroendocrine features (LCNEC and LC, respectively) constitutes 3-9% of non-small cell lung cancer but is poorly characterized at the molecular level. Herein we analyzed 41 LC and 32 LCNEC (including 15 previously reported cases) tumors using massive parallel sequencing for mutations in 26 cancer-related genes and gene fusions in ALK, RET, and ROS1. LC patients were additionally subdivided into three immunohistochemistry groups based on positive expression of TTF-1/Napsin A (adenocarcinoma-like, n = 24; 59%), CK5/P40 (squamous-like, n = 5; 12%), or no marker expression (marker-negative, n = 12; 29%). Most common alterations were TP53 (83%), KRAS (22%), MET (12%) mutations in LCs, and TP53 (88%), STK11 (16%), and PTEN (13%) mutations in LCNECs. In general, LCs showed more oncogene mutations compared to LCNECs. Immunomarker stratification of LC revealed oncogene mutations in 63% of adenocarcinoma-like cases, but only in 17% of marker-negative cases. Moreover, marker-negative LCs were associated with inferior overall survival compared with adenocarcinoma-like tumors (p = 0.007). No ALK, RET or ROS1 fusions were detected in LCs or LCNECs. Together, our molecular analyses support that LC and LCNEC tumors follow different tumorigenic paths and that LC may be stratified into molecular subgroups with potential implications for diagnosis, prognostics, and therapy decisions.
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| 26. |
- Karlsson, E., et al.
(författare)
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Clonal alteration of breast cancer receptors between primary ductal carcinoma in situ (DCIS) and corresponding local events
- 2014
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 1879-0852 .- 0959-8049. ; 50:3, s. 517-524
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Tidskriftsartikel (refereegranskat)abstract
- Background: Emerging data propose biomarker alteration due to clonal selection between the primary invasive breast cancer and corresponding metastases. In addition, impact on survival has been demonstrated. The present study investigates the relationship between the oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) between primary ductal carcinoma in situ (DCIS) and intra-individually matched ipsilateral event. Materials and methods: The cohort includes 1504 patients, diagnosed with a primary DCIS between 1986 and 2004. Of the 274 patients who developed a local relapse, 135 developed a new in situ carcinoma and 139 an invasive cancer up to 31st December 2011. ER and PR were identified by immunohistochemistry (IHC) and HER2 by silver-enhanced in situ hybridisation (SISH) as well as IHC. Results: ER (n = 112), PR (n = 113) and HER2 (n = 114) status from both the primary DCIS and the corresponding relapse were assessed and were demonstrated to be discordant in 15.1%, 29.2% and 10.5% respectively. The receptor conversion was both from negative to positive and from positive to negative with no general pattern being seen in spite of sub-dividing into in situ relapse and invasive relapse. However, primary DCIS was HER2 positive in 40.3% whereas in situ and invasive relapses were HER2 positive in 42.9% and 34.5% respectively. Conclusions: Receptor conversion for ER, PR and HER2 status occurred between primary DCIS and corresponding local relapse in 10-30%. This study could not confirm that HER2 overexpression in primary DCIS had any impact on tumour progression to invasive cancer which has been proposed. (C) 2013 Elsevier Ltd. All rights reserved.
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| 27. |
- Magnusson, Kristina, et al.
(författare)
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SATB2 in Combination With Cytokeratin 20 Identifies Over 95% of all Colorectal Carcinomas
- 2011
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Ingår i: American Journal of Surgical Pathology. - 0147-5185 .- 1532-0979. ; 35:7, s. 937-948
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Tidskriftsartikel (refereegranskat)abstract
- The special AT-rich sequence-binding protein 2 (SATB2), a nuclear matrix-associated transcription factor and epigenetic regulator, was identified as a tissue type-specific protein when screening protein expression patterns in human normal and cancer tissues using an antibody-based proteomics approach. In this respect, the SATB2 protein shows a selective pattern of expression and, within cells of epithelial lineages, SATB2 expression is restricted to glandular cells lining the lower gastrointestinal tract. The expression of SATB2 protein is primarily preserved in cancer cells of colorectal origin, indicating that SATB2 could function as a clinically useful diagnostic marker to distinguish colorectal cancer (CRC) from other types of cancer. The aim of this study was to further explore and validate the specific expression pattern of SATB2 as a clinical biomarker and to compare SATB2 with the well-known cytokeratin 20 (CK20). Immunohistochemistry was used to analyze the extent of SATB2 expression in tissue microarrays with tumors from 9 independent cohorts of patients with primary and metastatic CRCs (n = 1882). Our results show that SATB2 is a sensitive and highly specific marker for CRC with distinct positivity in 85% of all CRCs, and that SATB2 and/or CK20 was positive in 97% of CRCs. In conclusion, the specific expression of SATB2 in a large majority of CRCs suggests that SATB2 can be used as an important complementary tool for the differential diagnosis of carcinoma of unknown primary origin.
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| 28. |
- Michaut, Magali, et al.
(författare)
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Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer.
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Invasive lobular carcinoma (ILC) is the second most frequently occurring histological breast cancer subtype after invasive ductal carcinoma (IDC), accounting for around 10% of all breast cancers. The molecular processes that drive the development of ILC are still largely unknown. We have performed a comprehensive genomic, transcriptomic and proteomic analysis of a large ILC patient cohort and present here an integrated molecular portrait of ILC. Mutations in CDH1 and in the PI3K pathway are the most frequent molecular alterations in ILC. We identified two main subtypes of ILCs: (i) an immune related subtype with mRNA up-regulation of PD-L1, PD-1 and CTLA-4 and greater sensitivity to DNA-damaging agents in representative cell line models; (ii) a hormone related subtype, associated with Epithelial to Mesenchymal Transition (EMT), and gain of chromosomes 1q and 8q and loss of chromosome 11q. Using the somatic mutation rate and eIF4B protein level, we identified three groups with different clinical outcomes, including a group with extremely good prognosis. We provide a comprehensive overview of the molecular alterations driving ILC and have explored links with therapy response. This molecular characterization may help to tailor treatment of ILC through the application of specific targeted, chemo- and/or immune-therapies.
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| 29. |
- Nyström, Jenny, 1972, et al.
(författare)
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CRIM1 is localized to the podocyte filtration slit diaphragm of the adult human kidney
- 2009
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Ingår i: Nephrol Dial Transplant. - : Oxford University Press (OUP). - 1460-2385 .- 1460-2385 .- 0931-0509. ; 24:7, s. 2038-44
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: CRIM1 is a plasma membrane bound protein containing six cysteine-rich repeats (CRR). Through these, CRIM1 has been shown to interact with a subgroup of the TGF-beta superfamily, the bone morphogenic proteins (BMP) isoforms 2, 4 and 7. The probable action is to modulate the signalling properties of these factors. CRIM1 has also been shown to regulate the release of VEGFA by podocytes during renal organogenesis. Knock-out studies in mice have shown that CRIM1 is critically involved in the development of the central nervous system, eye and kidney. Replacement of CRIM1 with a defective version leads to renal dysgenesis and perinatal death. We have analysed the distribution of CRIM1 in adult human renal tissue. METHODS: To this end, we have used immunofluorescence, immunohistochemistry and immunoelectron microscopy. We performed western blotting for the CRIM1 protein, using lysates from isolated glomerular podocytes and human renal tissue homogenate. By using quantitative PCR, we compared the CRIM1 mRNA levels in podocytes, human renal tissue homogenate, primary human renal proximal tubular epithelial cells and primary human pulmonary artery smooth muscle cells. RESULTS: The results show that in the human adult kidney, CRIM1 is mainly expressed in the glomerular podocytes and is associated with the insertional region of the filtration slit diaphragm (SD) of the podocyte pedicles. CONCLUSIONS: CRIM1 is a protein that should be added to the list of proteins associated with the podocyte filtration SD and with the probable action of modulating BMP and VEGFA signalling.
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| 30. |
- Richards, Cathy E., et al.
(författare)
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Development of a novel weighted ranking method for immunohistochemical quantification of a heterogeneously expressed protein in gastro-esophageal cancers
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:6
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Tidskriftsartikel (refereegranskat)abstract
- High expression of Junctional Adhesion Molecule-A (JAM-A) has been linked with poor prognosis in several cancers, including breast cancers overexpressing the human epidermal growth factor receptor-2 (HER2). Furthermore, JAM-A expression has been linked with regulating that of HER2, and associated with the development of resistance to HER2-targeted therapies in breast cancer patients. The purpose of this study was to establish a potential relationship between JAM-A and HER2 in HER2-overexpressing gastro-esophageal (GE) cancers. Interrogation of gene expression datasets revealed that high JAM-A mRNA expression was associated with poorer survival in HER2-positive gastric cancer patients. However, high intra-tumoral heterogeneity of JAM-A protein expression was noted upon immunohistochemical scoring of a GE cancer tissue microarray (TMA), precluding a simple confirmation of any relationship between JAM-A and HER2 at protein level. However, in a test-set of 25 full-face GE cancer tissue sections, a novel weighted ranking system proved effective in capturing JAM-A intra-tumoral heterogeneity and confirming statistically sig-nificant correlations between JAM-A/HER2 expression. Given the growing importance of immuno-histochemistry in stratifying cancer patients for the receipt of new targeted therapies, this may sound a cautionary note against over-relying on cancer TMAs in biomarker discovery studies of heterogeneously expressed proteins. It also highlights a timely need to develop validated mechanisms of capturing intra-tumoral heterogeneity to aid in future biomarker/therapeutic target development for the benefit of cancer patients.
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