| 1. |
- Bradbury, Kathryn E., et al.
(författare)
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Circulating insulin-like growth factor I in relation to melanoma risk in the European prospective investigation into cancer and nutrition
- 2019
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 144:5, s. 957-966
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Tidskriftsartikel (refereegranskat)abstract
- Insulin-like growth factor-I (IGF-I) regulates cell proliferation and apoptosis, and is thought to play a role in tumour development. Previous prospective studies have shown that higher circulating concentrations of IGF-I are associated with a higher risk of cancers at specific sites, including breast and prostate. No prospective study has examined the association between circulating IGF-I concentrations and melanoma risk. A nested case-control study of 1,221 melanoma cases and 1,221 controls was performed in the European Prospective Investigation into Cancer and Nutrition cohort, a prospective cohort of 520,000 participants recruited from 10 European countries. Conditional logistic regression was used to estimate odds ratios (ORs) for incident melanoma in relation to circulating IGF-I concentrations, measured by immunoassay. Analyses were conditioned on the matching factors and further adjusted for age at blood collection, education, height, BMI, smoking status, alcohol intake, marital status, physical activity and in women only, use of menopausal hormone therapy. There was no significant association between circulating IGF-I concentration and melanoma risk (OR for highest vs lowest fifth = 0.93 [95% confidence interval [CI]: 0.71 to 1.22]). There was no significant heterogeneity in the association between IGF-I concentrations and melanoma risk when subdivided by gender, age at blood collection, BMI, height, age at diagnosis, time between blood collection and diagnosis, or by anatomical site or histological subtype of the tumour (Pheterogeneity≥0.078). We found no evidence for an association between circulating concentrations of IGF-I measured in adulthood and the risk of melanoma.
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| 2. |
- Edin, Sofia, et al.
(författare)
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Opposing roles by KRAS and BRAF mutation on immune cell infiltration in colorectal cancer : possible implications for immunotherapy
- 2024
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Ingår i: British Journal of Cancer. - : Springer Nature. - 0007-0920 .- 1532-1827. ; 130
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Tidskriftsartikel (refereegranskat)abstract
- Background: The immune response has important clinical value in colorectal cancer (CRC) in both prognosis and response to immunotherapy. This study aims to explore tumour immune cell infiltration in relation to clinically well-established molecular markers of CRC.Methods: Multiplex immunohistochemistry and multispectral imaging was used to evaluate tumour infiltration of cytotoxic T cells (CD8+), Th1 cells (T-bet+), T regulatory cells (FoxP3+), B cells (CD20+), and macrophages (CD68+) in a cohort of 257 CRC patients.Results: We found the expected association between higher immune-cell infiltration and microsatellite instability. Also, whereas BRAF-mutated tumours displayed increased immune-cell infiltration compared to BRAF wild-type tumours, the opposite was seen for KRAS-mutated tumours, differences that were most prominent for cytotoxic T cells and Th1 cells. The opposing relationships of BRAF and KRAS mutations with tumour infiltration of cytotoxic T cells was validated in an independent cohort of 608 CRC patients. A positive prognostic importance of cytotoxic T cells was found in wild-type as well as KRAS and BRAF-mutated CRCs in both cohorts.Conclusion: A combined evaluation of MSI status, KRAS and BRAF mutational status, and immune infiltration (cytotoxic T cells) may provide important insights to prognosis and response to immunotherapy in CRC.
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| 3. |
- Edwinsdotter Ardnor, Christina, et al.
(författare)
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The BRCA1 exon 13 duplication : clinical characteristics of 22 families in Northern Sweden
- 2019
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Ingår i: Familial Cancer. - : Springer. - 1389-9600 .- 1573-7292. ; 18:1, s. 37-42
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Tidskriftsartikel (refereegranskat)abstract
- The clinical management of BRCA1/2 mutation carriers requires accurate cancer risk estimates. Cancer risks vary according to type and location of the mutation and since there is limited information about mutation-specific cancer risks, genotype-phenotype correlation studies are needed. This is a report of 22 families with the same mutation, BRCA1 duplication exon 13, a mutation that is found world-wide, with the objective to describe the cancer history found in these families. We studied 69 confirmed carriers, 53 women and 16 men, and additionally 29 women who were clinically expected carriers. Among the confirmed carriers, 27 women (51%) were diagnosed with breast cancer, 10 (19%) with ovarian cancer, 5 (9%) with breast and ovarian cancer and 17 (32%) without cancer. Nine women (17%) with breast cancer were 35 years or younger at diagnose. Also, two cases of early onset colon cancer were found, and 37,5% of the male carriers were diagnosed with prostate cancer. These data may have implications for risk assessment and cancer prevention decision making for carriers of the BRCA1 duplication exon 13 mutation.
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| 4. |
- Faraz, Mahmood, et al.
(författare)
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LRIG1 gene copy number analysis by ddPCR and correlations to clinical factors in breast cancer
- 2020
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Ingår i: BMC Cancer. - : BioMed Central. - 1471-2407. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) copy number alterations and unbalanced gene recombination events have been reported to occur in breast cancer. Importantly, LRIG1 loss was recently shown to predict early and late relapse in stage I-II breast cancer.Methods: We developed droplet digital PCR (ddPCR) assays for the determination of relative LRIG1 copy numbers and used these assays to analyze LRIG1 in twelve healthy individuals, 34 breast tumor samples previously analyzed by fluorescence in situ hybridization (FISH), and 423 breast tumor cytosols.Results: Four of the LRIG1/reference gene assays were found to be precise and robust, showing copy number ratios close to 1 (mean, 0.984; standard deviation, +/-0.031) among the healthy control population. The correlation between the ddPCR assays and previous FISH results was low, possibly because of the different normalization strategies used. One in 34 breast tumors (2.9%) showed an unbalanced LRIG1 recombination event. LRIG1 copy number ratios were associated with the breast cancer subtype, steroid receptor status, ERBB2 status, tumor grade, and nodal status. Both LRIG1 loss and gain were associated with unfavorable metastasis-free survival; however, they did not remain significant prognostic factors after adjustment for common risk factors in the Cox regression analysis. Furthermore, LRIG1 loss was not significantly associated with survival in stage I and II cases.Conclusions: Although LRIG1 gene aberrations may be important determinants of breast cancer biology, and prognostic markers, the results of this study do not verify an important role for LRIG1 copy number analyses in predicting the risk of relapse in early-stage breast cancer.
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| 5. |
- Kerdreux, Maïwenn, et al.
(författare)
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Porphyromonas gingivalis in colorectal cancer and its association to patient prognosis
- 2023
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Ingår i: Journal of Cancer. - : Ivyspring International Publisher. - 1837-9664. ; 14:9, s. 1479-1485
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Tidskriftsartikel (refereegranskat)abstract
- Microbiota dysbiosis may affect both the development and progression of colorectal cancer (CRC). Large metagenomic studies have highlighted specific oral bacteria linked to CRC including Porphyromonas gingivalis. Few studies have however analysed the implications of this bacterium in CRC progression and survival. In this study, we investigated the intestinal presence of P. gingivalis by qPCR in both faecal and mucosal samples from two different patient cohorts, including patients with precancerous dysplasia or CRC, as well as controls. P. gingivalis was detected in 2.6-5.3% of CRC patients and significantly different levels of P. gingivalis were found in faeces of CRC patients compared to controls (P = 0.028). Furthermore, an association was found between the presence of P. gingivalis in faeces and tumour tissue (P < 0.001). Our findings further suggested a potential link between mucosal P. gingivalis and tumours of MSI subtype (P = 0.040). Last but not least, patients with faecal P. gingivalis were found to have a significantly decreased cancer-specific survival (P = 0.040). In conclusion, P. gingivalis could be linked to patients with CRC and to a worse patient prognosis. Further studies are needed to elucidate the role of P. gingivalis in CRC pathogenesis.
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| 6. |
- Li, Xingru, et al.
(författare)
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A Detailed Flow Cytometric Analysis of Immune Activity Profiles in Molecular Subtypes of Colorectal Cancer
- 2020
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 12:11
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Tidskriftsartikel (refereegranskat)abstract
- The local anti-tumour immune response has important prognostic value in colorectal cancer (CRC). In the era of immunotherapy, a better understanding of the immune response in molecular subgroups of CRC may lead to significant advances in personalised medicine. On this note, microsatellite instable (MSI) tumours have been characterised by increased immune infiltration, suggesting MSI as a marker for immune inhibitor checkpoint therapy. Here, we used flow cytometry to perform a comprehensive analysis of immune activity profiles in tumour tissues, adjacent non-malignant tissues and blood, from a cohort of 69 CRC patients. We found several signs of immune suppression in tumours compared to adjacent non-malignant tissues, including T cells more often expressing the immune checkpoint molecules programmed cell death protein (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). We further analysed immune cell infiltration in molecular subgroups of CRC. MSI tumours were indeed found to be associated with increased immune infiltration, including increased fractions of PD-1+ T cells. No correlation was, however, found between MSI and the fraction of CTLA-4+ T cells. Interestingly, within the group of patients with microsatellite stable (MSS) tumours, some also presented with increased immune infiltration, including comparably high portions of PD-1+ T cells, but also CTLA-4+ T cells. Furthermore, no correlation was found between PD-1+ and CTLA-4+ T cells, suggesting that different tumours may, to some extent, be regulated by different immune checkpoints. We further evaluated the distribution of immune activity profiles in the consensus molecular subtypes of CRC. In conclusion, our findings suggest that different immune checkpoint inhibitors may be beneficial for selected CRC patients irrespective of MSI status. Improved predictive tools are required to identify these patients.
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| 7. |
- Li, Xingru, et al.
(författare)
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A modified protein marker panel to identify four consensus molecular subtypes in colorectal cancer using immunohistochemistry
- 2021
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Ingår i: Pathology, Research and Practice. - : Elsevier. - 0344-0338 .- 1618-0631. ; 220
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is a heterogeneous disease with different genetic and molecular backgrounds, leading to a diverse patient prognosis and treatment response. Four consensus molecular subtypes (CMS 1–4) have recently been proposed based on transcriptome profiling. A clinically practical immunohistochemistry (IHC) based CMS classifier consisting of the four markers FRMD6, ZEB1, HTR2B, and CDX2 was then demonstrated. However, the IHC-CMS classifier did not distinguish between CMS2 and CMS3 tumours. In this study, we have applied the proposed transcriptome based and IHC-based CMS classifiers in a CRC cohort of 65 patients and found a concordance of 77.5 %. Further, we modified the IHC-CMS classifier by analysing the differentially expressed genes between CMS2 and CMS3 tumours using RNA-sequencing data from the TCGA dataset. The result showed that WNT signalling was among the most upregulated pathways in CMS2 tumours, and the expression level of CTNNB1 (encoding β-catenin), a WNT pathway hallmark, was significantly upregulated (P = 1.15 × 10−6). We therefore introduced nuclear β-catenin staining to the IHC-CMS classifier. Using the modified classifier in our cohort, we found a 71.4 % concordance between the IHC and RNA-sequencing based CMS classifiers. Moreover, β-catenin staining could classify 16 out of the 19 CMS2/3 tumours into CMS2 or CMS3, thereby showing an 84.2 % concordance with the RNA-sequencing-based classifier. In conclusion, we evaluated CMS classifiers based on transcriptome and IHC analysis. We present a modified IHC panel that categorizes CRC tumours into the four CMS groups. To our knowledge, this is the first study using IHC to identify all four CMS groups.
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| 8. |
- Li, Xingru, et al.
(författare)
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Ex Vivo Organoid Cultures Reveal the Importance of the Tumor Microenvironment for Maintenance of Colorectal Cancer Stem Cells
- 2020
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is a heterogeneous disease, with varying clinical presentations and patient prognosis. Different molecular subgroups of CRC should be treated differently and therefore, must be better characterized. Organoid culture has recently been suggested as a good model to reflect the heterogeneous nature of CRC. However, organoid cultures cannot be established from all CRC tumors. The study examines which CRC tumors are more likely to generate organoids and thus benefit from ex vivo organoid drug testing. Long-term organoid cultures from 22 out of 40 CRC tumor specimens were established. It was found that organoid cultures were more difficult to establish from tumors characterized as microsatellite instable (MSI), BRAF-mutated, poorly differentiated and/or of a mucinous type. This suggests that patients with such tumors are less likely to benefit from ex vivo organoid drug testing, but it may also suggest biological difference in tumor growth. RNA sequencing analysis of tumor sections revealed that the in vivo maintenance of these non-organoid-forming tumors depends on factors related to inflammation and pathogen exposure. Furthermore, using TCGA data we could show a trend towards a worse prognosis for patients with organoid-forming tumors, suggesting also clinical differences. Results suggest that organoids are more difficult to establish from tumors characterized as MSI, BRAF-mutated, poorly differentiated and/or of a mucinous type. We further suggest that the maintenance of cell growth of these tumors in vivo may be promoted by immune-related factors and other stromal components within the tumor microenvironment.
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| 9. |
- Lindgren, Moa, 1990-
(författare)
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Type IV collagen in breast and colorectal cancer : a potential biomarker of metastatic disease
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Metastatic colorectal cancer (mCRC) and metastatic breast cancer (mBC) are two leading causes of cancer-related mortality worldwide. Early detection of metastatic disease is critical, and sensitive, easily accessed and cost-effective biomarkers that can diagnose mBC and mCRC at an early stage would have high clinical value. The best circulating markers: CEA and CA 15-3 are suboptimal, but a combination with other proteins can improve their potential to detect metastatic disease. One potential source of new biomarkers is the tumor stroma, including the extracellular matrix (ECM), vasculature, and stromal cells like immune cells and fibroblasts. Both the tumor cell and stromal compartment are vital for cancer progression. A combination of biomarkers from both compartments could likely best reflect the heterogeneous nature of the metastatic disease. Stromal type IV collagen (COL IV) is the main constituent of the basement membrane of healthy tissues. COL IV is upregulated with some cancers, including colorectal liver metastases (CLM), and is considered a potential biomarker for CLM. The origin of elevated levels of COL IV in CLM is not known but may result from both increased ECM production and ECM degradation associated with cancer-related tumor stroma remodeling. Aims: In this thesis, COL IV and its potential to be used as a biomarker for mCRC and mBC is studied, with a specific emphasis on liver metastases. The aims are to compare levels of circulating COL IV (cCOL IV) in mCRC and mBC patients with controls and evaluate its diagnostic and prognostic value; to evaluate the combination of cCOL IV with other proteins; to determine the cellular origin of COL IV in CLM and study COL IV expression in cell lines; to study the expression of COL IV degrading proteases in CLM and to evaluate tissue expression of COL IV in bone and liver metastases from BC patients. Methods: Plasma levels of cCOL IV, CA 15-3, CEA, and other cancer-related proteins were analyzed with ELISA, ECLIA and Multiplex assay in mCRC and mBC patients, healthy controls and patients with primary CRC or BC as controls. The cellular origin of COL IV expression in CLM was examined with in situ hybridization, and the expression of COL IV in mBC tissue and COL IV degrading proteases (MMP -2, -7, -9 and -13) in CLMs were studied with immunohistochemistry. COL IV expression in CRC and fibroblast cell lines was analyzed with immunofluorescence.Results: cCOL IV is elevated in mBC patients and correlates with poor survival. The combination of cCOL IV with CA 15-3 and cCOL IV alone are superior to CA 15-3 at detecting mBC. COL IV is highly expressed in the tissue of liver- and bone BC metastases. Circulating COL IV, CEA, OPN, CYFRA 21-1, IL-8, HGF, and MIF are elevated, and TRAIL is lower in mCRC patients compared with controls. COL IV, CEA, OPN, CYFRA 21-1, and IL-8 were higher, and TRAIL was lower in mCRC patients with liver metastases compared to patients with extrahepatic disease. Circulating CEA, OPN, and HGF are very good, and cCOL IV is acceptable at distinguishing mCRC patients from patients with primary CRC. The combination of OPN + CEA is superior to CEA alone at detecting mCRC. High HGF and cCOL IV (one cohort) in mCRC patients correlate to poor prognosis. cCOL IV is elevated in CLM patients compared to healthy controls and is very good at discriminating between healthy controls and CLM patients. COL IV is expressed in CLM by cancer-associated fibroblasts, and COL IV degrading proteases are expressed primarily by stromal cells in CLM. COL IV is expressed by fibroblasts, not tumor cells, in vitro. Conclusion: cCOL IV is a promising tumor marker of metastatic BC and CRC and circulating HGF and OPN are potential biomarkers of mCRC. Our results show that the metastatic site can impact the circulating levels of numerous cancer-related proteins, which aligns with our hypothesis that combining biomarkers instead of using one might be best for detecting metastatic cancer through blood analysis. COL IV is expressed by stromal cells, not tumor cells, in CLM tissue and in vitro.
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| 10. |
- Lindgren, Moa, et al.
(författare)
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Type IV Collagen in Human Colorectal Liver Metastases—Cellular Origin and a Circulating Biomarker
- 2022
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 14:14
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Tidskriftsartikel (refereegranskat)abstract
- Circulating type IV collagen (cCOL IV) is a potential biomarker for patients with colorectal liver metastases (CLM) who present with elevated levels of COL IV in both CLM tissue and circulation. This study aimed to establish the cellular origin of elevated levels of COL IV and analyze circulating COL IV in CLM patients. The cellular source was established through in situ hybridization, immunohistochemical staining, and morphological evaluation. Cellular expression in vitro was assessed by immunofluorescence. Tissue expression of COL IV-degrading matrix metalloproteinases (MMPs)-2, -7, -9, and -13 was studied with immunohistochemical staining. Plasma levels of COL IV in CLM patients and healthy controls were analyzed with ELISA. This study shows that cancer-associated fibroblasts (CAFs) express COL IV in the stroma of CLM and that COL IV is expressed in vitro by fibroblasts but not by tumor cells. MMP-2, -7, -9, and -13 are expressed in CLM tissue, mainly by hepatocytes and immune cells, and circulating COL IV is significantly elevated in CLM patients compared with healthy controls. Our study shows that stromal cells, not tumor cells, produce COL IV in CLM, and that circulating COL IV is elevated in patients with CLM.
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