Development and validation of circulating protein signatures as diagnostic biomarkers for biliary tract cancer

Christensen, Trine; Maag, Emil; Larsen, Olav; Feltoft, Claus Larsen; Nielsen, Kaspar René; Jensen, Lars Henrik; Leerhøy, Bonna; Hansen, Carsten P.; Chen, Inna M.; Nielsen, Dorte; Johansen, Julia S.

doi:10.1016/j.jhepr.2022.100648

Cited by 3 publications

(4 citation statements)

References 47 publications

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“…The six proteins most prominently associated with OS (IL-6, IL-15, PD-L1, MUC-16, HGF, and PGF) were all elevated in patients with BTC as compared with controls (Figure S1 and submitted data). Our previous study also identified a potential diagnostic role of multiprotein signatures [28].…”

Section: Discussionmentioning

confidence: 73%

“…The use of the circulating proteins investigated here in patients with BTC is not limited to prognostic applications. Of the 44 proteins significantly associated with OS in the discovery cohort, 39 have been shown to have elevated plasma levels in patients with BTC as compared to controls (Figure S7) [28]. The six proteins most prominently associated with OS (IL-6, IL-15, PD-L1, MUC-16, HGF, and PGF) were all elevated in patients with BTC as compared with controls (Figure S1 and submitted data).…”

Section: Discussionmentioning

confidence: 94%

“…This complex cross-talk can stimulate tumor growth, invasion, angiogenesis, immunosuppression, and metastatic spread, as well as extracellular matrix modulation and inflammation [2,17,[25][26][27]. Several of the proteins released as part of this process leak to the bloodstream, leading to changes in the blood proteome, and many proteins have been found elevated in patients with BTC compared to controls [27,28]. However, very few proteins have been tested as prognostic markers, creating the great potential for new studies.…”

Section: Introductionmentioning

confidence: 99%

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Protein Signatures and Individual Circulating Proteins, including IL-6 and IL-15, Associated with Prognosis in Patients with Biliary Tract Cancer

Christensen

Madsen

Maag³

et al. 2023

Cancers

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Biliary tract cancer (BTC) is a rare gastrointestinal cancer with a dismal prognosis. Biomarkers with clinical utility are needed. In this study, we investigated the association between survival and 89 immuno-oncology-related proteins, with the aim of identifying prognostic biomarkers for BTC. The study included patients with BTC (n = 394) treated at three Danish hospitals. Patients were divided into four cohorts: the first-line discovery cohort (n = 202), first-line validation cohort (n = 118), second-line cohort (n = 56), and surgery cohort (n = 41). Plasma protein levels were measured using a proximity extension assay (Olink Proteomics). Twenty-seven proteins were associated with overall survival (OS) in a multivariate analysis in the discovery cohort. In the first-line validation cohort, high levels of interleukin (IL)-6, IL-15, mucin 16, hepatocyte growth factor, programmed cell death ligand 1, and placental growth factor were significantly associated with poor OS in univariate Cox regression analyses. When adjusting for performance status, location, and stage, the association was significant only for IL-6 (hazard ratio (HR) = 1.25, 95% confidence interval (CI) 1.08–1.46) and IL-15 (HR = 2.23, 95% CI 1.48–3.35). Receiver operating characteristic analyses confirmed IL-6 and IL-15 as the strongest predictors of survival. Combining several proteins into signatures further improved the ability to distinguish between patients with short (<6 months) and long survival (>18 months). The study identified several circulating proteins as prognostic biomarkers in patients, with BTC, IL-6, and IL-15 being the most promising markers. Combining proteins in a prognostic signature improved prognostic performance, but future studies are needed to determine the optimal combination and thresholds.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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Protein Signatures and Individual Circulating Proteins, including IL-6 and IL-15, Associated with Prognosis in Patients with Biliary Tract Cancer

Christensen

Madsen

Maag³

et al. 2023

Cancers

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“…Early detection and valid treatment options for PC have long been a formidable challenge. To overcome this obstacle, increasing attention has been paid to the complex interaction of plasma proteins and cancers in recent years: on the one hand, the onset and development of tumors could be accompanied by alteration in concentration of circulating proteins due to the secretion by oncocytes and tumor-associated stromal and immune cells, and these proteins might serve as valuable biomarkers for diagnosis and prognosis prediction [ 15 , 57 , 58 ]; on the other hand, these proteins are involved in multiple process of carcinogenesis, tumor invasion, metastasis, and shaping the tumor microenvironment [ 59 , 60 ]. Given the above facts, it is worthwhile to give a deep insight into the causal relationship between plasma protein and PC to assist efficient identification of potential diagnostic markers and interference targets by applying advanced analytic methodology with high-support evidence and less likelihood for confounding bias.…”

Section: Discussionmentioning

confidence: 99%

Integrating plasma protein-centric multi-omics to identify potential therapeutic targets for pancreatic cancer

Zhou,

Tao,

Guo

et al. 2024

J Transl Med

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Background Deciphering the role of plasma proteins in pancreatic cancer (PC) susceptibility can aid in identifying novel targets for diagnosis and treatment. Methods We examined the relationship between genetically determined levels of plasma proteins and PC through a systemic proteome-wide Mendelian randomization (MR) analysis utilizing cis-pQTLs from multiple centers. Rigorous sensitivity analyses, colocalization, reverse MR, replications with varying instrumental variable selections and additional datasets, as well as subsequent meta-analysis, were utilized to confirm the robustness of significant findings. The causative effect of corresponding protein-coding genes’ expression and their expression pattern in single-cell types were then investigated. Enrichment analysis, between-protein interaction and causation, knock-out mice models, and mediation analysis with established PC risk factors were applied to indicate the pathogenetic pathways. These candidate targets were ultimately prioritized upon druggability and potential side effects predicted by a phenome-wide MR. Results Twenty-one PC-related circulating proteins were identified in the exploratory phase with no evidence for horizontal pleiotropy or reverse causation. Of these, 11 were confirmed in a meta-analysis integrating external validations. The causality at a transcription level was repeated for neutrophil elastase, hydroxyacylglutathione hydrolase, lipase member N, protein disulfide-isomerase A5, xyloside xylosyltransferase 1. The carbohydrate sulfotransferase 11 and histo-blood group ABO system transferase exhibited high-support genetic colocalization evidence and were found to affect PC carcinogenesis partially through modulating body mass index and type 2 diabetes, respectively. Approved drugs have been established for eight candidate targets, which could potentially be repurposed for PC therapies. The phenome-wide investigation revealed 12 proteins associated with 51 non-PC traits, and interference on protein disulfide-isomerase A5 and cystatin-D would increase the risk of other malignancies. Conclusions By employing comprehensive methodologies, this study demonstrated a genetic predisposition linking 21 circulating proteins to PC risk. Our findings shed new light on the PC etiology and highlighted potential targets as priorities for future efforts in early diagnosis and therapeutic strategies of PC.

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Advancing Cholangiocarcinoma Care: Insights and Innovations in T Cell Therapy

Dadgar,

Arunachalam,

Hong

et al. 2024

Cancers

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Cholangiocarcinoma (CCA) is a rare and aggressive malignancy originating from the bile ducts, with poor prognosis and limited treatment options. Traditional therapies, such as surgery, chemotherapy, and radiation, have shown limited efficacy, especially in advanced cases. Recent advancements in immunotherapy, particularly T cell-based therapies like chimeric antigen receptor T (CAR T) cells, tumor-infiltrating lymphocytes (TILs), and T cell receptor (TCR)-based therapies, have opened new avenues for improving outcomes in CCA. This review provides a comprehensive overview of the current state of T cell therapies for CCA, focusing on CAR T cell therapy. It highlights key challenges, including the complex tumor microenvironment and immune evasion mechanisms, and the progress made in preclinical and clinical trials. The review also discusses ongoing clinical trials targeting specific CCA antigens, such as MUC1, EGFR, and CD133, and the evolving role of precision immunotherapy in enhancing treatment outcomes. Despite significant progress, further research is needed to optimize these therapies for solid tumors like CCA. By summarizing the most recent clinical results and future directions, this review underscores the promising potential of T cell therapies in revolutionizing CCA treatment.

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Development and validation of circulating protein signatures as diagnostic biomarkers for biliary tract cancer

Cited by 3 publications

References 47 publications

Protein Signatures and Individual Circulating Proteins, including IL-6 and IL-15, Associated with Prognosis in Patients with Biliary Tract Cancer

Protein Signatures and Individual Circulating Proteins, including IL-6 and IL-15, Associated with Prognosis in Patients with Biliary Tract Cancer

Integrating plasma protein-centric multi-omics to identify potential therapeutic targets for pancreatic cancer

Advancing Cholangiocarcinoma Care: Insights and Innovations in T Cell Therapy

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