Proteomics has emerged as a potentially important research tool for identifying novel etiological biomarkers of cancer risk. To date, apart from some specific proteins such as insulin-like growth factor -1 and sex hormone binding globulin, few protein biomarkers for breast cancer risk have been established. This study aimed to identify novel plasma proteins associated with premenopausal and postmenopausal breast cancer in a case-cohort study within the European Prospective Investigation into Cancer and Nutrition (EPIC). Plasma proteins were measured using the SomaScan 7k Assay in 970 incident breast cancer cases (231 premenopausal, 739 postmenopausal) and 2, 490 female subcohort participants from the EPIC cohort. Separately in premenopausal and postmenopausal women, Prentice-weighted Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between circulating proteins and breast cancer risk adjusted for known breast cancer risk factors. A false discovery rate-corrected P-value <0.05 was considered statistically significant. Of the 7, 363 assayed circulating proteins (aptamers), 19 were statistically significantly associated with premenopausal breast cancer risk. Of these, LEG1, KLK5, LACRT, LIPK, PIP, ADPGK, KRTAP2-4, CXCL13, LGSN, DNAJC11, SEMA4G, RLN2, FGF9, LYPD3, SHCBP1L and DEFB107A were positively associated (HRs ranged from 1.20 to 1.65 per 1 SD increment) and SUMO2, MPI, and XPNPEP1 were inversely associated with premenopausal breast cancer risk (HRs ranged from 0.56 to 0.63 per 1 SD increment). Three proteins - LEG1 (HR: 1.32; 95% CI: 1.21, 1.44), CST6 (HR: 1.31; 95% CI: 1.20, 1.44), and SAR1B (HR: 1.21; 95% CI: 1.12, 1.30) - were positively associated with postmenopausal breast cancer risk. In heterogeneity tests by menopausal status, 20 proteins were differentially associated with breast cancer risk in postmenopausal and premenopausal women. These findings point to potentially novel pathways and biomarkers of breast cancer development, with possible important differences by menopausal status. These results need to be replicated in other epidemiological studies. Yahya Mahamat-saleh, Alicia Heath, Vivian Viallon, Antonio Agudo, Giovanna Masala, Salvatore Panico, Carlotta Sacerdote, Karl Smith-Byrne, Ruth Travis, Rosario Tumino, Martijn Kolijn, Roel Vermeulen, Nicholas Wareham, Pietro Ferrari, Elio Riboli, Marc J. Gunter, Laure Dossus. Pre-diagnostic circulating proteins and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6366.
Plasma proteins play critical roles in various cancer-related processes, are frequently dysregulated in cancer, and represent a key source of druggable targets. The integration of high-throughput proteomic assays into large-scale population-based studies may provide important insights into mechanisms of cancer pathogenesis, identify biomarkers for cancer risk and early detection, and prioritize novel therapeutic targets for cancer prevention. Here, we describe initial findings from proteomic profiling of baseline plasma samples from a case-cohort of 6,073 incident cancer cases and 4,115 sub-cohort members within the European Prospective Investigation into Cancer and Nutrition (EPIC) using the SomaScan 7K assay. Participants at baseline were 53.8 (SD 8.7) years of age and 57.3% were women. Prentice weights and robust variance were used to account for the case-cohort design of the study. Models were stratified on sex, center, and age at recruitment and adjusted for education status and cancer type-specific risk factors. Pre-diagnostic plasma concentrations of 7,596 protein aptamers (representing 6,432 proteins) were evaluated for association with 24 cancer types. In total, 2,264 protein aptamer-cancer associations were observed at FDR P < 0.05, including 53 for overall cancer risk. The majority of aptamers (80%, 1,422/1,770) were associated with one cancer type with 11 associated with 4 or more types, including aptamers binding to GDF15, MMP12, and TNFRSF1B. Proteins represented among FDR-significant aptamers map to a diverse set of biological processes including the epithelial-mesenchymal transition, coagulation, and inflammatory signaling pathways. Around half of all aptamer-cancer associations (52%, 1,173/2,264) remained FDR-significant after excluding the first 5 years of follow-up, supporting the potential role of proteins in etiological processes, as opposed to being markers of latent/undiagnosed cancer at baseline. The number of FDR-significant associations per cancer type varied substantially, ranging from 885 for hepatocellular carcinoma and 403 for chronic lymphocytic leukemia to 3 for both pancreatic and thyroid cancer and 2 for endometrial cancer (median 23 aptamers per cancer type, IQR: 6-65). Our plasma-based proteomic profiling of a large case-cohort analysis established within the EPIC study has identified potentially novel biomarkers across a range of cancers, with evidence of both shared and distinct proteomic profiles across cancer types. Replication of findings in independent cohort studies and further interrogation of mechanistic pathways will help to validate proteins identified in this analysis and clarify their roles as potential markers for the early detection, prediction, and prevention of cancer. James Yarmolinsky, Vivian Viallon, David C. Muller, Antonio Agudo, Pietro Ferrari, Giovanna Masala, Salvatore Panico, Carlotta Sacerdote, Karl Smith-Byrne, Ruth C. Travis, Rosario Turmino, P.Martijn Kolijn, Roel C. Vermeulen, Monique Verschure, Nicholas Wareham, Elio Riboli, Marc J. Gunter. Pan-cancer proteomic profiling of the EPIC cohort identifies novel plasma biomarkers of cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4931.
Circulating proteins play a central role in the development of lymphoid malignancies and the immune system’s response to these cancers. In this study, we measured 6, 412 unique proteins in prediagnostic plasma samples using the SomaScan 7K panel from a total of 4, 565 participants of a case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)—484 who later developed a lymphoid malignancy (median follow-up 9 years) and 4, 081 who did not. We conducted subtype-specific analyses for non-Hodgkin lymphoma (NHL, n=348), chronic lymphocytic leukemia (CLL, n=80), multiple myeloma (MM, n=116), diffuse large B-cell lymphoma (DLBCL, n=80), follicular lymphoma (FL, n=51) and Hodgkin lymphoma (HL, n=20) using Prentice-weighted Cox regression with Benjamini-Hochberg correction for multiple testing. We observed significantly altered plasma levels prior to NHL diagnosis for 147 unique proteins (161 aptamers), of which 131 were upregulated and 16 were downregulated. Increased plasma levels of members of several major immunomodulatory protein families, including the FC-receptor family and the semaphorin family, were associated with increased risk of NHL. Alongside established biomarkers such as sCD23 for CLL, CXCL13 for DLBCL, and sBCMA for MM, we identified potent novel markers, including FCMR and FDCSP for NHL. Time-stratified analyses revealed that a subset of these protein-lymphoma associations are evident over a decade before diagnosis, underscoring the protracted preclinical phase of lymphoid malignancies. Pathway analyses revealed dysregulation in immune modulation, epigenetic regulation, cytokine and chemokine signaling, B-cell receptor signaling, the NF-κB signaling pathway, alternative splicing and N-glycan biosynthesis. In total, 2136 out of 6412 proteins measured in our current study overlapped with those measured in a recent UK biobank study. The significant protein-cancer associations observed in our current analyses within EPIC showed high concordance in the UK biobank in terms of both FDR-adjusted significance (58%-82%) and the direction of the association (89%-92%), meaning positively or negatively associated with cancer risk. In conclusion, we identified hundreds of proteins associated with lymphoid malignancy risk, revealing a robust set of markers detectable many years prior to diagnosis, and advancing our understanding of lymphoid malignancy pathogenesis. Pieter Martijn Kolijn, Karl Smith-Byrne, Vivian Viallon, Matthew Lee, Keren Papier, Anton W. Langerak, Florentin Späth, Arjan Diepstra, Raul Zamora-Ros, Alessandra Macciotta, Amaia Aizpurua, Rosario Tumino, Ruth C. Travis, Elio Riboli, Marc J. Gunter, James McKay, Roel C. Vermeulen. Proteomic profiling using high-dimensional multiplex platforms to identify prospective risk factors for lymphoid malignancies across multiple cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1889.
Worldwide, hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death. The remarkable improvements in treating HCC achieved in the last years have increased the complexity of HCC management. Following the need to have updated guidelines on the multidisciplinary treatment management of HCC, the Italian Scientific Societies involved in the management of this cancer have promoted the drafting of a new dedicated document. This document was drawn up according to the GRADE methodology needed to produce guidelines based on evidence. Here is presented the first part of guidelines, focused on the multidisciplinary tumor board of experts and surgical treatments of HCC.
