Author: Platz, Elizabeth A. ; Gauderman, W. James ; Vodicka, Pavel ; Albanes, Demetrius ; Newton, Christina C. ; White, Emily ; Li, Li ; Papadimitriou, Nikos ; Chan, Andrew T. ; Schoen, Robert E. ; Kundaje, Anshul ; Pellatt, Andrew J. ; Gruber, Stephen B. ; Campbell, Peter T. ; Barry, Elizabeth L. ; Wolk, Alicja ; Anderson, Laura N. ; Peters, Ulrike ; Le Marchand, Loïc ; Markozannes, Georgios ; Gunter, Marc J. ; Vymetalkova, Veronika ; Moreno, Victor ; Mendez, Joel Sanchez ; Peoples, Anita R. ; Pharoah, Paul D. ; Wu, Anna H. ; Morrison, John ; Yu, Ren ; Devall, Matthew A. ; Qu, Conghui ; Dimou, Niki ; Evangelou, Marina ; Chang-Claude, Jenny ; Drew, David A. ; Huyghe, Jeroen R. ; Gsur, Andrea ; Bouras, Emmanouil ; Thomas, Claire E. ; Kim, Andre E. ; Brenner, Hermann ; Um, Caroline Y. ; Keku, Temitope O. ; Tsilidis, Konstantinos K. ; Lynch, Brigid M. ; Carreras-Torres, Robert ; Cheng, Iona ; Hsu, Li ; Murphy, Neil ; Stern, Mariana C.

AbstractColorectal cancer (CRC) is a major public health concern, with incidence rates increasing over the past decades particularly among younger adults. The identification of novel intervention targets for CRC prevention becomes imperative.In the present study we explored patterns of genes and pathways underlying the observed associations using estimates from genome-wide interaction studies (GWIS) of 15 exposures with established or putative CRC risk. GWIS estimates were derived from a pool of 36 primary studies including up to 38, 578 CRC cases and 49, 658 controls. The 15 risk factors included body mass index (BMI), height, physical activity, smoking, type 2 diabetes, hormone replacement therapy (HRT), and intake of non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin, alcohol, calcium, fiber, folate, fruits, processed meat, red meat, and vegetables. We conducted pathway-environment interaction analysis for CRC risk to identify associated pathways using the adaptive combination of Bayes Factors (ADABF) framework. The pathway findings were further investigated by exploring the relevance of the enriched genes for CRC using publicly available resources [hallmarks of cancer, Open Targets Platform (OTP)].Using the ADABF, a total of 1, 973 pathways were enriched out of the 2, 950 analyzed for at least one exposure. Additionally, within the enriched pathways, 1, 227 genes showed evidence of interaction with at least one exposure. A high overlap of associated genes was observed between the three exposures with higher number of associated genes: BMI (n=768), followed by smoking (n=223) and NSAIDs (n=173), while for remaining exposures the number of enriched genes ranged from 3 to 27. Data were available for 811/1, 227 genes in the OTP, of which an overall association score >0.05 was found for 241 coding genes. Fifty percent of the genes (617/1, 227) mapped to at least one hallmark of cancer, most of which (388/617) pertained to the Sustaining Proliferative Signaling hallmark. Our findings reflect previously established pathways for CRC risk, such as mitogen-activated protein kinase (MAPK), Notch, PI3K/AKT, transforming growth factor-β (TGF-β), Wnt, and participating genes, for BMI, NSAIDs, and smoking, and highlight the emerging importance of several less studied genes (such as argonaute RISC component, UDP-glucuronosyltransferase, and taste receptor coding genes). Common pathways were found for several combinations of exposures (mostly for BMI, NSAIDs, and smoking), potentially suggesting common underlying mechanisms.The results of the present analysis can be used in future investigations, and, if confirmed, may aid in elucidating the etiological associations and inform personalized CRC prevention strategies.Citation Format:Emmanouil Bouras, Ren Yu, Andre E. Kim, Georgios Markozannes, Neil Murphy, Demetrius Albanes, Laura N. Anderson, Elizabeth L. Barry, Hermann Brenner, Peter T. Campbell, Robert Carreras-Torres, Andrew T. Chan, Jenny Chang-Claude, Iona Cheng, Matthew A. Devall, Niki Dimou, David A. Drew, Stephen B. Gruber, Andrea Gsur, Li Hsu, Jeroen R. Huyghe, Temitope O. Keku, Anshul Kundaje, Loïc Le Marchand, Li Li, Brigid M. Lynch, Victor Moreno, John Morrison, Christina C. Newton, Nikos Papadimitriou, Andrew J. Pellatt, Anita R. Peoples, Paul D. Pharoah, Elizabeth A. Platz, Conghui Qu, Joel Sanchez Mendez, Robert E. Schoen, Mariana C. Stern, Claire E. Thomas, Caroline Y. Um, Pavel Vodicka, Veronika Vymetalkova, Emily White, Alicja Wolk, Anna H. Wu, Marc J. Gunter, W. James Gauderman, Ulrike Peters, Marina Evangelou, Konstantinos K. Tsilidis. Using gene-environment interactions to explore pathways for colorectal 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 3817.

21 Apr 2025·Cancer Research

Abstract 1889: Proteomic profiling using high-dimensional multiplex platforms to identify prospective risk factors for lymphoid malignancies across multiple cohorts

Author: Lee, Matthew ; Gunter, Marc J. ; Diepstra, Arjan ; Langerak, Anton W. ; Aizpurua, Amaia ; Riboli, Elio ; Kolijn, Pieter Martijn ; Macciotta, Alessandra ; Tumino, Rosario ; McKay, James ; Smith-Byrne, Karl ; Travis, Ruth C. ; Vermeulen, Roel C. ; Viallon, Vivian ; Zamora-Ros, Raul ; Späth, Florentin ; Papier, Keren

AbstractIntroduction:Circulating proteins play a central role in the development of lymphoid malignancies and the immune system’s response to these cancers.Methods: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.Results: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.Conclusion: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.Citation Format: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.

21 Apr 2025·Cancer Research

Abstract 4039: An isogenic CRISPR screen identifies novel MYC-driven vulnerabilities

Author: Chan, Katherine ; Cruickshank, Jennifer ; Penn, Linda Z. ; Tong, Amy H. ; Ghamrasni, Samah El ; Cescon, David W. ; van Leeuwen, Jenna E. ; Pujana, Miquel ; Moffat, Jason ; Palomero, Luis ; Lin, Peter ; Lourenco, Corey

Abstractc-MYC (MYC) is a central regulatory protein that is dysregulated in >50% of all human cancers and is linked to aggressive disease. Developing MYC inhibitors would revolutionize cancer treatment; however, efforts to target MYC directly using small molecular inhibitors have historically failed. A promising approach is to identify and inhibit critical MYC partner proteins to inactivate MYC and trigger cancer cell death. Inhibiting these targets therapeutically can result in synthetic lethality (MYC-SL), which can be exploited in MYC-dysregulated cancers. To identify MYC-SL targets, we performed a genome-wide CRISPR knock-out screen using an isogenic pair of non-transformed and MYC-driven breast cancer cells. In contrast to other screens, this model is both dependent on MYC and recapitulates human disease at pathological and molecular levels in vivo. Finally, these hits were cross-referenced with our MYC protein-interactome data to reveal putative MYC partner proteins that are critical for MYC activity.From our screen results, we performed gene set enrichment analysis to identify biological activities that may represent core functional dependencies in MYC dysregulated cancer cells. Using this approach, we identified and validated topoisomerase 1 (TOP1) as an actionable vulnerability that can be targeted with clinically approved inhibitors. Genetic and pharmacological inhibition of TOP1 in multiple orthogonal assays resulted in MYC-driven cell death. Finally, drug response to TOP1 inhibitors correlated with MYC levels and activity across panels of breast cancer cell lines and patient-derived organoids, highlighting TOP1 as a promising target for MYC-driven cancers.The recent accessibility of large-scale datasets detailing functional dependencies across hundreds of cancer cell lines offers an unprecedented opportunity to prioritize targets with greater translational relevance, which is a major limitation of the synthetic-lethal approach for target discovery. As a secondary analysis of our hits, we utilized DEPMAP data to classify cancer cell lines as relatively MYC-dependent or MYC-independent, enabling the in silico evaluation of each MYC-SL hit’s differential essentiality. MYC-SLs that exhibited selective essentiality in MYC-dependent cell lines were prioritized for further investigation. Results from this strategy revealed critical MYC cofactors that have been validated by us and others (e.g., CDK9), providing confidence in this approach. Excitingly, previously underexplored targets were identified with promising validation to-date. Together, this work features two successful strategies to prioritize hits from hundreds of synthetic-lethal genome-wide CRISPR screens to identify novel MYC-driven vulnerabilities in cancer.Citation Format:Peter Lin, Corey Lourenco, Jennifer Cruickshank, Luis Palomero, Jenna E. van Leeuwen, Amy H. Tong, Katherine Chan, Samah El Ghamrasni, Miquel Pujana, David W. Cescon, Jason Moffat, Linda Z. Penn. An isogenic CRISPR screen identifies novel MYC-driven vulnerabilities [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 4039.

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