Citations

Abstract Background: Deletions in MTAP occur in 10-15% of cancers and are associated with poor prognosis. MTAP deletion (MTAPdel) leads to accumulation of MTA which causes partial inhibition of PRMT5, creating a synthetic lethality approach with PRMT5 inhibitors. Multiple investigational MTA-cooperative PRMT5 inhibitors have demonstrated early clinical efficacy in MTAPdel NSCLC and other cancers. MTAPdel, PRMT5 expression, and clinical outcomes to standard of care immune checkpoint inhibitors (ICI) and chemotherapy (chemo) have not been well characterized. Methods: The Tempus Lens Platform (Tempus AI, Inc., Chicago, IL) was used to query the Tempus multimodal de-identified database and establish and subsequently analyze a cohort of patients (pts)with NSCLC and DNA (Tempus xT) and RNA (Tempus xR) testing, treated with front-line (1L) ICI with or without chemo (N=3,676). PRMT5 expression was normalized as transcripts per million (TPM) and reported as log2(TPM + 1). Pts were classified into high vs low groups based on median PRMT5 expression and into MTAPdel vs intact (MTAPwt) based on MTAP biallelic loss. Immune infiltration was estimated using Quantiseq. Real-world overall survival (rwOS) was defined as the time from 1L start to death or last known follow-up. Real-world progression-free survival (rwPFS) was defined as the time from 1L start to death, progression or last known follow-up. Hazard ratios (HR) were calculated using Cox proportional hazards models and adjusted for age, sex, histology, smoking status and PDL1 status. Results: PRMT5 expression was moderately increased in pts with MTAPdel (6.65 v 6.70, p=0.012). Alterations in MYC, SMARCA4 and KEAP1 were enriched in PRMT5-high tumors in both MTAPdel and MTAPwt pts (p<0.03). Pts with PRMT5-high tumors had decreased infiltrate of multiple immune cells, including B cells, macrophages (M1 and M2), NK cells, CD4 and CD8 T cells (p<0.001). Pts with MTAPdel/PRMT5-high expression had shorter rwOS compared to MTAPwt/PRMT5-low when treated with ICI alone (HR 1.58, 95% CI 1.11-2.24, p=0.011) or with ICI + chemo (HR 1.65, 95% CI 1.34-2.03, p<0.001). These associations persisted on multivariate analysis. Pts with MTAPdel/PRMT5-high expression were also associated with worse rwPFS when treated with ICI + chemo (HR 1.5, 95% CI 1.22-1.86, p<0.001) on univariate and multivariate analysis, but did not associate with rwPFS in pts treated with ICI alone (HR=0.97, 95% CI 0.66-1.42, p=0.9). Conclusion: PRMT5 expression defines an immune suppressed subpopulation of pts with NSCLC. Pts with elevated PRMT5 expression and MTAPdel have poor outcomes with ICI+/- chemo, indicating PRMT5 RNA expression levels can be used to inform clinical trial designs, particularly those that are testing novel combinatorial strategies. Citation Format: Natalie Vokes, Stamatina Fragkogianni, Pooja A. Shah, Santiago G. Trevino, Konstantinos Leventakos, Lei Deng, Matthew Lee, Tali Azenkot, KAYLA LAYNG, JACOB MERCER, Jyoti Patel, Jordi Rodon Ahnert. High PRMT5 expression is associated with decreased immune infiltrate and worse outcomes to immune checkpoint inhibitors in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2446.

Abstract Background: The Alaska Tribal Health System is working to increase colorectal cancer (CRC) screening among Alaska Native peoples. It is unknown why people who initially agree to screening might not follow through to complete their screening. Methods: As part of a larger intervention investigating multi-target stool DNA (mt-sDNA) test use in rural Alaska communities, we interviewed Alaska Native people who had agreed to scheduling a colonoscopy or having a mt-sDNA kit sent to their home but who did not complete their selected test. Results: Of 531 Alaska Native people who initially agreed but did not complete screening, 299 (56%) were able to be contacted for a follow-up survey. Of those, 256 (86%) answered the survey; 187/224 (83%) who had chosen mt-sDNA, and 69/75 (93%) who had chosen colonoscopy. Reported reasons for non-completion of stool DNA test kits included being busy or forgetting, being uncomfortable doing a stool test, and not knowing how to do the test or concerns over how to return the kit for processing. Reasons for non-completion of colonoscopy included scheduling issues, physical health issues, travel, and housing barriers, as well as cost, fear, and being too busy. Of note, many respondents in both groups indicated they would still be interested in CRC screening in the future or were currently pursuing screening. Conclusions: This was the first exploration of reasons for non-adherence to CRC screening after initial test request by Alaska Native people. Many of the identified themes are amenable to health care system changes for future interventions to improve screening outreach and uptake. Citation Format: Diana Redwood, Christie A. Flanagan, Lauren Jeffries, Melissa Toffolon, Joseph Klejka, Lila J. Finney Rutten, Judith S. Kaur, John B. Kisiel. Non-completion of colorectal cancer screening among Alaska Native people in an intervention trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2474.

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to aggressive biology, stromal desmoplasia, and profound immunotherapy resistance. Tumor Treating Fields (TTFields) disrupt mitosis and induce immunogenic cell death (ICD), type I interferon signaling, and microenvironment remodeling, providing a rationale for combining TTFields with immune checkpoint inhibition. This is the first systematic review to comprehensively synthesize mechanistic and clinical evidence for TTFields immunotherapy combinations across solid tumors, with emphasis on their translation relevance to PDAC. Methods: A systematic search of PubMed, Scopus, Web of Science, Embase, Cochrane Library, and ClinicalTrials.gov was conducted through October 26, 2025, following PRISMA 2020 guidelines. Eligible studies evaluated TTFields combined with immunotherapy. Two reviewers independently screened and extracted data using Covidence. Evidence was summarized narratively by tumor type, study design, and immunotherapeutic approach. Results: Thirty-seven studies met criteria, including preclinical and clinical investigations across glioblastoma, NSCLC, mesothelioma, PDAC, and other tumors. Preclinical models consistently showed that TTFields trigger ICD hallmarks such as calreticulin exposure, HMGB1 and ATP release, and activate STING/type I interferon pathways, enhancing dendritic-cell maturation and T-cell and NK-cell function. Across in vivo models, TTFields combined with PD-1 or CTLA-4 blockade, vaccines, or other immunotherapies reduced tumor growth and increased lymphocyte infiltration. Clinical evidence, although early-phase and heterogeneous, indicates the combination is feasible, with toxicity dominated by low-grade skin reactions and no excess immune-related adverse events. In glioblastoma, adding TTFields to pembrolizumab and temozolomide showed numerically improved survival. The LUNAR phase 3 trial in metastatic NSCLC demonstrated an overall survival advantage when TTFields were added to systemic therapy, including immunotherapy. Evidence in PDAC remains preliminary, but the ongoing PANOVA-4 study combining TTFields with atezolizumab and chemotherapy highlights emerging translational relevance. Conclusions: TTFields enhance antitumor immunity when combined with immunotherapy across solid tumors. In PDAC, these mechanisms may help counteract the immunosuppressive microenvironment. Ongoing gastrointestinal trials will clarify optimal combinations, biomarkers of response, and the clinical role of TTFields-based immunomodulation. Citation Format: Douaa Albelal, Hari Krishnareddy Rachamala, Hani Babiker. Synergistic immunomodulation by Tumor Treating Fields combined with immunotherapy across solid tumors: A systematic review with translational relevance to pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3813.

Abstract Medical advancements with immunotherapy have cured some patients with previously incurable metastatic renal cancer. We present the case of a 74-year-old male metastatic renal cancer patient who received only one dose of the combination of ipilimumab with nivolumab. In response to his treatment, he developed autoimmune hepatitis, myasthenia, myositis, and myocarditis. Although these serious side effects are considered to rarely occur, they can quickly become life-threatening and even fatal. These immune-related adverse events (irAEs) may further develop into secondary life-threatening symptoms such as respiratory failure due to advanced myasthenia; cardiotoxicity of myocarditis with possible cardiogenic shock, cardiac arrest, and severe heart failure; and liver failure consequently from autoimmune hepatitis. Furthermore, the ability for physicians to detect immunotherapy toxicity early is extremely important in intervening in a timely manner to avoid lethal conditions for the patient. With patients receiving immunotherapy, communication, collaboration, and multidisciplinary care are essential. Any subtle or sudden changes in their health status or symptoms should prompt further investigation. It is our purpose to highlight this patient to raise awareness of toxicity to significantly reduce the fatality rates and increase the therapy’s success rate in the years to come. Citation Format: Orianna Guarisma-Lugo, Roderick Brice, Samuel Ramirez, Winston W. Tan. The unique presentation of four immunotherapy toxicities in a single patient [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3803.

Abstract Background: The BRAF(V600E) mutation in colorectal cancer (CRC) is associated with treatment resistance and a poor prognosis. CDK2/9 is frequently activated in human cancers, and we have previously shown that BRAFV600E can upregulate MCL-1, which can be suppressed by the selective CDK2/9 inhibitor fadraciclib. Herein, we determined whether targeting CDK2/9 by fadraciclib can be enhanced by concurrent Bcl-2/Bcl-xL inhibition using LP-118, which minimizes platelet toxicity in patients, compared to the Bcl-2 inhibitor venetoclax. Effects of the drugs on apoptosis, colony formation and tumor growth were studied in a zebrafish model. Methods: We utilized isogenic human RKO (BRAFV600E/V600E/WT) and T29 (BRAFWT/−/−) CRC cell lines in addition to HCT-116 (BRAFWT) and Bax knockout (HCT-116Bax-/-) CRC cells. Cells were treated for 24h with fadraciclib (500nM) plus encorafenib (500nM) in the presence or absence of LP-118 (1µM) or venetoclax (1µM). Apoptosis and cell growth inhibition were assessed using annexin V/PI staining and colony formation assays, respectively. Expression of MCL-1, Bcl-xL, Bcl-2, PARP, and cleaved caspase-3 (Asp175) proteins was analyzed. In a zebrafish tumor xenograft model, the effects of the drugs on caspase-3 cleavage and tumor growth were then evaluated. Results: Fadraciclib suppressed MCL-1 expression, induced apoptosis and significantly inhibited colony formation in all CRC cell lines. However, this effect was enhanced by encorafenib only in RKO (BRAFV600E/V600E/WT) cells. The addition of LP-118 to fadraciclib plus encorafenib potently enhanced apoptosis induction, shown by annexin V and cleavage of PARP, caspase-3, in RKO and HCT-116 cell lines, which was synergistic and Bax dependent. Treatment with LP-118 combined with fadraciclib and encorafenib suppressed both Bcl-xL and MCL-1 expression in RKO cells. The addition of LP-118 to fadraciclib plus encorafenib enhanced apoptosis (annexin V) to a greater extent than did venetoclax. In a zebrafish tumor xenograft model, the addition of LP-118 to fadraciclib plus encorafenib significantly enhanced caspase-3 activation and reduced the tumor xenograft size. Conclusion: LP-118 synergistically enhanced the antitumor activity of fadraciclib plus encorafenib in BRAFV600E human CRC cells, and to a greater extent than did venetoclax. Mechanistically, targeting Bcl-2/Bcl-xL concurrent with inhibition of MCL-1 and CDK2/9 by fadraciclib potently induced apoptosis and suppressed tumor cell growth. These findings suggest a novel and effective therapeutic strategy for BRAFV600E human CRCs. Citation Format: Md Mohiuddin, Vanda Póvoa, Beatriz Sebo, Rita Fior, Frank A. Sinicrope. Novel Bcl-2/Bcl-xL inhibitor, LP-118, enhances apoptosis induction by the CDK2/9 inhibitor, fadraciclib, in BRAF(V600E) human colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4658.

Abstract Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common type of malignant lymphoma. Previous studies have shown that DLBCL cells are susceptible to GPX4 (Glutathione peroxidase 4)-regulated ferroptosis, an iron-dependent type of programmed cell death characterized by increased reactive oxygen species and excessive lipid peroxidation. In addition to GPX4, FSP1 (Ferroptosis suppressor protein 1, previously known as AIFM2) is a glutathione-independent repressor of ferroptosis that has shown prognostic significance in solid tumors. In this study, we aimed to reveal the significance of GPX4 and FSP1 in DLBCL. Patients and Methods: We performed immunohistochemistry (IHC) for GPX4 and FSP1 in a large cohorts of patients with de novo DLBCL, and evaluated their cytoplasmic and nuclear expression. Prognostic analysis was performed for FSP1 and GPX4 expression in patients treated with rituximab (R)-CHOP or CHOP chemotherapy, respective of TP53 mutation status, as p53 regulates ferroptosis and TP53 mutation is associated with poorer prognosis in DLBCL. Results: FSP1 expression with a ≥10% cutoff was positive in 42.3% of DLBCL cases. Patients with TP53 mutations had a non-significant trend of higher mean FSP1 expression than those with wild-type (Wt) TP53 (P=0.11). Prognostic analysis revealed that cytoplasmic FSP1+ expression was associated with significantly poorer overall survival and progression-free survival in Wt-TP53 DLBCLs treated with R-CHOP (P=0.016 and P=0.003, respectively), and only showed non-significant unfavorable trends in TP53 mutated DLBCLs and patients treated with CHOP. In contrast, GPX4 expression did not show a significant unfavorable prognostic effect in DLBCL, and in fact, was associated with a non-significant trend of better survival. Previously we have quantified immune cell abundance and PD-1/PD-L1 expression in the tumor microenvironment of the study cohort using multiplex fluorescent IHC. Correlative analysis found that FSP1+ patients had significantly higher mean and median abundance of CD68+ cells (both M1 and M2 macrophages) and CD11c+ cells than FSP1- patients. Further analysis in Wt-TP53 and mutated TP53 subcohorts found that only in the TP53 mutated DLBCL subcohort, FSP1 expression was associated with significantly higher mean and median CD163-CD68+ (M1) and overall CD68+ macrophages, whereas in the Wt-TP53 DLBCL subcohort, FSP1 expression was associated with significantly higher median (but not mean) CD163+CD68+ (M2) macrophages and CD11c+ cells. Summary: Cytoplasmic FSP1 expression but not GPX4 had significantly adverse prognostic effect in patients with Wt-TP53 DLBCL treated with standard immunochemotherapy. Our results also suggest that in addition to ferroptosis regulation, macrophage abundance was relevant for the prognostic effects of FSP1 expression. Citation Format: Beibei Lyu, Zijun Xu-Monette, Xiaoxian X. Zhao, Eric D. Hsi, Ming Chen, Carlo Visco, Alexandar Tzankov, Karen Dybkaer, Mu-En Wang, Chang Wang, Qingyan Au, Harry Nunns, Zenggang Pan, Benjamin Parsons, Santiago Montes-Moreno, Fenghuang Zhan, Michael B. Møller, Leon Bernal-Mizrachi, Youli Zu, Shanxiang Zhang, Weina Chen, Govind Bhagat, Yong Li, KEN H. YOUNG. Expression of the ferroptosis suppressor FSP1 but not GPX4 shows significant adverse prognostic effect in diffuse large B-cell lymphoma with wild-type TP53 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4661.

Abstract Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with individual cancer risk, and polygenic risk scores (PRS) are typically derived from these cancer-specific variants. Although previous pan-cancer studies revealed shared genetic architectures across cancer types, latent factors contributing to cancer risk have not been explored. This may allow for improved prediction of cancer risk based on a latent cancer factor which leverages shared variants across cancers. Here, we conducted an integrative pan-cancer GWAS across seven solid tumors (breast, ovarian, endometrial, pancreatic, lung, colorectal, melanoma) to identify shared latent genetic factors and novel pleiotropic variants. We curated the most recent and large-scale GWAS summary statistics to maximize statistical power, comprising 398,917 cases and 1,501,715 controls of European ancestry. Shared genetic structures among 6,346,960 common variants were evaluated using Genomic Structural Equation Modeling (GenomicSEM). Three latent factors (Common Cancer Factor, Female-Specific Cancer Factor and Non-Sex Specific Cancer Factor) were constructed, and associations of individual variants with each latent factor were estimated. Genome-wide significant loci (p < 5x10-8) were functionally annotated and subjected to pathway enrichment analysis. Models capturing shared genetic risk across cancers fit the data well. A single “Common Cancer Factor” explained much of the shared risk (SRMR = 0.064 [lower is better], CFI = 0.938 [closer to 1 is better]), and a correlated two-factor model—distinguishing female-specific from other cancers—showed even stronger fit and biological relevance (SRMR = 0.055, CFI = 0.988). The one-factor (Common Cancer Factor; SRMR: 0.064, CFI: 0.938, AIC: 54.7, p_chisq: 0.021) and the two-factor (Female-Specific Cancer Factor and Non-Sex Specific Cancer Factor; SRMR: 0.055, CFI: 0.988, AIC: 45.4, p_chisq: 0.281) models demonstrated robust model fit and biological relevance. Factor-specific GWAS identified 233 genome-wide significant loci (p < 5x10-8) with 24 distinct loci showing shared susceptibility across cancers. More importantly, we identified eight novel variants that were not previously reported or related with any cancer risk, potentially regulating cancer-related genes such as PRC1, CEBPB, SMC2, KLF5 and ATXN2. Further analyses are needed to elucidate their roles in tumorigenesis. Our findings reveal a shared genetic architecture across major solid tumors and uncover novel pleiotropic variants with potential regulatory roles in oncogenesis. This study provides novel insights into the genetic basis of cancer susceptibility and supports the development of multi-cancer PRS to improve prediction in cancer prevention and prognosis. Citation Format: Xunxuan Chen, Gamaliel T. Taengwa, Brandon J. Coombes, Stacey J. Winham. Pan-cancer genome-wide study reveals shared genetic architecture and novel pleiotropic variants across seven solid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3600.

Abstract Background: Mantle cell lymphoma (MCL) is an aggressive and rare B-cell non-Hodgkin lymphoma with poor prognosis, even with treatment. Despite its clinical importance, the etiology of MCL remains largely unknown. Some studies have reported a positive association with family history, suggesting that genetic factors could contribute to risk. Methods: To identify germline genetic variants associated with risk, we conducted the first genome-wide association studies (GWAS) and GWAS meta-analysis for MCL, comprising 1,163 cases and 61,271 controls. The most significant loci were taken forward for replication in three independent studies, including 576 cases and 771,773 controls. To identify potential target genes and pathways of discovered loci, we conducted F-MAGMA, colocalization, and transcriptome-wide association study (TWAS) analyses. To gain insight into underlying regulatory mechanisms, we performed integrative epigenomic analyses using DNase I hotspots and histone mark ChIP-seq data across diverse cell types applying the FORGE2 framework. Results: In the joint analyses, we identified eight genome-wide significant loci (P<5x10-8) associated with MCL risk, several of which were located near genes with known DNA repair (ATM), telomere (TERT), or RNA-binding functions (RBM20). Further analyses using F-MAGMA, which uses DNase-seq data to prioritize genes from GWAS, identified genes that were significantly associated with risk, including SP140, a chromatin reader and immune regulator of pathogen response. This gene also displayed strong colocalization with our lead variant in whole blood (COLOC posterior probability PP4=0.97). TWAS demonstrated significant associations with SP140 and ACTA2, which has been linked to cell proliferation (P<3x10-6). Enrichment for DNase I hotspots was observed in B and T lymphocytes (q-value<0.05), providing evidence for a role in immune cell-specific regulatory regions. Enrichment for enhancer-associated histone mark H3K4me1 was observed in B cells (q-value<0.01), highlighting a role for immune cell-specific enhancers. Transcription factor (TF) motif enrichment analysis pointed to TFs critical for B-cell development and differentiation, notably TCF3 and EP300 (q<0.01 for both), suggesting an association between B-cell lineage regulation and MCL risk. Finally, genome-wide SNP-based heritability was estimated to be 17%, underscoring the importance of common variants in MCL risk. Conclusion: Our study provides novel insight into the inherited susceptibility of MCL by identifying eight significant loci and estimating substantial common variant heritability. These findings highlight a role for several distinct biological pathways -specifically DNA repair, telomerase function, and B-cell differentiation- in the etiology of MCL, offering new targets for mechanistic investigation. Citation Format: Charles E. Breeze, Alyssa Clay-Gilmour, Hanla A. Park, Ólafur B. Davíðsson, Angelica Macauda, Brenda M. Birmann, Elizabeth E. Brown, Murat Güler, Michelle A. T. Hildebrandt, Alexandra Nieters, Krystle Ong, Jojo Biel-Nielsen Dietz, Karin E. Smedby, Karl Smith-Byrne, Rosalie Griffin, Sophia S. Wang, Susan Slager, James R. Cerhan, Jonathan N. Hofmann, Qing Lan, Nathaniel Rothman, Ingrid Glimelius, Henrik Hjalgrim, James Mckay, Sonja I. Berndt. Genome-wide association study of mantle cell lymphoma identifies novel loci suggesting a critical role for B-cell chromatin readers and DNA repair mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3602.

Abstract Background. Genome-wide association studies (GWAS) have identified 35 genetic susceptibility single-nucleotide polymorphisms (SNPs) for multiple myeloma (MM) in individuals of European ancestry (EA) and shown strong genetic correlation between MM and its precursor, monoclonal gammopathy of undetermined significance (MGUS). We evaluate the contribution of the 35 MM variants to MGUS susceptibility overall and by prognostic subgroups. Methods. The study included 20,756 participants (14,486 controls, 1,883 with MGUS, and 2,163 with MM) from the Mayo Clinic. Logistic regression assuming an additive model estimated odds ratios (ORs) and 95% confidence intervals (CIs) for individual SNPs and for the MM-PRS, adjusted for age, sex, study, and principal components. The PRS was a weighted sum of 35 SNPs with effect estimates from the largest MM GWAS and was modeled continuously (per SD) and by quintiles (Q1-Q5). SNPnexus annotated variants that replicated in MGUS (P < 0.05 and OR > 1.01) versus those that did not (P > 0.05 and OR < 1.01). Results. The 35-SNP MM-PRS was strongly associated with MM risk and modestly with MGUS. Compared with the middle quintile (Q3), MM odds rose from OR=0.55 (CI=0.46-0.65, P=2.2e-11) in Q1 to OR = 1.82 (CI=1.59-2.09, P=6.2e-18) in Q5. MGUS showed a similar, attenuated pattern (Q1 OR = 0.74, CI=0.64-0.84, P=6.4e-6 / Q5 OR=1.36, CI=1.21-1.53, P=3.4e-7). Each SD increase in PRS corresponded to OR=1.52 (CI=1.45-1.59, P=1.3e-66) for MM and OR = 1.22 (CI=1.18-1.27, P=1.0e-23) for MGUS. Higher PRS values were linked to larger M-protein ((0.1-1.5 g/dL: OR=1.40, CI=1.18-1.65, P=5.8e-12) vs <0.1 g/dL: OR = 1.19, CI=1.13-1.24, P=5.8e-12)) and abnormal free light chain (FLC) ratio ((OR = 1.33, CI=1.21-1.46, P=1.0e-9) vs normal ratio (OR=1.19, CI=1.14-1.25, P=1.4e-13)). Ten risk loci replicated in MGUS, mapping to genes involved in plasma-cell function, immune regulation, and DNA repair and enriched for Rho GTPase signaling, NF-κB-mediated apoptosis, and RNA polymerase II transcription, implicating early plasma-cell activation and transcriptional control. The 12 non-replicating loci, including PHC3, ATG5, and NFIC, mapped to genes involved in chromatin remodeling, autophagy, and SUMOylation, suggesting roles in stress response and genomic maintenance. Conclusions. The MM-PRS captures shared heritability between MM and MGUS and correlates with MGUS subtype and severity. Replicating variants highlight immune and cell-cycle pathways relevant to MGUS onset, whereas non-replicating loci cluster in DNA-repair and stress-response processes, underscoring their potential role in progression. Citation Format: Alyssa Ione Clay-Gilmour, Angelica Macauda, Cristine Allmer, Danelle Moonen, Aaron D. Norman, Nicholas Boddicker, Janet E. Olson, Elizabeth E. Brown, Vincent S. Rajkumar, Esteban Braggio, David Murray, Susan Slager, Shaji Kunnathu Kumar, Celine Vachon. Implications of multiple myeloma polygenic risk scores (PRS) for MGUS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3603.

Abstract Background: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide. Prognostic models for HCC primarily rely on tumor burden and liver function, with limited consideration of inherited genetic contributions to survival variability. Identifying germline variants associated with survival could refine prognosis and reveal biological mechanisms underlying disease progression. Methods: We conducted a genome-wide association study (GWAS) of overall survival among 864 patients with HCC from the M.D. Anderson Cancer Center cohort. Genotyping, quality control, and imputation procedures followed previously described protocols (PMID: 38381705). Associations between genetic variants and overall survival were assessed using Cox proportional hazards models adjusted for age, sex, and the first five principal components. Genome-wide significance was defined as P < 5×10-8. Functional annotation and pathway enrichment analyses (MAGMA) were employed to investigate the biological relevance of the identified loci. Results: After quality control, 8,525,017 single-nucleotide polymorphisms (SNPs) were analyzed. We identified seven new loci associated with HCC survival at the genome-wide significance level. Five out of seven loci are associated with anthropometric traits and hematological measurement traits, reflecting metabolism, hematopoiesis, immune function, and inflammation. A variant in the 3′ untranslated region (UTR3) of STX7 showed a genome-wide significant association with overall survival (HR = 3.23; P = 2.56 ×10-8). Carriers of the risk allele had significantly shorter survival times compared with noncarriers. Pathway analysis revealed enrichment in biologically relevant processes, including liver growth and regeneration (growth hormone and Interleukin-6 (IL-6) signaling pathway), implicating hepatocyte proliferation and IL-6/STAT3-mediated inflammatory signaling. Immune-related pathways, such as regulation of T cell activation and myeloid leukocyte migration, highlight the role of germline variation in immune surveillance. Moreover, pathways governing vascular remodeling and metabolic stress response (e.g., JAK activation, mitochondrial dynamics) suggest that inherited determinants of microenvironmental structure and hepatocyte resilience influence patient outcomes. Conclusion: This germline GWAS of HCC survival identifies seven new genome-wide significant loci and implicates pathways involved in liver regeneration, inflammation, and tissue remodeling. These findings support a role for inherited genetic variation in shaping HCC prognosis and underscore the potential of integrating germline genetics into prognostic modelling and therapeutic target discovery. Citation Format: Younghun Han, Jinyoung Byun, Lewis R. Roberts, Katherine A. McGlynn, Manal M. Hassan, Christopher I. Amos. Identification of survival-associated germline variants in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3606.