tbuckley/cabot-search huggingface dataset:
Abstract A016: DNA methylation variability in aging and Clonal Hematopoiesis
Authors: Anthony J Pompetti, Woonbok Chung, Jaroslav Jelinek, Tanya Egodage, Jean-Pierre Issa
Journal: Cancer Research (2025)

Abstract DNA methylation (DNAm) reflects regions of the genome that are transcriptionally repressed or active depending on the methylation level. Multitudes of DNAm “clocks” have been created to predict biological age and health outcomes. Deviations in biological age from chronological age reflect an alteration in the normal biological aging process. Clonal hematopoiesis of indeterminate potential (CHIP) arises in hematopoietic stem cells that have accumulated somatic mutations in key driver genes which provide a selective advantage for clonal expansion. Subjects with CHIP mutations are more prone to negative clinical outcomes such as coronary heart disease. While DNAm and CHIP have been studied for the past decade, the associations between the two are only now starting to become apparent. In this study we propose an improved measurement of aging based on the Jenson-Shannon distance (JSD) and associate this measurement with CHIP and adverse clinical outcomes. Bisulfite amplicon sequencing of 20 CpG-rich targets that change in methylation with age was performed on an initial cohort of 155 individuals from the National Institute of Neurological Disorders and Stroke (NINDS). JSD was used to construct a DNA methylation chaos clock (DMC) on these targets. DMC provided better predictions of chronological age than DNAm alone (r=0.9; p&amp;lt;0.0001). We validated our findings in 286 individuals from Cooper University Hospital for Management of Trauma where the accuracy of the DMC was confirmed in correlations of predicted vs actual age (r=0.86; p&amp;lt;0.0001). We next examined the association between DMC age acceleration and clinical outcomes. It was found that in individuals over the age of 50, DMC acceleration was associated with smoking and disease incidence (e.g. congestive heart failure and chronic obstructive pulmonary disease) independent of chronological age. The incidence of CHIP mutations in three key driver genes (DNMT3A, TET2, and ASXL1) was assayed in a subset of 345 individuals from both cohorts. Individuals with CHIP mutations in key driver genes had greater deviations in their predicted age than individuals without CHIP mutations (p&amp;lt;0.001). This study demonstrates that the DMC assay is a candidate for improvements in our measurements of biological age and it reflects important changes in an individual’s biological aging process. Citation Format: Anthony J Pompetti, Woonbok Chung, Jaroslav Jelinek, Tanya Egodage, Jean-Pierre Issa. DNA methylation variability in aging and Clonal Hematopoiesis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr A016.
Abstract B014: MCED - DNA methylation-based liquid biopsy for early detection of HPV-related cancers
Authors: Belinda Nedjai
Journal: Cancer Research (2025)

Abstract Human papillomavirus (HPV)-related cancers, particularly cervical cancer, as well as other malignancies such as oropharyngeal, anal, and penile cancers, represent significant global health concerns. While HPV infections are common and usually transient, persistent infection with high-risk HPV types (such as HPV-16 and HPV-18) can lead to the development of cancer through a multi-step process that involves the integration of viral DNA into the host genome, leading to disruptions in cellular processes like DNA repair, apoptosis, and cell cycle regulation. In recent years, there has been growing interest in the use of methylation biomarkers as a tool for early detection and prognostication in HPV-related cancers. Methylation, the addition of a methyl group to DNA, is a key epigenetic modification that can influence gene expression without altering the DNA sequence itself. In the context of cancer, abnormal methylation patterns often serve as early indicators of disease, long before the emergence of genetic mutations or overt clinical symptoms. We have developed a DNA methylation biomarkers S5 classifier able to detect high grade cervical precancer lesions and cancer with high accuracy ranging from 93% for CIN3 to 100% for cancer. Here will demonstrate that the same classifier could detect anal, oropharyngeal and vulvar cancer. Results: Over the past 10 years we have extensicely validated this biomarker on cervical collected sanples urine and vagival samples and self-collected samples. We will share the results we ontained for the esrly dtection of cervical cancer, oropharungeal cancer anal cancer and multizonal cancer.This multicancer test could have range of application for gynaecologic cancers and also male cancers. Citation Format: Belinda Nedjai. MCED - DNA methylation-based liquid biopsy for early detection of HPV-related cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr B014.
Abstract B003: BRAFV600E is essential for maintenance of the CpG island methylator phenotype and DNA methylation of PRC2 target genes in colon cancer
Authors: Layla El Bouazzaoui, Jeroen M Bugter, Emre Küçükköse, André Verheem, Jasmin B Post, Nicola Fenderico, Inne H.M Borel Rinkes, Hugo J.G Snippert, Madelon M Maurice, Onno Kranenburg
Journal: Cancer Research (2025)

Abstract In colon cancer, the BRAFV600E mutation is strongly associated with the CpG island methylator phenotype (CIMP). Here, we characterized the contribution of BRAFV600E to maintenance of aberrant DNA methylation. A reverse CRISPR gene editing approach was applied to revert the V600E mutation in BRAF back to wildtype (E600V) in organoids derived from a late-stage tumour. DNA methylation analyses identified 5187 differentially methylated CpGs within CpG islands, predominantly hypermethylated (82%) in BRAFV600E organoids, including genes associated with CIMP, as well as Polycomb Repressor Complex 2 (PRC2) target genes. RNA sequencing showed that expression of those genes was concordantly repressed. Furthermore, BRAFV600Einduced high expression of PRC2 core components (EZH2, SUZ12, EED), caused PRC2-induced H3K27 trimethylation in promoter regions, and maintained a PRC2-associated embryonic phenotype. This phenotype was lost following mutation correction or pharmacological inhibition of DNA methylation. These findings show that BRAFV600E maintains aberrant DNA and histone methylation patterns in advanced colon cancer, likely preserving the transformed phenotype by silencing of PRC2 target genes. Epigenetic therapies may have value in the treatment of BRAFV600E-mutant colon cancer. Citation Format: Layla El Bouazzaoui, Jeroen M Bugter, Emre Küçükköse, André Verheem, Jasmin B Post, Nicola Fenderico, Inne H.M Borel Rinkes, Hugo J.G Snippert, Madelon M Maurice, Onno Kranenburg. BRAFV600E is essential for maintenance of the CpG island methylator phenotype and DNA methylation of PRC2 target genes in colon cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr B003.
Abstract IA022: Harnessing epigenetic profiles in MDS for the development of predictive biomarkers
Authors: Maria E Figueroa
Journal: Cancer Research (2025)

Abstract While significant progress has been made in understanding the genetic landscape of MDS, less is known about the epigenetic makeup of this disease and how this may impact biology and response to azacitidine (AZA). To address this, we performed genomic, epigenomic, and transcriptomic analyses on CD34+ cells from a multicenter cohort of 94 intermediate or higher-risk MDS patients treated with AZA who had documented responses. DNA methylation (DNAme) by ERRBS, gene expression (GE) by RNA-seq, mutational profiling, and detailed clinical, cytogenetic, and laboratory data were documented. Supervised and unsupervised analyses revealed that aberrant DNAme in MDS is not distributed randomly but rather is highly correlated with disease phenotypes, capturing clinically relevant heterogeneity, beyond what is identified by methodologies used in the past that focused solely on promoter regions. Moreover, this epigenetic information can be harnessed for the development of robust biomarkers predictive of AZA response and integrative approaches combining clinical, mutation, GE and DNAme data can further improve the predictive performance of these biomarkers, with an AUC score=0.94. Citation Format: Maria E Figueroa. Harnessing epigenetic profiles in MDS for the development of predictive biomarkers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr IA022
Abstract B025: Inducible mouse models of cancer driver mutations as a powerful tool for in vivo and epigenetic studies of colorectal cancer
Authors: Manpreet Kalkat, Toshinori Hinoue, Liang Kang, Peter W. Laird, Mary Olesnavich
Journal: Cancer Research (2025)

Abstract Human colorectal cancer (CRC) most often arises as a result of spontaneous genetic driver mutations such as APC, BRAF, KRAS, SMAD4, and TP53. These are among the most common drivers of CRC and are thought to contribute directly to cancer initiation and growth. CRC tumors harboring BRAFV600E mutation exhibit a CpG Island Methylator Phenotype (CIMP). Other drivers are also more weakly associated with distinct DNA methylation profiles. It is not clear whether these DNA methylation profiles are a result of differences in the cells-of-origin for these cancers, with pre-existing methylation patterns or whether there is selective pressure for various DNA methylation alterations that cooperate with each driver. To address this question, we have modeled this in mice by inducing colon tumors in a controlled cell population at the same age, with either BRAFF-V600E, KRASLSLG12D, Smad4, or Trp53 drivers in combination with Apc heterozygosity. We have profiled DNA methylation in tumors arising in these mice to determine the interaction between different driver mutations and the tumor methylome. Using a multiple linear regression model, we have identified DNA methylation alterations that are shared across all tumor samples, as well as changes that are specific to each of the different genetic drivers. The DNA methylation profiles accurately recapitulate well-established findings, including high levels of hypermethylation in KRASLSLG12D and BRAF F-V600E tumors reminiscent of CpG Island Methylator Phenotype (CIMP), universal tumor hypermethylation at binding sites for transcription factors involved in intestinal epithelial differentiation, and hypomethylation at AP1 complex component binding sites. Driver-specific histology findings broadly align with those observed in human cancers, such as sessile serrated morphology in BRAFF-V600E mutated tumors. The tumor models with different driver mutations also show variation in hypermethylation of polycomb repressive complex target sites and replicative history. We are using the differences in the DNA methylation profiles between the driver tumor models in conjunction with RNA-seq analysis and conservation of the alterations in human CRC to identify epigenetic events cooperative with the drivers and functionally relevant to tumorigenesis. Citation Format: Manpreet Kalkat, Toshinori Hinoue, Liang Kang, Peter W. Laird, Mary Olesnavich. Inducible mouse models of cancer driver mutations as a powerful tool for in vivo and epigenetic studies of colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr B025.
Abstract B002: DNA methylation protects cancer cells against senescence
Authors: Xiaoying Chen, Kosuke Yamaguchi, Brianna Rodgers, Delphine Goehrig, David Vindrieux, Xavier Lahaye, Matthieu Nolot, Laure Ferry, Nadine Martin, Pierre Dubus, Fumihito Miura, Takashi Ito, Nicolas Manel, Masato Kanemaki, David Bernard, Pierre-Antoine Defossez
Journal: Cancer Research (2025)

Abstract Inhibitors of DNA methylation such as 5-aza-deoxycytidine are widely used in experimental and clinical settings. However, their mechanism of action is such that DNA damage inevitably cooccurs with loss of DNA methylation, making it challenging to discern their respective effects. Here we deconvolute the effects of decreased DNA methylation and DNA damage on cancer cells, by using degron alleles of key DNA methylation regulators (DNMT1 and UHRF1). We report that cancer cells with decreased DNA methylation — but no DNA damage— enter cellular senescence, with G1 arrest, senescence-associated secretory phenotype (SASP) expression, and senescence-associated beta-galactosidase (SA-β-gal) positivity. This senescence is independent of p53 and Rb, but involves p21, which is cytoplasmic and inhibits apoptosis. The suppression of cyclic GMP-AMP synthase (cGAS) alleviates SASP response and lysosomal activity, and this process is independent of stimulator of interferon genes (STING). Xenograft experiments show that tumor cells can be made senescent in vivo by decreasing DNA methylation. These findings reveal the intrinsic effects of loss of DNA methylation in cancer cells and have practical implications for future therapeutic approaches. Citation Format: Xiaoying Chen, Kosuke Yamaguchi, Brianna Rodgers, Delphine Goehrig, David Vindrieux, Xavier Lahaye, Matthieu Nolot, Laure Ferry, Nadine Martin, Pierre Dubus, Fumihito Miura, Takashi Ito, Nicolas Manel, Masato Kanemaki, David Bernard, Pierre-Antoine Defossez. DNA methylation protects cancer cells against senescence [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr B002.
Abstract B004: Promoter methylation gains in aging and cancer are independent of replication
Authors: Sara-Jayne Thursby, Zhicheng Jin, Nibedita Patel, Yong Tao, Yuba Bhandari, Daniel Petkovich, Shangzhi Lu, Lijing Yang, Tza-Huei Wang, Thomas R. Pisanic, Stephen B Baylin, Hariharan Easwaran
Journal: Cancer Research (2025)

Abstract DNA methylation alterations are observed across multiple cancers, occurring early during tumor initiation. However, evolution and drivers of these changes remain poorly understood and difficult to assess at the clonal level. Consequently, we developed a method for profiling genome-wide DNA methylation from low DNA amounts and applied it to the organoid model of BRAFV600E oncogene-induced colon cancer (CC) tumorigenesis. Single organoid clones, derived from single stem cells, were profiled every month for 5 months to map nucleotide-level dynamic heterogeneity in methylation changes. Uninduced control organoids exhibit a pattern of epigenetic drift leading towards clonal convergence not until 5 months. Whereas BRAFV600E-induced organoids exhibit a step-wise divergence throughout the different time points, likely explained by progressive clonal takeovers. The methylation changes in BRAFV600E induced organoids are explained by the age-in-culture associated methylation changes; especially BRAFV600E did not induce epigenetic changes, as previously thought. The CpG sites affected in the control and BRAFV600E comparison were not shared but mapped to the same genomic elements, indicating common drivers of methylation changes regardless of oncogene. Investigation of promoter CpG-island methylation gains revealed that they are decoupled from replication. External validation in other pre-cancerous and CC datasets, and experimental cell line data sets, show that methylation gains at regulatory elements are a function of “biological aging” and independent of replication or cell division cycles. Our studies provide new insights into the early epigenetic changes involved in BRAFV600E driven carcinogenesis rooted in the age-dependent drivers of epigenetic alterations. Citation Format: Sara-Jayne Thursby, Zhicheng Jin, Nibedita Patel, Yong Tao, Yuba Bhandari, Daniel Petkovich, Shangzhi Lu, Lijing Yang, Tza-Huei Wang, Thomas R. Pisanic II, Stephen B Baylin, Hariharan Easwaran. Promoter methylation gains in aging and cancer are independent of replication [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr B004.
Abstract A008: Epigenetic dynamics in KMT2A-amplified leukemia
Authors: Jayme Ogino, Yang Liu, Wentao Yang, Madina Sukhanova, Sheng Li, Yali Dou
Journal: Cancer Research (2025)

Abstract The lysine methyltransferase KMT2A/MLL1 plays a crucial role in normal development and hematopoiesis. Rearrangement of KMT2A results in the formation of a KMT2A fusion protein with aberrant activity, which is a well-characterized driver of leukemogenesis and is therapeutically targetable. In contrast to the widely studied KMT2A translocation, the molecular consequences of other KMT2A alterations, including KMT2A amplification, remain unknown. KMT2A amplification is detected in highly aggressive and treatment-resistant myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). It strongly associates with TP53 mutations and complex karyotypes. Unlike KMT2A rearrangement, KMT2A amplification is reported mostly in patients older than 65 and treated with alkylating agents. Here, we conducted a comprehensive molecular analysis of KMT2A-amplified MDS/AML by long-read nanopore sequencing. We have revealed the unique epigenetic landscape, including DNA methylation, histone modification, and chromatin accessibility, associated with KMT2A amplification. We also explored the potential of targeting KMT2A or KMT2A-medicated pathways to block leukemogenesis. These results provide a foundation for targeting the KMT2A complex in KMT2A-amplified disease, representing a promising first step toward treating MDS/AML associated with KMT2A amplification. Citation Format: Jayme Ogino, Yang Liu, Wentao Yang, Madina Sukhanova, Sheng Li, Yali Dou. Epigenetic dynamics in KMT2A-amplified leukemia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr A008.
Abstract B005: The functional role of transposable element-oncogene chimeric transcript during cancer progression
Authors: Wesley N Saintilnord, Yixin Wu, Yonghao Liang, Ting Wang
Journal: Cancer Research (2025)

Abstract Nearly half of the human genome is composed of transposable elements (TEs), which were once considered “junk” DNA due in part to their repetitive and non-coding characteristics. However, TEs are now emerging as important regulators of gene activity, especially when they escape typical epigenetic silencing mechanisms like DNA methylation and histone modifications. When activated, TEs can contribute sequences that are exploited as disruptors of genomic stability or novel gene regulatory elements, making them important factors in both development and disease, including cancer. In cancer, these previously silenced elements can act as alternative promoters of oncogenes, leading to the production of TE-chimeric transcripts in a process called “onco-exaptation”. While these oncoexaptation events are reported to be widespread across many cancers, only a few TE-chimeric transcripts have been validated as active contributors to cancer progression. Additionally, it remains unclear whether these TE-chimeric transcripts are merely a consequence of the inherent genomic instability in cancer or whether they can initiate cancer. To address these gaps, we designed a cDNA overexpression library incorporating our previously identified pan-cancer TE-chimeric transcript candidates. This library is used in early passage (EP) BJ fibroblast, a cell line known for its transformation potential in the well-established Weinberg transformation model, which allows us to systematically investigate these onco-exaptation events during cancer progression. Our initial analyses indicate that most TE-chimeric oncogenes are not expressed in EP fibroblast, but are activated in subsequent transformation stages following hTERT, SV40 and HRas induction, underscoring the model viability. We are currently using this model to distinguish TE-chimeric transcripts that act as drivers (TE-chimeric oncogenes) from those requiring previous vulnerabilities, such as telomere inactivation by hTERT or p53 and Rb inactivation by SV40. Ultimately, this work will identify novel biomarkers and therapeutic targets, enhance insights into gene regulation, and provide opportunities for early detection and intervention. These findings have the potential to improve cancer treatment and patient outcomes. Citation Format: Wesley N Saintilnord, Yixin Wu, Yonghao Liang, Ting Wang. The functional role of transposable element-oncogene chimeric transcript during cancer progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr B005.