bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2409: Circulating differential methylation allele fraction (DMAF) strongly correlates with circulating tumor DNA (ctDNA) variant allele fraction (VAF)
Authors: Srinivasan Preethi , Chen Tzu-Chun , Haghshenas Ehsan , Kordi Misagh , Tunc Ilker , Chan Wenching , Solari Omid Shams , Babiarz Joshua , Nakamura Yoshiaki , Yoshino Takayuki , Aleshin Alexey , Kawli Trupti , Reiter Johannes G. 
Published: March 2024

Abstract
Measurement of ctDNA has been established as a prognostic biomarker of cancer disease burden. Emerging evidence has demonstrated that differential methylation patterns can serve as an accurate biomarker both for cancer detection and for predicting the tissue of origin. While it is important to distinguish cancer-positive from cancer-negative patients, clinical decision making increasingly depends on the exact level of the measured biomarker. To that end, we report on the correlation between ctDNA VAF and DMAF across patients with colorectal cancer (CRC). Pre-surgical plasma samples from patients with CRC (N=70) were sourced from the prospective GALAXY, observational arm of ongoing CIRCULATE-Japan study trial (UMIN000039205). Samples classified as ctDNA-positive by a tumor-informed ctDNA assay (SignateraTM) were included in this analysis and ctDNA VAF (%) was calculated. We performed deep methylation sequencing (Illumina Novaseq) across multiple target regions using two independent target sets. DMAF was calculated computationally, which estimates the fraction of differential methylation alleles for circulating cell-free DNA across target regions. Among 70 CRC patients, 68 had positive ctDNA results. Median age at testing was 64.0 years and male individuals represented 55.9% (n=38) of the cohort. Among them, 9 (13.2%) were stage I, 24 (35.3%) were stage II, 22 (32.3%) were stage III, 8 (11.7%) were stage IV, and 5 (7.3%) had unknown staging. The correlation of DMAF with ctDNA VAF was 0.894 (Spearman’s Rank Correlation Coefficient) and was independent of disease stage, histology, age, and sex. Among MSS (micro-satellite stable; n=58) and MSI-H (micro-satellite unstable n=10) patients, the DMAF correlation was 0.9 and 0.915, respectively. The correlation between two target sets evaluating DMAF with differing numbers of targeted regions was high (0.89). These data demonstrate that abundance of differential methylation in CRC patients correlates with VAF regardless of clinicopathologic features of patients with CRC. Methylation-based assays are a promising tool for cancer detection and quantifying the disease burden.
Citation Format: Preethi Srinivasan, Tzu-Chun Chen, Ehsan Haghshenas, Misagh Kordi, Ilker Tunc, Wenching Chan, Omid Shams Solari, Joshua Babiarz, Yoshiaki Nakamura, Takayuki Yoshino, Alexey Aleshin, Trupti Kawli, Johannes G. Reiter. Circulating differential methylation allele fraction (DMAF) strongly correlates with circulating tumor DNA (ctDNA) variant allele fraction (VAF) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2409.
Abstract 2432: Improved liquid biopsy assay performance using sequencing by binding (SBB)
Authors: Nasko Dan , Pham Phillip , Joshi Stuti , Kim Kristi , Pezeshkian Nairi , Kim Young , Sockell Alexandra , Korlach Jonas 
Published: March 2024

Abstract
Liquid biopsy is revolutionizing the field of early cancer detection research through non-invasive detection of tumor DNA in the blood. However, existing liquid biopsy assays are limited in their sensitivity for ctDNA detection at low variant allele frequencies (VAFs), with most relying on extreme sequencing depth and computational error correction to separate the true ctDNA signal from background errors. This limitation is particularly problematic in the area of early cancer detection, in which expected ctDNA allele frequencies are extremely low. Novel strategies are therefore needed to help improve liquid biopsy assay sensitivity and reduce per-sample sequencing requirements. Here we describe PacBio’s application of the Onso short-read sequencing system to enable detection of ctDNA at low VAFs using the SeraCare Complete ctDNA Mutation Mix reference standard. The Onso system makes use of a novel sequencing by binding (SBB) method to achieve up to 15x greater quality scores, with ≥90% of reads at Q40 or above. We performed targeted capture and sequencing of libraries prepared from the SeraCare reference mix diluted into WT human DNA at the following VAFs: 0.00% (WT), 0.05%, 0.10%, 0.25%, and 0.50%, and compared the sensitivity at each VAF for SBB compared to a competitor method using sequencing by synthesis (SBS) at varying sequencing depths. We observed superior sensitivity for ctDNA detection at low VAFs (0.05%, 0.1%) using SBB at half the sequencing depth compared to SBS, in part due to reduced false positive calling in the WT sample for SBB. Furthermore, SBB was able to achieve comparable sensitivity results to SBS using four-fold less sequencing, and without the use of computational error correction. Finally, combining SBB with computational error-correction methods boosted sensitivity even further, suggesting an additive value for these technologies. Taken together, our results demonstrate the potential of SBB to improve upon existing methods of liquid biopsy and better enable research on early cancer detection.
Citation Format: Dan Nasko, Phillip Pham, Stuti Joshi, Kristi Kim, Nairi Pezeshkian, Young Kim, Alexandra Sockell, Jonas Korlach. Improved liquid biopsy assay performance using sequencing by binding (SBB) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2432.
Abstract 2446: Genomic landscape of longitudinally collected preinvasive airway lesions
Authors: Alhendi Ahmed , Kalinke Lukas , Pennycuick Adam , Davies Kate , Durrenberger Pascal , Gowers Kate , Grigoriadis Kristiana , McGranahan Nicholas , Janes Sam 
Published: March 2024

Abstract
Lung carcinoma in situ (CIS) lesions, as precursors to squamous cell carcinoma, exhibit microscopic uniformity while displaying diverse clinical trajectories. Half of these lesions progress to invasive cancer, while the remaining half either regress or remain indolent. Previous genomic profiling efforts have elucidated progression-specific genomic changes against a backdrop of inherent heterogeneity and notable chromosomal instability signatures. Here, we present a novel approach by analyzing longitudinally collected samples of preinvasive airway lesions, encompassing both progressive and indolent trajectories.
Our findings reveal that genomic integrity and cell cycle dynamics constitute key distinctions between progressive and indolent lesions. Notably, a decrease in clonal diversity and an inverse correlation between TCRA-Tcell fraction and genomic instability are observed as lesions approach invasion. Somatic mutations in cancer driver genes BRAC2, CSMD3, and MUC16 are found significantly associated with lesion progression. Furthermore, progressive lesions exhibit a higher frequency of copy number changes compared to indolent lesions. Copy number loss in 1p, 3p, 9p, and 17p are found to be significantly associated with lesion progression. Phylogenetic analysis further confirms positive selection for copy number loss in these specific genomic regions, providing insights into the evolutionary trajectory of alterations in progressive lesions. The comprehensive understanding derived from these genomic analyses is anticipated to advance early detection strategies, mitigate overtreatment, and facilitate the development of preventative therapies targeting early clonal events in lung cancer.
Citation Format: Ahmed Alhendi, Lukas Kalinke, Adam Pennycuick, Kate Davies, Pascal Durrenberger, Kate Gowers, Kristiana Grigoriadis, Nicholas McGranahan, Sam Janes. Genomic landscape of longitudinally collected preinvasive airway lesions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2446.
Abstract 2453: Soluble B7H3 has a potential of novel serum biomaker for colorectal cancer
Authors: Koizumi Akihiro , Ito Tomoaki , Kato Kazunori , Iwasawa Takumi , Kushida Tomoyuki , Sato Koichi , Okamoto Chikako 
Published: March 2024

Abstract
B7H3 (also known as CD276, an immune checkpoint molecule) is aberrantly over expressed in many types of cancer. Recently, several reports indicate a crucial role for B7H3 in promoting carcinogenesis and metastasis. We investigated whether concentration of the soluble B7H3 could be used as a new prognostic predictor of colorectal cancer by measuring serum level of B7H3. Recently we established a new mAb to B7H3 and developed sandwich ELISA-system detecting human serum B7H3 with high sensitivity and specificity. Measuring the levels of B7H3 in the serum specimens of colorectal cancer donors, we examined the usefulness of B7H3 as a novel biomarker for colorectal cancers. We tested the blood from the 82 donors of colorectal cancers and 9 healthy donors who agreed in writing to this research, just before the operation. The mean value + 2SD in 9 healthy donors was set as the cutoff value. We classified cancer patients into 2 groups with high value of B7H3 and low value of B7H3. We also analyzed the relationships between serum B7H3 levels and disease-free survival (DFS) and overall survival (OS). Serum B7H3 levels were also compared with diagnostic biomarkers such as CEA and CA19-9. B7H3 immunostaining was also performed on tissue samples. The serum levels of B7H3 in patients with colorectal cancer were significantly higher than those of healthy donors. However, there were no correlation between B7H3 and other diagnostic markers CEA and CA19-9. Regarding DFS, the higher value group of serum B7H3 showed a tendency for DFS to decrease in Stage II and III. Regarding OS, there was no significant difference of serum levels of B7H3 in Stage I and IV cases, however, in Stage II and III, OS decreased significantly in the high B7H3 group. In B7H3 immunostaining, the tissue was not sufficiently stained. These data indicate that serum B7-H3 should be useful for novel biomarker for a rationale of disease monitoring and prognosis of colorectal cancer.
Citation Format: Akihiro Koizumi, Tomoaki Ito, Kazunori Kato, Takumi Iwasawa, Tomoyuki Kushida, Koichi Sato, Chikako Okamoto. Soluble B7H3 has a potential of novel serum biomaker for colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2453.
Abstract 2484: Association of artificial intelligence (AI)-based HER2 scoring with clinical outcomes to first-line trastuzumab plus chemotherapy in HER2-positive metastatic gastric cancer (mGC)
Authors: Kang Minsu , Lim Yoojoo , Oh Hyeon Jeong , Lee Ji Ae , Kim Jin Won , Kim Ji-Won , Song Sanghoon , Song Heon , Lee Keun-Wook 
Published: March 2024

Abstract
Background: Although trastuzumab plus chemotherapy is the treatment of choice for HER2-positive mGC, not all patients respond to the therapy. To date, there is no reliable and efficient biomarker that can predict the response to trastuzumab-based treatment.
Methods: Clinical data and pathology slides from HER2-positive mGC patients treated with first-line trastuzumab and capecitabine/5-fluorouracil plus cisplatin were retrospectively collected. HER2 positivity was confirmed using standard methods with immunohistochemistry (IHC) and/or in situ hybridization. An AI-based model was applied to a single HER2 IHC-stained whole slide image (WSI) of each patient to identify and quantify the tumor cells with HER2 IHC staining intensity categories of 0, 1+, 2+, or 3+ on the slide. The proportion of tumor cells with 3+ staining intensity among total tumor cells (h3 percentage) in each slide was calculated and analyzed in relation to clinical outcomes.
Results: A total of 160 cases were included in this analysis. Overall, the median progression-free survival (PFS) was 9.2 mo, and the overall survival (OS) was 18.9 mo. By standard IHC HER2 grading, 107 (66.9%) 3+ and 53 (33.1%) 2+ cases were included. The median AI-estimated h3 percentage in these patients was 14.8% (range 0 - 99.5%). The patients with their best tumor response of complete (CR) or partial response (PR) (44.4%) exhibited significantly higher h3 percentages (mean h3 percentage 46.6% in CR/PR vs. 29.4% in stable or progressive disease, p = 0.018). The h3 percentage exhibited strong associations as a continuous variable with longer PFS (hazard ratio [HR] 0.94 [95% confidence interval (CI) 0.90 - 0.99] for 10% change of h3 percentages, p = 0.015) or OS (HR 0.93 [95% CI 0.89 - 0.98] for 10% change of h3 percentages, p = 0.004). Notably, patients having a proportion of 3+ tumor cells at ≥ 90% (27/160, 16.9%) showed particularly longer PFS (median PFS 21.4 mo in ≥ 90% vs. 8.5mo in &lt; 90%, p = 0.006) and OS (median OS 40.3 mo in ≥ 90% vs. 16.6 mo in &lt; 90%, p = 0.004).
Conclusion: AI-based models interpreting WSI can provide additive predictive information to HER2-positive mGC patients treated with trastuzumab plus chemotherapy.
Citation Format: Minsu Kang, Yoojoo Lim, Hyeon Jeong Oh, Ji Ae Lee, Jin Won Kim, Ji-Won Kim, Sanghoon Song, Heon Song, Keun-Wook Lee. Association of artificial intelligence (AI)-based HER2 scoring with clinical outcomes to first-line trastuzumab plus chemotherapy in HER2-positive metastatic gastric cancer (mGC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2484.
Abstract 2531: rs822336 as a predictive biomarker for anti-PD-1/PD-L1 immunotherapy in advanced NSCLC: Unraveling molecular mechanisms
Authors: Polcaro Giovanna , Liguori Luigi , Manzo Valentina , Chianese Annalisa , Donadio Giuliana , Caputo Alessandro , Scognamiglio Giosuè , Dell'Annunziata Federica , Langella Maddalena , Corbi Graziamaria , Ottaiano Alessandro , Cascella Marco , Perri Francesco , De Marco Margot , Col Jessica Dal , Pagliara Valentina , Zeppa Pio , Filippelli Amelia , Franci Gianluigi , Piaz Fabrizio Dal , Conti Valeria , Pepe Stefano , Sabbatino Francesco 
Published: March 2024

Abstract
Efficient predictive biomarkers are needed for immune checkpoint inhibitor (ICI)-based immunotherapy in non-small-cell lung cancer (NSCLC). So far, testing the predictive value of single nucleotide polymorphisms (SNPs) in programmed cell death 1 (PD-1) or its ligand 1 (PD-L1) has shown contrasting results. Here, we aimed to validate the predictive value of PD-L1 SNPs in advanced NSCLC patients treated with ICIs as well as to define the molecular mechanisms underlying the role of identified SNP candidate. rs822336 SNP efficiently predicted response to anti-PD-1/PD-L1-based immunotherapy in advanced NSCLC patients as compared to rs2282055 and rs4143815 SNPs. rs822336 SNP mapped on promoter/enhancer region of PD-L1, differentially affecting the induction of PD-L1 expression in human NSCLC cell lines. The induction of PD-L1 expression by rs822336 SNP was predicted by allele-specificity binding of two identified transcription factors: C/EBPβ and NFIC. As a result, silencing of C/EBPβ and NFIC differentially modulated the induction of PD-L1 expression in human NSCLC cell lines carrying different rs822336 genotypes. In addition, binding microarray validated the allele- specificity binding of C/EBPβ and NFIC to PD-L1 promoter/enhancer region based on rs822336 genotype in human NSCLC cell lines. Lastly, the induction of PD-L1 expression by rs822336 genotype differentially affected the susceptibility to anti-PD-1 monoclonal antibody nivolumab of human NSCLC cell lines co-cultured with HLA class I antigen matched PBMC. These results have clinical relevance since identified rs822336 SNP and the induction of PD-L1 expression as novel biomarkers for predicting ICI-based immunotherapy in NSCLC patients.
Citation Format: Giovanna Polcaro, Luigi Liguori, Valentina Manzo, Annalisa Chianese, Giuliana Donadio, Alessandro Caputo, Giosuè Scognamiglio, Federica Dell'Annunziata, Maddalena Langella, Graziamaria Corbi, Alessandro Ottaiano, Marco Cascella, Francesco Perri, Margot De Marco, Jessica Dal Col, Valentina Pagliara, Pio Zeppa, Amelia Filippelli, Gianluigi Franci, Fabrizio Dal Piaz, Valeria Conti, Stefano Pepe, Francesco Sabbatino. rs822336 as a predictive biomarker for anti-PD-1/PD-L1 immunotherapy in advanced NSCLC: Unraveling molecular mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2531.
Abstract 256: A novel transcriptional complex of OLIG2-STAT5 mediates glioma stem cell self renewal and invasion
Authors: Miller Aunay , Lo Cascio Costanza , Blomquist Mylan , McNamara James B. , Orndorff Keely , Dufault Matthew , Sereduk Christopher , Loftus Joseph , Mehta Shwetal , Tran Nhan L. 
Published: March 2024

Abstract
Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults, despite current treatment options. One of the major contributing factors to this dismal outcome is a subset of cells called glioma stem cells (GSCs) that are highly tumorigenic, invasive, and resistant to conventional treatments. Thus, studies that focus on the properties of GSC biology are needed to develop novel therapies to improve overall survival. Here we report a novel role of STAT5 in GSC stemness and survival. In GBM tumors, STAT5 has been shown to be active in the infiltrative, residual population of cells remaining post-surgery. Knockdown of STAT5 results in the decrease in GSC stemness and therapeutic resistance. Interestingly, we find that expression of OLIG2, a key cell fate factor important for the tumorigenic potential of GSCs, affects STAT5 activation with a positive correlation between OLIG2 and STAT5 mRNA expression in GBM tumors. Furthermore, we find that in GSCs expressing EGFRvIII, STAT5 interacts with OLIG2 and pharmacological inhibition of STAT5 activation or knockdown of STAT5 expression results in decrease of OLIG2-mediated GSC invasion. Together, these data suggest a novel transcriptional complex, STAT5-OLIG2, in the potential role for GSC survival, maintenance, and invasion.
Citation Format: Aunay Miller, Costanza Lo Cascio, Mylan Blomquist, James B. McNamara, Keely Orndorff, Matthew Dufault, Christopher Sereduk, Joseph Loftus, Shwetal Mehta, Nhan L. Tran. A novel transcriptional complex of OLIG2-STAT5 mediates glioma stem cell self renewal and invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 256.
Abstract 258: An organoid model for investigating Lynch syndrome tumorigenesis
Authors: Guild Caroline , Heinen Christopher , Nadeau Samantha 
Published: March 2024

Abstract
Lynch syndrome (LS) is the most common inherited predisposition for developing colon cancer and is caused by germline variants in mismatch repair (MMR) genes. Still, the mechanism of tumorigenesis in these patients is unknown. An LS patient inherits one defective copy of an MMR gene. At some point in their lifetime, the remaining wild-type allele is lost in a cell rendering it entirely MMR deficient. MMR deficiency increases mutational rate and the chance of acquiring mutations in an oncogene or tumor suppressor that drive tumor initiation. However, loss of MMR in cells also leads to increased resistance to certain forms of DNA damage. Thus, our question is whether this phenotype imparts a selective advantage in colonic cells that may lead to clonal expansion of MMR-deficient cells as a first step towards tumorigenesis in LS patients.
To test this, we are using stem cell-derived human colonic organoids and CRISPR gene editing to examine competition between MMR-deficient (MMRd) and MMR-proficient (MMRp) colonic cells over time. We have initially observed that MMRd stem cells are much more efficient at generating colonic organoids that grow larger and survive longer, consistent with our hypothesis of a selective advantage. To mimic the spontaneous loss of heterozygosity that occurs in LS patients’ colonic crypts, we are forming organoids from differentially labeled MMRd and MMRp stem cells. Live fluorescent imaging of individual organoids is used to quantify changes in cell population over time. Preliminary data indicate that MMRd cells can outgrow MMRp cells resulting in a shift in the ratio of green to red cells over a two-week time period while challenged with a DNA-damaging agent. These results suggest that loss of MMR function imparts an immediate selective advantage in colonic cells in response to DNA damage.
Citation Format: Caroline Guild, Christopher Heinen, Samantha Nadeau. An organoid model for investigating Lynch syndrome tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 258.