bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 5755: Mutation profiling of homologous recombination-related (HRR) genes in sarcoma patients
Authors: Gao Feng , Liu Xuejiao , Wang Xiaojuan , Wang Chunyang , Ma Tonghui , Yang Changsheng
Published: June 2022

BACKGROUND: Homologous recombination deficiency (HRD) is associated with tumorigenesis. Therapy directed toward HRD has been approved in breast and ovarian cancer, however, whether there is a chance of benefit for patients with other cancers remains unknown. Herein, we investigated the mutation characteristics of homologous recombination-related (HRR) genes in Chinese patients with sarcoma to explore possible benefit opportunities for sarcoma patients.

METHODS: The genetic landscape of HRR genes was assessed in 700 Chinese sarcoma patients with different subtypes including Rhabdomyosarcoma (RMS, n = 67), Liposarcoma (LPS, n = 58), Osteosarcoma (n = 34), Synovial sarcoma (n = 30), Leiomyosarcoma (n = 29), Ewing's sarcoma (EWS, n = 27), Angiosarcoma (n = 20), other rare (n = 375) and unknown subtypes (n = 60). Molecular profiles were performed by using next generation sequencing (NGS)-based Onco Panscan plus࣪ at Genetronhealth, a laboratory accredited by College of American Pathologists and Clinical Laboratory Improvement Amendments.

RESULTS: Among the 700 patients, the overall mutation frequency of HRR genes was 19.0%. Correspond to specific subtypes, the mutation frequency of HRR genes were higher in Leiomyosarcoma (27.6%, 8/29), Angiosarcoma (25.0%, 5/20) and LPS (17.2%, 10/58) compared with RMS (14.9%, 10/67), Osteosarcoma (14.7%, 5/34), Synovial sarcoma (13.3%, 4/30) and EWS (3.7%, 1/27). ATRX was the most commonly mutated gene (5.1%, n = 36) and was preferentially identified in Leiomyosarcoma (10.3%) and Angiosarcoma. (10.0%), followed by ARID1A (3.1%, n = 22), ATM (2.1%, n = 15) and FANCA/C/D2/E/F/G/L (1.7%, n = 12). The median tumor mutational burden (TMB) was 2.35 in patients with HRD and 0.94 in patients without HRD. Although BRCA1 and BRCA2 mutations were less common overall (1.1% and 0.7%), a significant proportion of BRCA1 and BRCA2 mutations was found in Angiosarcoma, Liposarcoma and Leiomyosarcoma (5.0%, 3.4% and 3.4%, respectively).

CONCLUSION: Our results reported the genetic landscape of HRR genes in Chinese sarcoma patients, providing a reference for the clinical application of PARP inhibitors.

Citation Format: Feng Gao, Xuejiao Liu, Xiaojuan Wang, Chunyang Wang, Tonghui Ma, Changsheng Yang. Mutation profiling of homologous recombination-related (HRR) genes in sarcoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5755.
Abstract 5758: Characteristic profile of blood-based ctDNA suggests angiogenesis and immune escape in hepatocellular carcinoma
Authors: Yan Lin Chia , Miao Liu , Xue Hu , Li Huang Meng
Published: June 2022

Background: Circulating tumor DNA (ctDNA) is a type of DNA released from tumor cells captured in blood circulation system. It provides a noninvasive approach to interrogate a patient’s genomic landscape and actionable mutations with well application prospect. However, the difference of genomic profiles between tissue and ctDNA still brings confusions to related researches. Therefore, we tried to elucidate whether blood-based ctDNA has its own characteristic profile to reflect tumor status in hepatocellular carcinoma (HCC).

Methods: Tumor tissue and blood samples from 118 HCC patients of Xiangya Hospital Central South University, were analyzed using NGS (panel on 147 gene). NGS data from a Chinese population extended cohort (385 tissues and 79 blood samples) of HCC were used to validate the mutation characteristics. Data from HCC cohorts of The Cancer Genome Atlas (TCGA) was used to analyze the disease-free survival (DFS) of different mutations.

Results: In the hospital cohort, there were 9 high-frequency mutant genes in tissue and blood, including TP53 (74.58% vs 74.58%), MSH2(23.73% vs 8.47%), LRP1B (20.34% vs 23.73%), ATM (18.64% vs 13.56%), CTNNB1 (11.86% vs 13.56%) et.al which consistent with previous reports. There were 32 genes (74.04%) with a mutation frequency of more than 6% that were unique to blood samples. In extended cohort, the mutation profile was similar to the hospital cohort, in which 35 genes (52.24%) specific in ctDNA profile and 18 genes of them identical to the hospital cohort. Interestingly, when these ctDNA-specific genes were analysed by gene ontology, most genes were involved in angiogenesis. The prognostic analysis in ctDNA-specific genes showed that patients with higher level of MAP3K1 had worse DFS (p=0.028). In addition, the gene co-expression network analysis showed MAP3K1 and NOTCH1/2/3 expression had a significant positive correlation, that Notch family members were also belonged to the ctDNA-specific genes and associated with tumor immune escape.

Conclusions: The results showed the mutation characteristic of tissues and ctDNA in HCC, and suggest that angiogenic and tumor immune escape related ctDNA-specific genes might be able to predict recurrence risk independently of baseline tissue samples.

Citation Format: Lin Chia Yan, Liu Miao, Hu Xue, Huang Meng Li. Characteristic profile of blood-based ctDNA suggests angiogenesis and immune escape in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5758.
Abstract 5763: Comprehensive characteristics between genomic alterations and tumor differentiation in Chinese patients with colorectal cancer
Authors: Cui Xiaolong , Ren Aigang , Chen Hao , Huo Yaoliang , Zeng Yanwu , Zhang Hao , Hu Meizhen , Huang He , Guo Yuntong
Published: June 2022

Background: Colorectal cancer (CRC) is a malignant tumor that seriously threatens human health. Valuable diagnostic and prognostic biomarkers are urgently needed for colorectal cancer. We aim to analyze the mutational characteristics of Chinese CRC patients with different tumor differentiation degree, in order to improve the diagnosis and prognosis of this population.

Methods: We retrospectively analyzed tumor tissue specimens from colorectal cancer patients who were treated at the First Affiliated Hospital of Shanxi Medical University from 2019 to 2021. Targeted NGS for 450 genes was performed in OrigiMed (Shanghai, China), a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory.

Results: There were 35 males (55.6%) and 28 females (44.4%) with a median age of 60 (range 23-87) years were involved, including 55 moderately and well differentiated and 8 poorly differentiated colorectal tumors. The mutational frequency of BRAF in the poorly differentiated group was significantly higher than that in moderately and well differentiated group(25% vs. 1.8%, p=0.04). The mutational frequencies of the chromosome folding pathway, notch pathway, and PI3K pathway in poorly differentiated group were significantly lower than that in moderately and well differentiated group(p=0.975X10-15,p=0.97 X 10-26,and p=0.00517, respectively). In this study, the mutations of PDCD1 (programmed cell death 1) and TSC2 Significantly associated with tumor mutation burden (p=0.007 and p=0.047, respectively). In addition, high-frequency co-mutations of chromosome folding-related genes and DNA damage repair-related genes, such as co-mutations between ARID1A-MLH1,KMT2D-MSH6,KMT2D-MSH2, KMT2D-BRCA1, ARID1A-CHEK2, were detected in this study.

Conclusions: We compared the genomic alterations between well-differentiated group and poorly-differentiated group in Chinese CRC patients. Our data showed significant differences in mutational frequency of chromosome folding pathways, notch pathways, and PI3K pathways between well-differentiated group and poorly-differentiated group. Meanwhile, we also identified the high-frequency and complex co-mutation characteristics of chromosome folding pathway genes and DNA damage repair genes in Chinese CRC patients.

Citation Format: Xiaolong Cui, Aigang Ren, Hao Chen, Yaoliang Huo, Yanwu Zeng, Hao Zhang, Meizhen Hu, He Huang, Yuntong Guo. Comprehensive characteristics between genomic alterations and tumor differentiation in Chinese patients with colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5763.
Abstract 5786: Mitochondrial genome evolution in gliomas under therapy
Authors: Wade Taylor E. , Varn Frederick S. , Johnson Kevin C. , Verhaak Roel G.
Published: June 2022

Gliomas are the most common malignant brain tumors and characterized by high recurrence rate and therapeutic resistance. Gliomas are clinically separated by mutations in isocitrate dehydrogenase (IDH) genes, but all subtypes have an altered energy metabolism. Mitochondria are essential cellular organelles that mediate many biological processes associated with tumorigenesis, such as energy metabolism and cell death, that can be impacted by mitochondrial mutations and copy number. As part of the Glioma Longitudinal AnalyiSiS consortium, we characterized mitochondrial genome evolution in response to treatment, using whole-genome sequencing data and associated RNA sequencing data from 152 paired tumor samples from 76 patients. Mitochondrial mutations are unequally distributed across the mitochondrial glioma genome, with only 4 of 13 mtDNA genes harboring a mutation across the cohort. Previous consortium analyses have investigated nuclear DNA hypermutation and changes in aneuploidy in response to chemotherapy and radiation treatment. Previous findings have identified hypermutation and copy number alterations as mechanisms of therapeutic resistance in glioma, but did not include analyses on mitochondrial DNA. Our analysis identified key differences between mitochondrial genome evolution and nuclear genome evolution. The mitochondrial mutational burden was not correlated with an increase in nuclear mutational burden. Unlike the nuclear DNA, we did not observe any samples with treatment-associated hypermutation. Mitochondrial copy number varied greatly but was increased at recurrence in IDH wild-type tumors. In tumors with a mutation in the IDH1 gene, mitochondrial copy number decreases were associated with an increase in aneuploidy score in samples that received radiation therapy. Expression analyses highlighted key differences in the active repair mechanisms between mtDNA and nuclear DNA. Our findings shed light on the variations in DNA repair mechanisms between the nucleus and the cytoplasm in glioma and lay the foundation for further analyses on the co-evolution of the mitochondrial and nuclear genomes in treatment-resistant tumors.

Citation Format: Taylor E. Wade, Frederick S. Varn, Kevin C. Johnson, Roel G. Verhaak. Mitochondrial genome evolution in gliomas under therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5786.
Abstract 58: Novel enzymatic fragmentation for challenging samples and methods
Authors: Sexton Brittany S. , Heider Maggie , Williams Louise , Langhorst Bradley , Dimalanta Eileen , Apone Lynne
Published: June 2022

Next Generation Sequencing (NGS) requires fragmentation of DNA molecules upstream of sequencing. Current methods for fragmentation include mechanical shearing and enzymatic fragmentation for NGS library preparation. Mechanical shearing requires costly instruments, can be difficult to automate for high throughput labs, and results in sample loss. In comparison, enzymatic fragmentation methods do not require expensive instruments and are automation friendly. However, current enzymatic fragmentation methods on the market can remove DNA modifications such as methylation, cement DNA damage resulting from formalin fixation in final libraries and can introduce sequencing artifacts or bias. Therefore, while many fragmentation methods are commercially available, challenges remain for sequencing samples such as FFPE DNA or for detecting DNA modification (e.g., 5-methylcytosine).

We have developed a novel enzymatic fragmentation method that can be used upstream of library preparation for DNA methylation assessment or FFPE DNA. The novel enzymatic fragmentation method is quick and robust, taking as little as 20 minutes. It is automation-friendly and can be used to generate DNA fragments ranging from as small as 50 bp up to over 1000 bp.

Here we demonstrate the use of the novel enzymatic fragmentation method upstream of 5mC library preparation methods. This fragmentation method maintained the methylation marks. These libraries showed improvements in GC bias, library yield, library complexity and other sequencing metrics over libraries generated with mechanically sheared DNA.

The use of the novel enzymatic fragmentation method with FFPE DNA library preparation resulted in improvements in sequencing metrics (increased proper pairs, etc.). There was reduced FFPE-damage-derived mutations compared to mechanical shearing or other enzymatic fragmentation methods.

Fragmenting DNA to defined sizes for diverse applications and sample types remains a challenging aspect of NGS library preparation. This new, robust enzymatic fragmentation method overcomes the limitations of some traditional mechanical and enzymatic fragmentation methods and improves the library preparation and sequencing for both DNA modification assessment studies and FFPE DNA.

Citation Format: Brittany S. Sexton, Maggie Heider, Louise Williams, Bradley Langhorst, Eileen Dimalanta, Lynne Apone. Novel enzymatic fragmentation for challenging samples and methods [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 58.
Abstract 5800: Germline pathogenic variant of cancer predisposition genes in pancreatic cancer patients
Authors: Kim Yena , Kim Min Kyeong , Ryu Kum Hei , Shim Hyoeun , Han Ji Sun , Chun Jung Won , Kim Yun-Hee , Song Ju Sun , Kim Young-gon , Woo Sang Myung , Kong Sun-Young
Published: June 2022

Purpose: Genetic attribution for pancreatic cancer has been reported as 2-10%. However, the incidence of genetic predisposition and germline pathogenic variants (PVs) in Korean pancreatic cancer patients has not been well investigated. Therefore we studied to identify the clinical characteristics of the causative gene mutations and incidence of PV for future treatment strategies in pancreatic cancer.

Methods: Total of 283 (145 male and 138 female) patients were enrolled in National Cancer Center in Korea (IRB no. NCC2019-0034, NCC2021-0338) and their median age was 67 years (range: 33-90). Resectable (25.1%), borderline resectable or locally advanced (25.5%), and metastatic (46.3%) stages were included. Germline hereditary cancer panel tests with 28 genes and BRCA1/2 gene were done in 97.2% (n=275) and 2.8% (n=8) of patients, respectively.

Results: PVs were detected in 17 patients (median age 64, range 49-80) in ATM (n=5, 29.4%), BRCA1 (n=3, 17.6%), BRCA2 (n=2, 11.8%), RAD51D (n=2, 11.8%), TP53 (n=1, 5.9%), PALB2 (n=1, 5.9%), PMS2 (n=1, 5.9%), RAD50 (n=1, 5.9%), and SPINK1 (n=1, 5.9%). Eight patients (4 ATM PVs, 2 BRCA1 1 BRCA2, 1 PALB2 PV) presented various type of cancers in their families and three patients with ATM PVs showed pancreatic cancer in their first degree relatives. Nine patients without family cancer history represented median age as 66 (49-80) which was not significantly different of those with family history as 63 (51-75).

Conclusions: This study showed 6.0% of incidence of germline PVs in Korean pancreatic cancer patients. Though we still don’t have guidelines for germline predisposition gene test in pancreatic cancer patients in Korea, this result showed that the incidence of PVs were comparable with that of the country which have recommendation to do genetic tests for all pancreatic cancer patients. To expand our knowledge for the incidence and involving genes of cancer predisposition for Korean pancreatic cancer patients, further analysis in larger number of patients is needed. (This study was supported by National cancer center, Korea, Grant no. 2110181).Keywords: Germ-line Mutation; Pancreatic Neoplasms; Incidence

Citation Format: Yena Kim, Min Kyeong Kim, Kum Hei Ryu, Hyoeun Shim, Ji Sun Han, Jung Won Chun, Yun-Hee Kim, Ju Sun Song, Young-gon Kim, Sang Myung Woo, Sun-Young Kong. Germline pathogenic variant of cancer predisposition genes in pancreatic cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5800.
Abstract 5804: The inhibition of PLA2G2A decreases K-ras-driven pancreatic cancer growth and migration through damaging cell membrane and mitochondria function
Authors: zhang Mingquan , huang Peng
Published: June 2022

The activation of oncogenic K-ras by mutations may stimulate multiple cellular processes including lipids modification. However, the mechanisms by which K-ras affects lipid metabolism remain poorly understood. In this study, we found that PLA2G2A, an enzyme that hydrolyzes membrane phospholipids at sn-2 position to release polyunsaturated fatty acids (PUFA), was up-regulated by K-ras activation and its high expression was correlated with poor survival of patients with pancreatic ductal adenocarcinoma (PDAC). Abrogation of PLA2G2A by siRNA silencing or pharmacological inhibition significantly suppressed the proliferation of K-ras-driven cancer cells, as evidenced by inhibition of cell growth and loss of colony formation capacity. Suppression of PLA2G2A could also decrease K-ras-driven PDAC cell migration. Mechanistic study showed that PLA2G2A inhibition rendered cells vulnerability to lipid peroxidation, likely due to accumulation of excessive PUFA in the membranes. Such alterations resulted in membrane damage and mitochondrial dysfunction with elevated ROS, leading to a reduction in energy production and a decrease in acetyl-CoA, which further compromised de novo lipid biosynthesis. Our study suggests that PLA2G2A-mediated cell membrane remodeling plays an important role in cell survival and proliferation in during K-ras-driven cancer, and that PLA2G2 could be a potential therapeutic target for pancreatic cancer treatment.

Citation Format: Mingquan zhang, Peng huang. The inhibition of PLA2G2A decreases K-ras-driven pancreatic cancer growth and migration through damaging cell membrane and mitochondria function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5804.
Abstract 5809: eIF2α O-GlcNAcylation promotes oxidative stress in arginine-starved triple-negative breast cancer cells
Authors: Hung Yu-Wen , Wang Yi-Chang , Ann David K.
Published: June 2022

Redox balance is the critical liaison for cancer homeostasis. Moderate increases in reactive oxygen species (ROS) levels can lead to cancer formation and progression. However, a disproportional increase of ROS levels changes equilibrium in cell redox status and leads to cancer cell death. Therefore, exogenous agents or antioxidant inhibitors which augment ROS generation become a potential new way to target cancer cells. We have found excessive accumulation of cellular proteins during arginine starvation causes stresses on the endoplasmic reticulum (ER) protein folding machinery resulting in elevated ROS levels. In this study, we continue to examine that arginine starvation-attenuated heme oxygenase-1 (HO-1) translation exacerbates the high ROS level to kill the cancer cells. In addition, HO-1 translational downregulation is due to arginine starvation-induced O-GlcNAcylation of eIF2α at S219, T239, and T241 residues. Loss of O-GlcNAcylation at eIF2α significantly rescues arginine starvation-reduced HO-1 protein level, resulting in better recovery and migratory properties from starvation and lower ROS level. In addition, arginine starvation-induced O-GlcNAcylation of eIF2α to suppress HO-1 translation is independent of its phosphorylation at S51, which is another stress-stimuli modification that regulates eIF2 involved protein translation. Arginine starvation exploits O-GlcNAcylation to antagonize eIF2α phosphorylation-induced HO-1 expression. Taken together, arginine starvation is a potential anti-cancer therapy in which induced eIF2α O-GlcNAcylation presents itself as a critical role for metabolic adaptation and tumor growth by dysregulating the antioxidant protein in cancer cells.

Citation Format: Yu-Wen Hung, Yi-Chang Wang, David K. Ann. eIF2α O-GlcNAcylation promotes oxidative stress in arginine-starved triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5809.
Abstract 5827: Increased miR150 expression in tumors enhances lymphocytes infiltration causing immunosuppression through inflammatory chemokines
Authors: Maiti Aparna , Oshi Masanori , Wu Rongrong , Hait Nitai , Takabe Kazuaki
Published: June 2022

Dysregulated miRNAs play key roles in multiple biological processes and cancer. miR-150-5p, a cancer-related miRNA, has been reported to be aberrantly expressed in various cancers. We found that triple-negative and HER2+ breast cancer patients have elevated expression of miR150 in the TCGA and METABRIC patient cohort. Both cohorts showed significantly increased expression of miR150 in grade IV patients. Further studies explained that miR150 is strongly correlated with CD8+ T cells and B cells in accord with increased expression of immune-checkpoint markers PD-1, PDL-1, and CTLA4. We, therefore, hypothesized that higher expression of miR150 in tumors attracted more immune cells in the tumor microenvironment. We use two triple negative breast cancer cell lines MDA-231 and BT-549 cells and overexpressed miR150 followed by co-culture them with Jurkart and B cells. Our data revealed that both jurkart and B cells had increased migration towards cancer cells overexpressed miR150 mimic compared to miR150 mimic negative control. Interestingly, overexpressed miR150 mimic in cancer cells inhibited migration in both triple-negative breast cancer cells. Overexpression of miR150 mimic in cancer cells did not alter cell proliferation. To understand further the role of miR150 in breast cancer, we overexpressed miR150 mimic and its corresponding negative control in MDA-231 and did RNA seq analysis. RNA seq data explained that approximately 4927 genes are upregulated with miR150 mimic overexpression. Interestingly several chemokines and mediators of metastasis (CXCL2, CXCL1 CCL20, IGBP3, and ANGPTL4) are upregulated among the top 50 upregulated genes. In addition, gene enrichment analysis explained that TNF-α signaling pathways, Hypoxia, epithelial-mesenchymal pathways, E2F signaling, and Inflammatory pathways are a few upregulated pathways with miR150 mimic overexpression compared to the negative control. We also found miR150 high tumor enriched correlated with interferon-alpha and gamma signaling, inflammatory response pathways similar with cohort analysis data. In conclusion, miR150 in cancer plays a key role in interferon and inflammatory signaling pathways attracting more immune cells and suppressing the tumor microenvironment.

Citation Format: Aparna Maiti, Masanori Oshi, Rongrong Wu, Nitai Hait, Kazuaki Takabe. Increased miR150 expression in tumors enhances lymphocytes infiltration causing immunosuppression through inflammatory chemokines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5827.
Abstract 5850: p53 gene expression and nitric oxide levels after artemisinin-caffeine treatment in breast, lungs and liver of DMBA-induced tumorigenesis
Authors: Dokunmu Titilope M. , Opara Sandra C. , Awani Omiete U.
Published: June 2022

Background: With increasing incidence of cancers globally and limited resources in some affected countries, repurposing existing drugs for reducing tumorigenesis is highly important. Artemisinin and caffeine have potent anti-oxidative and anti-cancer properties, although they are therapies for other diseases. When p53 is activated, it repairs DNA damage, prevents tumorigenesis and induces apoptosis whereas nitric oxide is a pro-apoptotic modulator which can upregulate p53 thereby reducing tumorigenesis. We evaluated the biochemical and p53 gene modulatory effects of doses of artemisinin-caffeine combination on breast, lung and liver tumors in rats induced with DMBA.

Methods: After due ethical approval, 30 animals were treated with 40mg/kg single dose of 7,12-dimethylbenzene anthracene (DMBA) as a model for DNA damage and induction of carcinogenesis. Five animals each received low dose artemisinin (4mg/kg), low dose caffeine (25mg/kg), low dose combination of Art + Caff (4+25mg/kg), high dose combination of Art + Caff (8+50 mg/kg) or no treatment. All treatment doses were orally administered daily for two weeks post-DMBA treatment, normal control received saline. Nitric oxide levels were assessed and p53 relative gene expression was determined by primer-specific RT-PCR (GAPDH was used as loading control) and amplicons were resolved by gel electrophoresis.

Results: DMBA induced lesions in breast, liver, and lung tissues were evident from histology analysis, compared to untreated group. In all 3 tissues, low dose caffeine and combination of Art + Caff significantly reduced p53 gene expression (p < 0.05), but there was significant increase in of p53 expression in low dose Art and high dose Art + Caff groups, which were similar to DMBA group (p<0.05). There was also decrease in nitric oxide levels in treated groups compared to DMBA group.

Conclusions: This study shows a dose-dependent anticancer effects of caffeine and artemisinin combination on p53 gene and nitric oxide regulation and hence can mitigate against tumorigenesis.

Citation Format: Titilope M. Dokunmu, Sandra C. Opara, Omiete U. Awani. p53 gene expression and nitric oxide levels after artemisinin-caffeine treatment in breast, lungs and liver of DMBA-induced tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5850.
Abstract 5851: Negative regulation of p53 by ZnT1
Authors: Brik Ben , Carino Kathleen , Narrow Wade , Harris Chris R. , Yu Xin , Carpizo Darren R.
Published: June 2022

Rationale and Background: p53 is a powerful tumor suppressor protein that also autorepresses by inducing expression of its own negative regulators, such as MDM2. Here we explore another potential mechanism for p53 autorepression, regulation of zinc metabolism. Proper folding of p53 requires zinc binding and cancer-associated mutations in p53 often lower the affinity of the mutant proteins for zinc. Our previous work showed that ZMC1, a zinc metallochaperone, can reactivate certain p53 mutants by raising intracellular zinc concentrations. Here we show that p53 activates transcription of ZnT1. ZnT1 can then export zinc from the cell, which in turn lowers p53 activity.

Methods: To explore the relationship between ZnT1 and p53, we studied several human cancer cell lines under various conditions, including ZnT1 overexpression, ZnT1 silencing, and p53 activation. For silencing gene expression, we used CRISPR-Cas9 with a lentiviral vector to knock out ZnT1 and also employed shRNAs to knockdown expression of p53 or ZnT1. To analyze the relationship between TP53 and ZnT1 genes in clinical samples, data from cBioPortal were examined.

Results: ZnT1 transcription increased after p53 was activated in several p53+ cell lines but did not increase in isogenic p53-null cell lines, suggesting that ZnT1 transcription is dependent on p53. p53 also bound to the ZnT1 promoter by chromatin immunoprecipitation assay, and activated transcription of a ZnT1/luciferase promoter fusion. Overexpression of ZnT1 decreased p21 transcription, indicating lowered p53 function; conversely, knockdown of ZnT1 increased p21 transcription. By cBioPortal analysis, ZnT1 gene amplifications were mutually exclusive with TP53 gene mutations in breast and lung tumors.

Conclusion: These data suggest that autorepression of p53 occurs in part due to lowered intracellular zinc caused by upregulation of ZnT1.

Citation Format: Ben Brik, Kathleen Carino, Wade Narrow, Chris R. Harris, Xin Yu, Darren R. Carpizo. Negative regulation of p53 by ZnT1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5851.
Abstract 5867: Examination of race/ethnicity differences in patient reported outcomes (PROs) among elderly female breast cancer patients in the SEER-MHOS database
Authors: Krebsbach Kendra R. , Stallion Chloe L. , Dookeran Keith A.
Published: June 2022

We use regression models to examine baseline differences in physical and mental health PROs [Physical and Mental Component Summary T-scores (PCS/MCS: are linear transformations of the 0-100 possible range scoring for 8 SF-36/VR-12 sub-scales, with mean of 50 and standard deviation (SD) of 10, normed to the US population)] among non-Hispanic black (NHB), non-Hispanic white (NHW), and Hispanic elderly female patients, with newly diagnosed breast cancer (BC) between 2010-2015 in the Surveillance, Epidemiology and End Results-Medicare Health Outcomes Survey (SEER-MHOS) database (a cancer registry that provides value health-related quality of life information on patients enrolled in Medicare Advantage). The study analytic sample consisted of 11,765 NHW, 1,988 NHB and 1,361 Hispanic women with overall mean age and BMI of 50.1 years (SD: 10.5) and 27.5 kg/m^2 (SD: 6.6), respectively. Compared with NHW both NHB and Hispanic women had significantly elevated BMI [NHB risk difference (RD) 3.43, 95% CI: 3.09, 3.77; Hispanic RD 0.84, 95% CI: 0.44, 1.24]; but significantly lower age at diagnosis [NHB RD -2.86, 95% CI: -3.36, -2.37; Hispanic RD -1.67, 95% CI: -2.26, -1.09]. Compared with NHW, both crude PCS and MCS scores were significantly worse for NHB and Hispanic women [PCS: NHB RD -4.26, 95% CI: -4.87, -3.65; Hispanic RD -3.29, 95% CI: -4.01, -2.56; MCS: NHB RD -3.79, 95% CI: -4.37, -3.22; Hispanic RD -4.09, 95% CI: -4.76, -3.43]. These differences also persisted after adjustment for BMI and age [compared with NHW, PCS: NHB RD -2.09, 95% CI: -2.76, -1.43; Hispanic RD -3.26, 95% CI: -4.06, -2.45; MCS: NHB RD -3.2, 95% CI: -3.86, -2.54; Hispanic RD -4.21, 95% CI: -4.99, -3.43]. There were however no significant differences in PCS or MCS scores between NHB and Hispanic women after adjustment for age and BMI. Our results show that elderly NHB and Hispanic women with BC in the SEER-MHOS database are significantly more likely to have poorer physical and mental outcomes compared with NHW. However, this PRO disparity was not evident between NHB and Hispanic women and requires further exploration.

Citation Format: Kendra R. Krebsbach, Chloe L. Stallion, Keith A. Dookeran. Examination of race/ethnicity differences in patient reported outcomes (PROs) among elderly female breast cancer patients in the SEER-MHOS database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5867.
Abstract 5868: Factors associated with exercise participation in patients with breast cancer
Authors: Marell Paulina S. , Olson Janet E. , Herrmann Joerg , Larson Nicole L. , LeBrasseur Nathan K. , D'Andre Stacy D. , Cheville Andrea L. , Barksdale Toure , Loprinzi Charles L. , Couch Fergus J. , Ruddy Kathryn J.
Published: June 2022

BACKGROUND: The American Cancer Society recommends at least 150 minutes of moderate and/or strenuous exercise and muscle-strengthening activities each week for adults. Exercise has been associated with decreased breast cancer mortality and adverse symptoms. This study’s purpose is to understand prevalence and predictors of inadequate aerobic exercise in patients recently diagnosed with breast cancer to inform interventions to increase exercise participation.

METHODS: Patients seen at least once at Mayo Clinic Rochester were prospectively enrolled within one year of an initial breast cancer diagnosis in the Mayo Clinic Breast Disease Registry after providing informed consent. This analysis includes those who completed a baseline survey with self-reported exercise data using the Godin Leisure-Time Exercise Questionnaire. This longitudinal cohort study was approved by the Mayo Clinic institutional review board.

RESULTS: 1,738 participants reported their usual weekly quantity of moderate and strenuous exercise an average of 95 days (SD 71 days, range 0-365) after diagnosis. Table 1 displays participant characteristics overall and by whether participants reported at least 150 minutes of moderate and/or strenuous activity weekly (“met guidelines”) or not (“did not meet guidelines”). Overall, 39% of participants met guidelines, including 56% of those aged 18-39 years, 40% of those aged 40-69 years, and 27% of those aged 70+ years.

CONCLUSION: Older age was associated with less likelihood of meeting exercise guidelines (all age groups vs 70+, p < 0.05). A more diverse cohort will be needed to evaluate differences by gender and race/ethnicity. There did not appear to be any obvious impact on exercise level by time since diagnosis (during the first year after diagnosis) or educational status, though substantial missing data limit conclusions related to the latter. Additional research is needed to assess exercise levels later in survivorship and the impact of various treatment modalities on exercise habits

Table 1. Patient and tumor characteristics

Citation Format: Paulina S. Marell, Janet E. Olson, Joerg Herrmann, Nicole L. Larson, Nathan K. LeBrasseur, Stacy D. D'Andre, Andrea L. Cheville, Toure Barksdale, Charles L. Loprinzi, Fergus J. Couch, Kathryn J. Ruddy. Factors associated with exercise participation in patients with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5868.
Abstract 5880: Diabetes incidence after obesity-related cancer diagnosis and survival in the women’s health initiative
Authors: Karra Prasoona , Winn Maci , Haaland Benjamin , Anderson Garnet , Thomson Cynthia A. , Shadyab Aladdin H. , Luo Juhua , Saquib Nazmus , Strickler Howard , Chlebowski Rowan , Arthur Rhonda , Hardikar Sheetal , Playdon Mary C.
Published: June 2022

Introduction: Obesity-related cancer (ORC) diagnosed individuals are at an elevated risk of new-onset diabetes compared with cancer-free individuals. However, less is known about mortality among those with incident type 2 diabetes after cancer.

Methods: In the Women’s Health Initiative (N=14,455 ORC cases), we measured the association of incident type 2 diabetes diagnosed 0-1 years, >1-3, >3-5, >5-7 and >7-10 years after ORC diagnosis with cancer-specific and overall mortality using stratified Cox proportional hazards regression analysis.

Results: The participants were post-menopausal females with ORC and predominantly white. The number of WHI participants with ORC who developed diabetes after cancer diagnosis were: 0-1 years - 205/12992 (1.58%); 1-3 years - 326/11322 (2.88%); 3-5 years - 276/9784 (2.82%); 5-7 years - 268/8420 (3.18%); and 7-10 years - 510/6419 (7.95%). The median survival after the first year of cancer diagnosis for participants without diabetes was 16.6 years (95% CI: 16.17-17.0 years) and for those with diabetes was 10.3 years (95% CI: 7.97-14.9 years). New-onset diabetes after ORC diagnosis showed elevated overall mortality and cancer-specific mortality when compared with no diabetes diagnosis.

Conclusions: Incident type 2 diabetes is associated with worse cancer-specific and overall survival, particularly in the year after diagnosis, among women with ORC.

Type 2 Diabetes from time since cancer diagnosis Overall mortality HR (95% CI)a Cancer-specific mortality HR (95% CI)a 0-1 years 1.79 (1.41-2.29) 1.56 (1.04-2.34) >1-3 years 1.22 (0.99-1.51) 1.05 (0.72-1.55) >3-5 years 1.21 (0.95-1.55) 1.37 (0.89-2.12) >5-7 years 1.02 (0.78-1.33) 0.80 (0.47-1.36) >7-10 years 1.10 (0.87-1.40) 0.97 (0.59-1.60) aModel adjusted for demographics (age, education, race/ethnicity, marital status), body mass index (BMI)) and cancer characteristics (cancer type, stage, grade). CI = confidence interval; HR = Hazard ratio.

Citation Format: Prasoona Karra, Maci Winn, Benjamin Haaland, Garnet Anderson, Cynthia A. Thomson, Aladdin H. Shadyab, Juhua Luo, Nazmus Saquib, Howard Strickler, Rowan Chlebowski, Rhonda Arthur, Sheetal Hardikar, Mary C. Playdon. Diabetes incidence after obesity-related cancer diagnosis and survival in the women’s health initiative [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5880.
Abstract 5921: Machine learning based detection of pancreatic tumors using the Dxcover® cancer platform
Authors: Sala Alexandra , Cameron James M. , Jenkins Cerys A. , Barr Hugh , Christie Loren , Conn Justin J. , Evans Thomas (Jeff) R. , Harris Dean A. , Palmer David S. , Rinaldi Christopher , Theakstone Ashton G. , Baker Matthew J.
Published: June 2022

Pancreatic cancer is the 7th most deadly cancer worldwide with over 460,000 victims per year. In the current diagnostic pathway, carbohydrate antigen (CA) 19-9 serum test is the first method used for detection of pancreatic cancer; although, with poor positive predictive values reported, it cannot provide certain information about the presence of a pancreatic tumor or other surrounding tumors in symptomatic patients. Attenuated total reflection - Fourier transform infrared spectroscopy (ATR-FTIR) has demonstrated exceptional potential in human blood serum analysis for cancer diagnostics and its implementation in the clinical environment could represent a significant step forward in the early detection of pancreatic cancer. This proof-of-concept study was focused on the discrimination between both cancer versus healthy control samples, and cancer versus symptomatic control samples from patients with comorbidities and/or confounding diseases. The study aimed to investigate the use of the Dxcover® cancer platform as a novel approach for pancreatic cancer detection. Various machine learning algorithms were applied to discriminate between cancer (n=100) and healthy control samples (n=100), achieving results amounting to a sensitivity of 91.0 ± 5.6%, specificity of 87.6 ± 5.8%, and accuracy of 89.3 ± 3.8% with partial least squares-discriminant analysis (PLS-DA). Moreover, an area under the curve (AUC) equal to 0.9536 was obtained through receiving operating characteristic (ROC) analysis. The same algorithms were also applied to discriminate between cancer (n=35) and symptomatic control samples (n=35) achieving a balanced sensitivity and specificity over 75% with an AUC of 0.8436. Both discriminations underwent bootstrapping validation and were proven statistically significant. Herein, we present these results and demonstrate that ATR-FTIR spectroscopic analysis of serum is a cost-effective, minimally invasive, highly sensitive and specific test for detection of pancreatic cancer.

Citation Format: Alexandra Sala, James M. Cameron, Cerys A. Jenkins, Hugh Barr, Loren Christie, Justin J. Conn, Thomas (Jeff) R. Evans, Dean A. Harris, David S. Palmer, Christopher Rinaldi, Ashton G. Theakstone, Matthew J. Baker. Machine learning based detection of pancreatic tumors using the Dxcover® cancer platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5921.
Abstract 5926: Hepatocellular carcinoma in the hepatitis B vaccinated and nonvaccinated age groups in The Gambia
Authors: Bittaye Sheikh Omar , Njie Ramou
Published: June 2022

INTRODUCTION: Hepatitis B vaccination was started in The Gambia in July 1986 and nationwide coverage was achieved in February1990. However not much is known about its effect in the prevention of Hepatocellular carcinoma (HCC) in The Gambia.

OBJECTIVE: We assess the differences in the features of HCC in both the Hepatitis B vaccinated and non-vaccinated age groups in The Gambia.

METHOD: Patients with suspected HCC who were referred to the main liver clinic at the Medical Research Council, Gambia Unit (MRCG) were recruited from June 2011 to September 2019. The diagnostic criteria for HCC comprised of ultrasound demonstration of liver mass ≥2 cm with or without clinical features combined with alpha-fetoprotein (AFP) level of ≥200 ng/ml and/or histopathological confirmation. Clinical, radiological, fibroelastrography and laboratory data were collected in all patients.

RESULTS: Five hundred and forty two patients were recruited into the study. The majority (91.3%) of the patients were in the non-vaccinated age group and most (88.8%) were born in The Gambia. Those born outside The Gambia were mostly Senegalese, Sierreleonean, and Guineans. The patients in the vaccinated age group were much younger and less likely to be born in The Gambia. They were also more likely to have higher AFP levels, positive HBsAg and a lower creatinine level as compared to those patients in the non-vaccinated age group. There was no difference in clinical manifestations, Liver Function tests and median survival.

CONCLUSIONS: The early introduction of Nationwide Hepatitis B vaccination in 1990 into the EPI program in The Gambia may have had a positive effect in the incidence of Hepatocellular Carcinoma in the vaccinated age group. Compared to neighbouring countries, The Gambia seems to be leading the path for Hepatitis B elimination.To strengthen these gains, a nationwide screening and treatment program needs to be implemented for those in the non-vaccinated age groups.

Citation Format: Sheikh Omar Bittaye, Ramou Njie. Hepatocellular carcinoma in the hepatitis B vaccinated and nonvaccinated age groups in The Gambia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5926.
Abstract 5930: Identifying effective communication for recruitment of minority women to a breast cancer prevention study: A novel focus group approach
Authors: Ridley-Merriweather Katherine E. , Younker Stephanie M. , Evans Madeline D. , Wu Cynthia Y.
Published: June 2022

Ensuring that minoritized women are involved in breast cancer research is important to address well-documented current disparities in cancer incidence, stages of diagnosis, and mortality rates. This study used a novel interactive focus group method to identify innovative communication strategies for recruiting women from two minority groups—Latinas and Asian Americans—into the Komen Tissue Bank, a specific breast cancer biobank clinical trial. Through activities that employed visual interactive tools to facilitate group discussion and self-reflection, the authors examined perspectives and motivations for Asian American women (N=17) and Latinas (N=14) toward donating their healthy breast tissue. Findings included three themes that, while common to both groups, were unique in how they were expressed: lack of knowledge concerning breast cancer risks and participation in clinical research, cultural influences in breast cancer risk thinking, and how altruism relates to perceived personal connection to breast cancer. More significantly, this study illuminated the importance of using innovative methods to encourage deeper, more enlightened participation among underrepresented populations that may not arise in a traditional focus group format. The findings from this study will inform future health communication efforts to recruit women from these groups into clinical research projects like the Komen Tissue Bank. These findings also illustrate the importance of applying rigorous qualitative work to supplement quantitative research to increase the inclusion of minoritized populations in clinical trials.

Citation Format: Katherine E. Ridley-Merriweather, Stephanie M. Younker, Madeline D. Evans, Cynthia Y. Wu. Identifying effective communication for recruitment of minority women to a breast cancer prevention study: A novel focus group approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5930.
Abstract 5931: Development and validation of a novel circulating cell-free microRNA diagnostic model with high accuracy for multi-cancer early detection
Authors: Zhang Andrew , Hu Hai
Published: June 2022

Introduction: Early detection is critical to reduce cancer deaths as treating early stage cancers is more likely to be successful. We aimed to develop and validate a noninvasive blood-based diagnostic model capable of detecting multiple cancers by assessing the expression levels of serum microRNAs (miRNAs).

Patients and Methods: Four microarray datasets assessing expression profiles of 2588 serum miRNAs with a standardized platform were assembled from Gene Expression Omnibus (GEO) totaling 7536 participants including 3604 cancer patients across 13 cancer types and 3932 non-cancer controls. A diagnostic model was built in a training set of 416 participants, including 208 lung cancer patients and 208 non-cancer controls matched for age, sex, and smoking history. The model performance was assessed in the validation sets consisting of all the remaining 7120 participants.

Results: A 4-miRNA diagnostic model was developed from the lung cancer training set. The model showed 99% sensitivity and specificity in the lung cancer validation set (n=3328, 1358 cancer & 1970 non-cancer participants); and the sensitivity remained to be >99% for patients with stage 1 disease. When applied to the additional dataset of 3792 participants including 2038 cancer patients across 12 cancer types and 1754 independent non-cancer controls, the model showed high sensitivities ranging from 83⋅2% to 100% for biliary tract, bladder, colorectal, esophageal, gastric, glioma, liver, pancreatic, and prostate cancers, and reasonable sensitivities of 68⋅2% and 72⋅0% for ovarian cancer and sarcoma, respectively, while maintaining 99⋅3% specificity (Table 1).

Conclusion: The study provided a proof-of-concept demonstrating that the 4-miRNA model has the potential to be developed into a simple, inexpensive and noninvasive blood test for early detection of multiple cancers with high accuracy.

Table 1. Sensitivities of the 4-miRNA diagnostic model in 12 cancer types. N Sensitivity Lung Cancer 1358 99.3% Biliary Tract Cancer 40 97.5% Bladder Cancer 392 98.2% Colorectal Cancer 155 85.8% Esophageal Cancer 124 84.7% Gastric Cancer 150 100% Glioma 40 87.5% Liver Cancer 348 84.2% Ovarian Cancer 333 68.2% Pancreatic Cancer 149 83.2% Prostate Cancer 40 92.5% Sarcoma 132 72.0%

Citation Format: Andrew Zhang, Hai Hu. Development and validation of a novel circulating cell-free microRNA diagnostic model with high accuracy for multi-cancer early detection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5931.