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HELICOBACTER PYLORI PROMOTES DNA DAMAGE AND INHIBITS TUMOR PROLIFERATION AND MIGRATION THROUGH THE ACVR1-IRF3-POLD1 SIGNALING AXIS

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Introduction

Helicobacter pylori（H.pylori） is a major risk factor for gastric cancer. Our previous study found that activin A receptor type I (ACVR1) plays an important role in the pathogenesis of gastric mucosal lesions caused by Helicobacter pylori. Meanwhile, transcriptome data showed that ACVR1 was negatively correlated with POLD1, the gene encoding the catalytic subunit of EUkaryotic DNA polymerase (Pol δ) P125. However, the specific roles of ACVR1 and ACVR1 in H.pylori carcinogenesis remain unclear. This study investigated the molecular mechanism and potential association between H.pylori, ACVR1 and POLD1 in gastric cancer.

Aims & Methods

Gastric cancer cells, human tissue and mouse model were used in this study. We used helicobacter pylori infection models in vitro and in vivo, and Western blot, QRT-PCR, immunofluorescence, COIP, CCK8, Transwell and other tests for molecular, mechanism and function studies.To explore the role of Helicobacter pylori in DNA damage repair through ACVR1.

Results

Transcriptome data showed a negative correlation between ACVR1 and POLD1 expression. In vitro results showed that Hp infection could up-regulate the expression of ACVR1 and γ-H2AX, and decrease the expression of POLD1. After the deletion of ACVR1, the expression of POLD1 was increased. The expression of POLD1 decreased when ACVR1 was overexpressed. By predicting transcription factors, it was found that IRF3 could regulate the transcription of POLD1, and Hp infection could down-regulate the expression of IRF3, which was related to the virulence factor CagA. In addition, interference with the expression of POLD1 can up-regulate the expression of γ-H2AX, and inhibit cell proliferation, invasion and migration.

Conclusion

In summary, our study found that the ACVR1-IRF3-POLD1 signaling axis plays an important role in the process of Helicobacter pylori infection causing gastric cancer, and the ACVR1-IRF3-POLD1 axis can promote the occurrence of DNA damage while inhibiting the biobehavioral function of tumor cells.

HELICOBACTER PYLORI PROMOTES DNA DAMAGE AND INHIBITS TUMOR PROLIFERATION AND MIGRATION THROUGH THE ACVR1-IRF3-POLD1 SIGNALING AXIS

Xinbo Xu 1, Yi Hu 1, Cong He 1, Nianshuang Li 2, Nonghua Lv 1, Zhu Yin 1

1 The First Affiliated Hospital of Nanchang University, NanChang, China

2 The First Affiliated Hospital of Nanchang University, Nanchang, China

Event

UEG Week Copenhagen 2023

Topics

Digestive Oncology Gut Microbiota Stomach & H. Pylori

Submission format

Abstract

Session

H. pylori: From disease pathway to therapy

Citation

United European Gastroenterology Journal 2023; 11 (Supplement 8)

Published

2023

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NGS-guided therapies in GI oncology

Thomas Seufferlein 1

1 Universitätsklinikum Ulm - Klinik für Innere Medizin I, Ulm, Germany

Event

UEG Week Copenhagen 2023

Topics

Colorectal Digestive Oncology Hepatobiliary Mechanisms & Personalised Medicine

Session

Precision molecular medicine in GI cancers

Published

2023

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The future of microbiome therapeutics

Haggai Bar-Yoseph 1

1 Rambam Health Care Campus, Haifa, Israel

Event

UEG Week Copenhagen 2023

Topics

Gut Microbiota Mechanisms & Personalised Medicine

Session

Microbiota in clinical practice: What is new and what is true?

Published

2023

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Introduction: Best of hepatology in UEG Journal

Iris J. M. Levink 1, Joana Roseira 2

1 Erasmus University Medical Center, Rotterdam, Netherlands

2 Algarve Universitary Hospital Center, Portimão, Algarve, Portugal

Event

UEG Week Copenhagen 2023

Topics

Hepatobiliary

Session

Best of hepatology in UEG Journal

Published

2023

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Liver and Biliary

Gyongyi Szabo 1

1 Harvard Medical School, Boston, United States

Event

UEG Week Copenhagen 2023

Session

Best of DDW

Published

2023

UEG Presentation

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CANCER SUSCEPTIBILITY GENE TESTING IN PATIENTS WITH PANCREATIC DUCTAL ADENOCARCINOMA: IMPLEMENTATION IN AN ACADEMIC TERTIARY REFERRAL CANCER CENTER ONCOLOGY CLINIC

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Introduction

Approximately 10% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) carry a pathogenic variant in a PDAC susceptibility gene. Current guidelines recommend offering germline cancer susceptibility testing for all individuals with PDAC regardless of family history. Previous studies have shown moderate rates of uptake of gene testing, highlighting the need for efficient and accessible clinical pathways for delivering gene testing education and counseling. We evaluated the uptake of gene testing when offered at the point-of-care by an oncology nurse specialist in an outpatient setting.

Aims & Methods

We undertook a retrospective chart review of PDAC patients treated at the Johns Hopkins Hospital between January 2021 and December 2023. Patients were educated about germline testing by an oncology nurse specialist during their initial clinic visit, and provided with instructional handouts, links to videos, instructions on kit ordering and given time to consider testing. “MyChart” reminders are sent as needed. Patients who desired testing were sent a saliva kit to their home that they had to send back to the testing lab. Results were communicated by the oncology nurse to the patients, and those with pathogenic variants or variants of uncertain significance (VUS) are referred to formal genetic counseling.

Results

Of 1022 patients seen by the oncology and surgery teams, all but 2 were seen by oncology, 377 underwent surgery, 52% were male, 74.9% were White, 15.8% African American (AA), 6% were Asian, 3% were Hispanic, and 17.5% had a family history of pancreatic cancer. At diagnosis, median age was 67.1 +/- 10.6 years; 51.9% of cases had resectable-stage disease.
Among the 87.5% of patients offered gene testing, 77.6% completed testing. Completion rates among those offered testing increased from 72.4% (2021) to 78.5% (2022) and 82.2% (2023).
Factors significantly associated with reduced gene testing uptake included African American patients, those that were single, had advanced-stage disease, did not receive chemotherapy and of older age at diagnosis (Table 1).
Among tested individuals, 55 (7.9%) involving PDAC susceptibility genes, with BRCA2, ATM and PALB2 being the most common. 50 out of these 55 patients (91%) were referred to genetic counseling, with 76% completing their counseling visit to date. Germline testing results led to a change in the treatment regimen in 23 of the 55 patients.

		Coefficient	Odds Ratio	95% Confidence Interval	P Value
Sex	Male vs Female	0.215	1.240	0.872-1.763	0.231
Race	White vs AA White vs Asian White vs Other	-1.065 0.440 -1.508	0.345 1.553 0.221	0.224- 0.531 0.671- 3.596 0.083- 0.590	<0.001 0.304 0.003
Ethnicity	Non-Hispanic Vs Hispanic	1.038	2.822	0.733- 10.863	0.131
Marital Status	Married vs Single	-0.755	0.471	0.295- 0.750	0.002
Stage at diagnosis	Resectable vs Metastatic Resectable vs Locally advanced	-0.5738 0.170	0.564 1.185	0.379-0.839 0.767-1.830	0.005 0.444
Age at diagnosis		-0.022	0.978	0.961- 0.996	0.015
Family History of PDAC	Yes vs No	-0.354	0.702	0.434- 1.136	0.149
Personal history of other cancers	Yes vs No	-0.036	0.965	0.629- 1.480	0.869
Received Chemotherapy	Yes vs No	-1.162	0.313	0.107- 0.910	0.033

Table 1: Multivariate analysis results for completion of germline genetic testing among offered patients.

Conclusion

The implementation of point-of-care encounters for cancer susceptibility gene testing by an oncology nurse specialist in the outpatient setting yielded a high uptake of testing. African American, older-age, single and advanced-stage disease individuals had lower rates of completing gene testing.

CANCER SUSCEPTIBILITY GENE TESTING IN PATIENTS WITH PANCREATIC DUCTAL ADENOCARCINOMA: IMPLEMENTATION IN AN ACADEMIC TERTIARY REFERRAL CANCER CENTER ONCOLOGY CLINIC

Hassan Sinan 1, Dea Cunningham 1, Thomas McPhaul 1, Jin He 1, Richard Burkhart 1, Lei Zheng 1, Nilofer S. Azad 1, Daniel Laheru 1, Michael Goggins 2

1 Johns Hopkins University, Baltimore, United States

2 Johns Hopkins University, Baltimore, United States|||Johns Hopkins University, Baltimore, United States|||Johns Hopkins University, Baltimore, United States

Event

UEG Week Vienna 2024

Topics

Digestive Oncology Mechanisms & Personalised Medicine Pancreas

Submission format

Abstract

Session

Pancreatic cancer: From bench to bedside

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

UEG Poster

Standard Poster

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Introduction

Gastric emptying scintigraphy (GES) is an accepted standard for gastroduodenal function (GDF) testing, while various other investigations are available for the assessment of dyspeptic symptoms. However, in the absence of guidelines, it remains uncertain which test one should favour.

Aims & Methods

This study examined variation in GDF testing between centres to establish the status of current practice. A web-based questionnaire assessing availability, standard operating procedures and interpretation of 15 different GDF testing techniques was distributed among specialist practitioners via professional organizations. Availability, indication, meal-related characteristics and standard operating procedures (SOP) were compared.

Results

Fifty-nine complete responses (57 clinical practice, 86% tertiary care) were included from 28 countries. Eleven (19%) respondents referred more than 10 patients for further testing monthly. Accessibility for clinical practice were as follows: 100% gastroscopy, 91% measurement of gastric emptying (79% by GES; 19% gastric emptying breath testing (GEBT); 5% SPECT), 39% intragastric pressure measurements (IGP), 33% pyloric Endoflip (PE), 30% gastric MRI, 19% nutrient drinking challenge (NDC), 18% gastric ultrasound (US), 18% motility capsule (MC) and 16% antroduodenal manometry (AM). Other techniques were available to less than 15% of the respondents. In clinical practice, meal-related dyspeptic symptoms and chronic unexplained nausea and vomiting (CUNV) represented the main indications for GE studies as compared to epigastric pain, burning or discomfort (GES: 70% and 94% vs. 20%, p<.00001; GEBT: 100% and 100% vs. 0%, p<.001), Similar results were present for PE (73% and 93% vs. 33%, p=.002), NDC (100 and 82 vs. 27%, p=.0006). MC (33% and 67% vs. 0%, p=.05), AM (28% and 75% vs. 25%, p=.11), MRI (75% and 88% vs. 38%, p=.09) and IGP (33% and 33% vs. 0%, p=.15) By contrast, US was indiscriminately performed (57% and 71% vs. 57%, p=.82).There was a large heterogeneity in the type of meal and meal quantity used for each test as well as between tests. Symptoms were recorded by only half the respondents during GES and MRI, with higher percentages for other testing modalities. Variation in the specific symptoms included in questionnaires was present.

Conclusion

GES is widely available in clinical practice. Meal-related symptoms and CUNV represent the main indications for GDF testing in clinical practice. A large variation in the availability of GDF testing and SOPs exists between centres. This hampers clinical interpretation, data transfer between centres and research collaboration. These findings emphasise the need for an international co-operation effort at standardisation.