Correction: A novel epigenetic modulating agent sensitizes pancreatic cells to a chemotherapy agent.

[This corrects the article DOI: 10.1371/journal.pone.0199130.].

Promoter methylation of ADAMTS1 and BNC1 as potential biomarkers for early detection of pancreatic cancer in blood.

BACKGROUND: Despite improvements in cancer management, most pancreatic cancers are still diagnosed at an advanced stage. We have recently identified promoter DNA methylation of the genes ADAMTS1 and BNC1 as potential blood biomarkers of pancreas cancer. In this study, we validate this biomarker panel in peripheral cell-free tumor DNA of patients with pancreatic cancer. RESULTS: Sensitivity and specificity for each gene are as follows: ADAMTS1 87.2% and 95.8% (AUC = 0.91; 95% CI 0.71-0.86) and BNC1 64.1% and 93.7% (AUC = 0.79; 95% CI 0.63-0.78). When using methylation of either gene as a combination panel, sensitivity increases to 97.3% and specificity to 91.6% (AUC = 0.95; 95% CI 0.77-0.90). Adding pre-operative CA 19-9 values to the combined two-gene methylation panel did not improve sensitivity. Methylation of ADAMTS1 was found to be positive in 87.5% (7/8) of stage I, 77.8% (7/9) of stage IIA, and 90% (18/20) of stage IIB disease. Similarly, BNC1 was positive in 62.5% (5/8) of stage I patients, 55.6% (5/9) of stage IIA, and 65% (13/20) of patients with stage IIB disease. The two-gene panel (ADAMTS1 and/or BNC1) was positive in 100% (8/8) of stage I, 88.9% (8/9) of stage IIA, and 100% (20/20) of stage IIB disease. The sensitivity and specificity of the two-gene panel for localized pancreatic cancer (stages I and II), where the cancer is eligible for surgical resection with curative potential, was 94.8% and 91.6% respectively. Additionally, the two-gene panel exhibited an AUC of 0.95 (95% CI 0.90-0.98) compared to 57.1% for CA 19-9 alone. CONCLUSION: The methylation status of ADAMTS1 and BNC1 in cfDNA shows promise for detecting pancreatic cancer during the early stages when curative resection of the tumor is still possible. This minimally invasive blood-based biomarker panel could be used as a promising tool for diagnosis and screening in a select subset of high-risk populations.

Lung Cancer Screening and Epigenetics in African Americans: The Role of the Socioecological Framework.

Lung cancer is the leading cause of cancer morbidity and mortality in the U.S. and racial/ethnic minorities carry the greatest burden of lung cancer disparities with African Americans (AAs) impacted disproportionately. Inequities in lung cancer health disparities are often associated with multiple bio-behavioral and socio-cultural factors among racial/ethnic minorities. Epigenetic research has advanced the understanding of the intersectionality between biological and socio-cultural factors in lung cancer disparities among AAs. However, gaps exist in the engagement of diverse populations in epigenetic lung cancer research, which poses a challenge in ensuring the generalizability and implementation of epigenetic research in populations that carry an unequal cancer burden. Grounding epigenetic lung cancer research within a socio-ecological framework may prove promising in implementing a multi-level approach to community engagement, screening, navigation, and research participation among AAs. The University of Illinois Cancer Center (UI Cancer Center) is employing an evidence-based (EB) model of community/patient engagement utilizing the socio-ecological model (SEM) to develop a culturally sensitive epigenetic lung cancer research program that addresses multiple factors that impact lung cancer outcomes in AAs. By implementing epigenetic research within a group of Federally Qualified Health Centers (FQHCs) guided by the SEM, the UI Cancer Center is proposing a new pathway in mitigating lung cancer disparities in underserved communities. At the individual level, the framework examines tobacco use among patients at FQHCs (the organizational level) and also tailors epigenetic research to explore innovative biomarkers in high risk populations. Interpersonal interventions use Patient Navigators to support navigation to EB tobacco cessation resources and lung cancer screening. Community level support within the SEM is developed by ongoing partnerships with local and national partners such as the American Lung Association (ALA) and the American Cancer Society (ACS). Lastly, at the policy level, the UI Cancer Center acknowledges the role of policy implications in lung cancer screening and advocates for policies and screening recommendations that examine the current guidelines from the United States Preventive Services Task Force (USPTF).

A novel epigenetic modulating agent sensitizes pancreatic cells to a chemotherapy agent.

Pancreatic ductal adenocarcinoma (PDAC) is expected to be the second leading cause of cancer mortality by 2030. PDAC remains resistant to the majority of systemic chemotherapies. In this paper, we explore if epigenetic sensitization can improve chemotherapy response in PDAC. Multiple PDAC cell lines were tested with serial concentrations of the epigenetic modulators 5-azacitidine (Aza) and guadecitabine (SGI-110). Guadecitabine was effective at inhibiting the expression of DNA Methyltransferase 1 (DNMT1) and in decreasing cell viability at nanomolar concentrations. We also report that guadecitabine has increased efficacy following a delay period or as we reference, a 'rest period'. Sensitization with guadecitabine improved response to the chemotherapeutic agent-Irinotecan- as measured by decreased cell viability and accompanied by an increase in caspase activity. Additional studies are needed to understand the mechanism of action.

Lung cancer early detection and health disparities: the intersection of epigenetics and ethnicity.

Lung cancer is the most prominent cause of cancer-related mortality. Significant disparities in incidence and outcome characterize the disease's manifestations among ethnically and racially diverse populations. Complete surgical resection is the most effective curative treatment. However, success relies on early tumor detection. The National Lung Cancer Screening trial showed that lung cancer related mortality can be reduced by the use of low-dose CT (LDCT) screening. However, this test is plagued by a high false positive rate of 97% and the device itself is limited to designated cancer centers due to its expense and size. This restriction makes it difficult for underserved groups to access LDCT screening, the current standard of care. Highly sensitive and specific epigenetic DNA methylation-based biomarkers have the potential to work independently or in conjunction with LDCT screening to identify early-stage tumors. These tests could reduce unnecessary invasive confirmatory diagnostic tests and their associated morbidity and mortality. These tests also have the opportunity to bring lung cancer screening to the community thereby reducing unequal accessibility. However, epigenetic alterations are closely linked to the interplay between hereditary and environmental factors such as diet, lifestyle, ethnic ancestry, toxin exposure, residential segregation, and disparate community support structures. Despite this, the overwhelming number of early detection DNA methylation biomarker studies to date have either failed to control for ethnicity or have employed heavily Caucasian-biased patient cohorts. This review seeks to summarize the literature related to the early detection of lung cancer through molecular biomarkers among different ethnicities. Ethnical specific epigenetic biomarkers have the potential to be the first step towards an accessible, available personalized medicine approach to cancer through liquid biopsy.