In:
Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 25, No. 3_Supplement ( 2016-03-01), p. B11-B11
Abstract:
Latino women in the United States have the highest cervical cancer incidence rate, yet the highest death rate from cervical cancer is among Black women. The disproportionate burden of cervical cancer in the United States is primarily due to lack of screening, among the medically underserved, regardless of race or ethnicity. Rural and inner city women living in poverty have lower rates of screening and higher rates of cervical cancer in the US. The advent of molecular diagnostics provides an opportunity to develop novel cervical cancer screening and triage tools that can be packaged as point of care and self-testing solutions. We set out to identify a panel of methylated HPV DNA and human genes that can discriminate between CIN2+ and normal/CIN1 patients in liquid prep samples and in Transrenal DNA (TrDNA) isolated from urine. We used three independent cohorts, from Chile, Baltimore and Puerto Rico, to develop a method that can be used to triage into colposcopy, HPV+ women with abnormal cytology. Participants were women with no cervical intraepithelial lesions or malignancy and women with abnormal cervical biopsies– Cervical Intraepithelial Neoplasia (CIN), carcinoma in-situ and cervical cancer. Using DNA methylation arrays for Discovery and quantitative Methylation Specific PCR (qMSP) for Validation, we found that promoter methylation of ZNF516, FKBP6, and INST1 discriminates samples with CIN2+ lesions from samples with no intraepithelial lesions or malignancy (NILM): 88.3% sensitivity, 88.9% specificity, 93.2 Area Under the Curve (AUC), 86.9% positive predictive value (PPV) and 90.2% negative predictive value (NPV). Using custom sequence capture pools of baits, we pulled down genomic and bisulfite converted high-risk HPV DNA before library prep for NGS in 454 and MiSeq instruments, respectively. Using our NGS results, we optimized a Syber Greeen qPCR assay to detect high risk HPV DNA and a qMSP primer-probe set to detect methylated HPV. We replicated the results in liquid prep samples (n=67), adding HPV16 methylation to the panel: 90.9% sensitivity, 60.9% specificity, 90.1 (AUC), 52.6% positive predictive value (PPV) and 93.3% NPV. These results were verified in plasma DNA (AUC=80.7) and TrDNA (AUC=86.1) isolated from a subset of patients who provided the liquid prep samples. Our results suggest that our panel of viral and host gene methylation markers may be used as a reflex test in liquid prep to triage high risk HPV positive women into colposcopy, or as a screening and triage test in TrDNA, in combination with our high risk HPV test. There are several commercial co-testing options for identification of oncogenic high-risk HPV types (HPV+) in patients with abnormal cytology. However, there are currently no tests that can reliably identify the HPV+ patients with abnormal cytology that need to be referred for colposcopy. Consequently, more than half of the women that are referred to colposcopy either have a negative biopsy, or a grade 1 Cervical Intraepithelial Neoplasia (CIN1) diagnosis, which usually reverts to normal in 12-24 months. A triage test from cytology to colposcopy that can identify in the liquid prep sample those patients with a CIN grade more likely to progress to cervical cancer (CIN2+), would decrease the number of unnecessary cervical mucosa biopsies performed today, decreasing health care cost and improving the quality of health care delivery. These molecular tools can also be packaged as point of care and self-testing solutions to eliminate cervical cancer disparities in medically underserved women. Note: This abstract was not presented at the conference. Citation Format: Rafael Guerrero-Preston, Anne Jedlicka, Blanca L. Valle, Nitesh Turaga, Liliana Florea, Oluwasina Folawiyo, Francesca Pirini, Fahcina Lawson, Angelo Vergura, Maartje Noordhuis, Gabriela Perez, Marisa Renehan, Carolina Guerrero-Díaz, Edgardo De Jesus, Teresa Diaz-Montes, Bruce Trock, Keimari Mendez, Josefina Romaguera, David Sidransky. Viral and host gene methylation in liquid prep: novel molecular screening and triage tools to reduce cervical cancer disparities. [abstract] . In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr B11.
Type of Medium:
Online Resource
ISSN:
1055-9965
,
1538-7755
DOI:
10.1158/1538-7755.DISP15-B11
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2016
detail.hit.zdb_id:
2036781-8
detail.hit.zdb_id:
1153420-5
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