Browsing by Author "Smith, Jennifer S"

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    Association between PEG3 DNA methylation and high-grade cervical intraepithelial neoplasia.
    (Infectious agents and cancer, 2021-06) Bosire, Claire; Vidal, Adriana C; Smith, Jennifer S; Jima, Dereje; Huang, Zhiqing; Skaar, David; Valea, Fidel; Bentley, Rex; Gradison, Margaret; Yarnall, Kimberly SH; Ford, Anne; Overcash, Francine; Murphy, Susan K; Hoyo, Cathrine

    Background

    Epigenetic mechanisms are hypothesized to contribute substantially to the progression of cervical intraepithelial neoplasia (CIN) to cervical cancer, although empirical data are limited.

    Methods

    Women (n = 419) were enrolled at colposcopic evaluation at Duke Medical Center in Durham, North Carolina. Human papillomavirus (HPV) was genotyped by HPV linear array and CIN grade was ascertained by biopsy pathologic review. DNA methylation was measured at differentially methylated regions (DMRs) regulating genomic imprinting of the IGF2/H19, IGF2AS, MESTIT1/MEST, MEG3, PLAGL1/HYMAI, KvDMR and PEG10, PEG3 imprinted domains, using Sequenom-EpiTYPER assays. Logistic regression models were used to evaluate the associations between HPV infection, DMR methylation and CIN risk overall and by race.

    Results

    Of the 419 participants, 20 had CIN3+, 52 had CIN2, and 347 had ≤ CIN1 (CIN1 and negative histology). The median participant age was 28.6 (IQR:11.6) and 40% were African American. Overall, we found no statistically significant association between altered methylation in selected DMRs and CIN2+ compared to ≤CIN1. Similarly, there was no significant association between DMR methylation and CIN3+ compared to ≤CIN2. Restricting the outcome to CIN2+ cases that were HR-HPV positive and p16 staining positive, we found a significant association with PEG3 DMR methylation (OR: 1.56 95% CI: 1.03-2.36).

    Conclusions

    While the small number of high-grade CIN cases limit inferences, our findings suggest an association between altered DNA methylation at regulatory regions of PEG3 and high grade CIN in high-risk HPV positive cases.
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    Bacterial vaginosis as a risk factor for high-grade cervical lesions and cancer in HIV-seropositive women.
    (Int J Gynaecol Obstet, 2011-09) Denslow, Sheri A; Westreich, Daniel J; Firnhaber, Cynthia; Michelow, Pam; Williams, Sophie; Smith, Jennifer S
    OBJECTIVE: To assess the effect of bacterial vaginosis (BV) on the risk of high-grade squamous intraepithelial lesions (HSIL) among HIV-seropositive women. METHODS: A hospital-based prospective cohort study of HIV-seropositive women was conducted in Johannesburg, South Africa from January 2005 to September 2009. Multivariate log-binomial and Poisson regressions were used to estimate prevalence and rate ratios, respectively. RESULTS: Among 1954 HIV-seropositive women, the baseline prevalence of HSIL was 17%. BV prevalence was high (54%) and showed no association with prevalence of HSIL (adjusted prevalence ratio, 1.12; 95% confidence intervals (CI), 0.92-1.35) nor with cervical lesion progression at follow-up visit (n=503) (adjusted rate ratio: 1.00; 95% CI, 0.65-1.53). CONCLUSION: Among HIV-seropositive women, BV was not associated with an increased risk of HSIL or cervical lesion progression.
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    Distribution of HPV genotypes in cervical intraepithelial lesions and cervical cancer in Tanzanian women.
    (Infect Agent Cancer, 2011-11-14) Vidal, Adriana C; Murphy, Susan K; Hernandez, Brenda Y; Vasquez, Brandi; Bartlett, John A; Oneko, Olola; Mlay, Pendo; Obure, Joseph; Overcash, Francine; Smith, Jennifer S; van der Kolk, Mike; Hoyo, Cathrine
    BACKGROUND: Infection with human papillomavirus (HPV) is associated with uterine cervical intraepithelial neoplasia (CIN) and invasive cancers (ICC). Approximately 80% of ICC cases are diagnosed in under-developed countries. Vaccine development relies on knowledge of HPV genotypes characteristic of LSIL, HSIL and cancer; however, these genotypes remain poorly characterized in many African countries. To contribute to the characterization of HPV genotypes in Northeastern Tanzania, we recruited 215 women from the Reproductive Health Clinic at Kilimanjaro Christian Medical Centre. Cervical scrapes and biopsies were obtained for cytology and HPV DNA detection. RESULTS: 79 out of 215 (36.7%) enrolled participants tested positive for HPV DNA, with a large proportion being multiple infections (74%). The prevalence of HPV infection increased with lesion grade (14% in controls, 67% in CIN1 cases and 88% in CIN2-3). Among ICC cases, 89% had detectable HPV. Overall, 31 HPV genotypes were detected; the three most common HPV genotypes among ICC were HPV16, 35 and 45. In addition to these genotypes, co-infection with HPV18, 31, 33, 52, 58, 68 and 82 was found in 91% of ICC. Among women with CIN2-3, HPV53, 58 and 84/83 were the most common. HPV35, 45, 53/58/59 were the most common among CIN1 cases. CONCLUSIONS: In women with no evidence of cytological abnormalities, the most prevalent genotypes were HPV58 with HPV16, 35, 52, 66 and 73 occurring equally. Although numerical constraints limit inference, findings that 91% of ICC harbor only a small number of HPV genotypes suggests that prevention efforts including vaccine development or adjuvant screening should focus on these genotypes.
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    Epigenome-wide methylation and progression to high-grade cervical intraepithelial neoplasia (CIN2+): a prospective cohort study in the United States.
    (BMC cancer, 2023-11) Bukowski, Alexandra; Hoyo, Cathrine; Vielot, Nadja A; Graff, Misa; Kosorok, Michael R; Brewster, Wendy R; Maguire, Rachel L; Murphy, Susan K; Nedjai, Belinda; Ladoukakis, Efthymios; North, Kari E; Smith, Jennifer S

    Background

    Methylation levels may be associated with and serve as markers to predict risk of progression of precancerous cervical lesions. We conducted an epigenome-wide association study (EWAS) of CpG methylation and progression to high-grade cervical intraepithelial neoplasia (CIN2 +) following an abnormal screening test.

    Methods

    A prospective US cohort of 289 colposcopy patients with normal or CIN1 enrollment histology was assessed. Baseline cervical sample DNA was analyzed using Illumina HumanMethylation 450K (n = 76) or EPIC 850K (n = 213) arrays. Participants returned at provider-recommended intervals and were followed up to 5 years via medical records. We assessed continuous CpG M values for 9 cervical cancer-associated genes and time-to-progression to CIN2+. We estimated CpG-specific time-to-event ratios (TTER) and hazard ratios using adjusted, interval-censored Weibull accelerated failure time models. We also conducted an exploratory EWAS to identify novel CpGs with false discovery rate (FDR) < 0.05.

    Results

    At enrollment, median age was 29.2 years; 64.0% were high-risk HPV-positive, and 54.3% were non-white. During follow-up (median 24.4 months), 15 participants progressed to CIN2+. Greater methylation levels were associated with a shorter time-to-CIN2+ for CADM1 cg03505501 (TTER = 0.28; 95%CI 0.12, 0.63; FDR = 0.03) and RARB Cluster 1 (TTER = 0.46; 95% CI 0.29, 0.71; FDR = 0.01). There was evidence of similar trends for DAPK1 cg14286732, PAX1 cg07213060, and PAX1 Cluster 1. The EWAS detected 336 novel progression-associated CpGs, including those located in CpG islands associated with genes FGF22, TOX, COL18A1, GPM6A, XAB2, TIMP2, GSPT1, NR4A2, and APBB1IP.

    Conclusions

    Using prospective time-to-event data, we detected associations between CADM1-, DAPK1-, PAX1-, and RARB-related CpGs and cervical disease progression, and we identified novel progression-associated CpGs.

    Impact

    Methylation levels at novel CpG sites may help identify individuals with ≤CIN1 histology at higher risk of progression to CIN2+ and inform risk-based cervical cancer screening guidelines.
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    HPV genotypes and cervical intraepithelial neoplasia in a multiethnic cohort in the southeastern USA.
    (Cancer causes & control : CCC, 2014-08) Vidal, Adriana C; Smith, Jennifer S; Valea, Fidel; Bentley, Rex; Gradison, Maggie; Yarnall, Kimberly SH; Ford, Anne; Overcash, Francine; Grant, Kathy; Murphy, Susan K; Hoyo, Cathrine

    Purpose

    For poorly understood reasons, invasive cervical cancer (ICC) incidence and mortality rates are higher in women of African descent. Oncogenic human papillomavirus (HPV) genotypes distribution may vary between European American (EA) and African-American (AA) women and may contribute to differences in ICC incidence. The current study aimed at disentangling differences in HPV distribution among AA and EA women.

    Methods

    Five-hundred and seventy-two women were enrolled at the time of colposcopic evaluation following an abnormal liquid-based cytology screen. HPV infections were detected using HPV linear array, and chi-squared tests and linear regression models were used to compare HPV genotypes across racial/ethnic groups by CIN status.

    Results

    Of the 572 participants, 494 (86 %) had detectable HPV; 245 (43 %) had no CIN lesion, 239 (42 %) had CIN1, and 88 (15 %) had CIN2/3. Seventy-three percent of all women were infected with multiple HPV genotypes. After adjusting for race, age, parity, income, oral contraception use, and current smoking, AAs were two times less likely to harbor HPV 16/18 (OR 0.48, 95 % CI 0.21-0.94, p = 0.03) when all women were considered. This association remained unchanged when only women with CIN2/3 lesions were examined (OR 0.22, 95 % CI 0.05-0.95, p = 0.04). The most frequent high-risk HPV genotypes detected among EAs were 16, 18, 56, 39, and 66, while HPV genotypes 33, 35, 45, 58, and 68 were the most frequent ones detected in AAs.

    Conclusions

    Our data suggest that while HPV 16/18 are the most common genotypes among EA women with CIN, AAs may harbor different genotypes.
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    Vaginal Self-Sampling for Human Papillomavirus Infection as a Primary Cervical Cancer Screening Tool in a Haitian Population.
    (Sex Transm Dis, 2015-11) Boggan, Joel C; Walmer, David K; Henderson, Gregory; Chakhtoura, Nahida; McCarthy, Schatzi H; Beauvais, Harry J; Smith, Jennifer S
    BACKGROUND: Human papillomavirus (HPV) testing as primary cervical cancer screening has not been studied in Caribbean women. We tested vaginal self-collection versus physician cervical sampling in a population of Haitian women. METHODS: Participants were screened for high-risk HPV with self-performed vaginal and clinician-collected cervical samples using Hybrid Capture 2 assays (Qiagen, Gaithersburg, MD). Women positive by either method then underwent colposcopy with biopsy of all visible lesions. Sensitivity and positive predictive value were calculated for each sample method compared with biopsy results, with κ statistics performed for agreement. McNemar tests were performed for differences in sensitivity at ≥cervical intraepithelial neoplasia (CIN)-I and ≥CIN-II. RESULTS: Of 1845 women screened, 446 (24.3%) were HPV positive by either method, including 105 (5.7%) only by vaginal swab and 53 (2.9%) only by cervical swab. Vaginal and cervical samples were 91.4% concordant (κ = 0.73 [95% confidence interval, 0.69-0.77], P < 0.001). Overall, 133 HPV-positive women (29.9%) had CIN-I, whereas 32 (7.2%) had ≥CIN-II. The sensitivity of vaginal swabs was similar to cervical swabs for detecting ≥CIN-I (89.1% vs. 87.9%, respectively; P = 0.75) lesions and ≥CIN-II disease (87.5% vs. 96.9%, P = 0.18). Eighteen of 19 cases of CIN-III and invasive cancer were found by both methods. CONCLUSIONS: Human papillomavirus screening via self-collected vaginal swabs or physician-collected cervical swabs are feasible options in this Haitian population. The agreement between cervical and vaginal samples was high, suggesting that vaginal sample-only algorithms for screening could be effective for improving screening rates in this underscreened population.