Associations Between Methylation of Paternally Expressed Gene 3 (PEG3), Cervical Intraepithelial Neoplasia and Invasive Cervical Cancer.

Cytology-based screening for invasive cervical cancer (ICC) lacks sensitivity and specificity to discriminate between cervical intraepithelial neoplasia (CIN) likely to persist or progress from cases likely to resolve. Genome-wide approaches have been used to identify DNA methylation marks associated with CIN persistence or progression. However, associations between DNA methylation marks and CIN or ICC remain weak and inconsistent. Between 2008-2009, we conducted a hospital-based, case-control study among 213 Tanzania women with CIN 1/2/3 or ICC. We collected questionnaire data, biopsies, peripheral blood, cervical scrapes, Human papillomavirus (HPV) and HIV-1 infection status. We assessed PEG3 methylation status by bisulfite pyrosequencing. Multinomial logistic regression was used to estimate odds ratios (OR) and confidence intervals (CI 95%) for associations between PEG3 methylation status and CIN or ICC. After adjusting for age, gravidity, hormonal contraceptive use and HPV infection, a 5% increase in PEG3 DNA methylation was associated with increased risk for ICC (OR = 1.6; 95% CI 1.2-2.1). HPV infection was associated with a higher risk of CIN1-3 (OR = 15.7; 95% CI 5.7-48.6) and ICC (OR = 29.5, 95% CI 6.3-38.4). Infection with high risk HPV was correlated with mean PEG3 differentially methylated regions (DMRs) methylation (r = 0.34 p<0.0001), while the correlation with low risk HPV infection was weaker (r = 0.16 p = 0.047). Although small sample size limits inference, these data support that PEG3 methylation status has potential as a molecular target for inclusion in CIN screening to improve prediction of progression. Impact statement: We present the first evidence that aberrant methylation of the PEG3 DMR is an important co-factor in the development of Invasive cervical carcinoma (ICC), especially among women infected with high risk HPV. Our results show that a five percent increase in DNA methylation of PEG3 is associated with a 1.6-fold increase ICC risk. Suggesting PEG3 methylation status may be useful as a molecular marker for CIN screening to improve prediction of cases likely to progress

Invasive Disease Caused by Nontuberculous Mycobacteria, Tanzania

Data on nontuberculous mycobacterial (NTM) disease in sub-Saharan Africa are limited. During 2006–2008, we identified 3 HIV-infected patients in northern Tanzania who had invasive NTM; 2 were infected with “Mycobacterium sherrisii” and 1 with M. avium complex sequevar MAC-D. Invasive NTM disease is present in HIV-infected patients in sub-Saharan Africa

Female genital schistosomiasis as an evidence of a neglected cause for reproductive ill-health: a retrospective histopathological study from Tanzania

BACKGROUND: Schistosomiasis affects the reproductive health of women. Described sequelae are ectopic pregnancy, infertility, abortion, and cervical lesions and symptoms mimicking cervical cancer and STIs. There are indications that cervical schistosomiasis lesions could become co-factors for viral infection such as HIV and HPV. METHODS: In a retrospective descriptive histopathological study clinical specimens sent between 1999 and 2005 to the pathology department of a consultant hospital in Tanzania were reviewed to analyse the occurrence and features of schistosomiasis in female genital organs. RESULTS: During the study period, schistosomiasis was histopathologically diagnosed in 423 specimens from different organs (0.7% of all specimens examined in the study period), out of those 40% were specimens from female and male organs. The specimens were sent from 24 hospitals in 13 regions of mainland Tanzania. Female genital schistosomiasis was diagnosed in 125 specimens from 111 patients. The main symptoms reported were bleeding disorders (48%), ulcer (17%), tumor (20%), lower abdominal pain (11%) and infertility (7%). The majority of cases with genital schistosomiasis were diagnosed in cervical tissue (71 cases). The confirmation of cervical cancer was specifically requested for 53 women, but the diagnosis could only be verified for 13 patients (25%), in 40 cases only severe cervical schistosomiasis was diagnosed. Vulval/labial schistosomiasis was seen in specimens from young women. Infertility was reported in four patients with schistosomiasis of the Fallopian tubes. CONCLUSION: Genital schistosomiasis adds to the disease burden of women in all age groups. Pathological consequences due to the involvement of different genital organs can be damaging for the affected women. Clinical unawareness of genital schistosomiasis can lead to misdiagnosis and therefore false and ineffective therapy. In endemic areas cervical schistosomiasis should be considered as differential diagnosis of cancer

Distribution of participant characteristics by case-control status.

*<p>ICC/Cancer subtype: 45 patients had squamous cell carcinoma; 3 had adenosquamous carcinomas.</p><p>High Risk HPV- 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68.</p><p>Low/Other Risk HPV – 6,11, 26, 40, 42, 55, 61, 62, 69, 70, 72, 73, 81, 82, 83, 84.</p

Adjusted odds ratios for the associations between mean DMR methylation for <i>PEG3</i>, HPV status and CIN and ICC.

*<p>Controlling for HIV-1 status, HPV positive status, age, and oral contraceptive (OC) use.</p><p>Per 5% methylation increase.</p

Validation of the <i>PEG3</i> pyrosequencing assay.

<p>Defined mixtures (x-axis) of methylated and unmethylated DNAs were prepared and analyzed in quintuplicate by pyrosequencing (y-axis). The results shown represent the mean; error bars indicate standard deviations. The Pearson rho is 0.953 with a p-value of 0.004.</p

Correlation between High and Low Risk HPV status and methylation fraction means at differentially methylated region (DMRs) of <i>PEG3</i>.

<p>High Risk HPV - 16,18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68.</p><p>Low/Other Risk HPV – 6, 11, 26,40, 42, 55, 61, 62, 69, 70, 72, 73, 81, 82, 83, 84.</p

Dietary patterns and breast cancer risk among women in northern Tanzania: a case–control study

BACKGROUND: Breast cancer is the second most common cancer among women in the Kilimanjaro Region of Tanzania. It was tested within a case–control study in this region whether a specific dietary pattern impacts on the breast cancer risk. METHODS: A validated semi-quantitative Food Frequency Questionnaire was used to assess the dietary intake of 115 female breast cancer patients and 230 healthy age-matched women living in the same districts. A logistic regression was performed to estimate breast cancer risk. Dietary patterns were obtained using principal component analysis with Varimax rotation. RESULTS: The adjusted logistic regression estimated an increased risk for a “Fatty Diet”, characterized by a higher consumption of milk, vegetable oils and fats, butter, lard and red meat (OR = 1.42, 95 % CI 1.08–1.87; P = 0.01), and for a “Fruity Diet”, characterized by a higher consumption of fish, mango, papaya, avocado and watery fruits (OR = 1.61, 95 % CI 1.14–2.28; P = 0.01). Both diets showed an inverse association with the ratio between polyunsaturated and saturated fatty acids (P/S ratio). CONCLUSION: A diet characterized by a low P/S ratio seems to be more important for the development of breast cancer than total fat intake