||5R01CA141018-02 Interpret this number
||University Of Washington
||Epigenetic Changes Predict Disease Course of HPV-Related Lesions in Women 16-24
This study addresses the ARRA goal "05-CA-102* Comparative Effectiveness Research on Cancer Screening". The proposed study goal of developing a method to predict the natural history of CIN 2,3 contributes to the ARRA public health goals in the following way. Over the last 30 years, cervical cancer (ICC)
control has been based on screening for, and treating of, all women with CIN 2,3 and CIN 3/CIS, the presumed precursors of ICC. Immediate treatment of all CIN 2,3 lesions (by physical destruction), is the standard of care, despite the fact that only a subset of such lesions ever progress to ICC if left untreated, and further, that in adolescents/young women, many CIN 2,3 lesions spontaneously regress. Such "over treatment" has been accepted, first, as there is no way to predict which CIN 2,3 lesions will regress, persist or progress. (Currently available biomarkers lack necessary specificity for predicting the natural history of such lesions). Further, there are no good alternative medical treatments available. In addition, it was believed that surgical and/or ablative removal of CIN 2,3 and CIN 3/CIS was without untoward consequences. However, recent studies report all
excisional approaches (including the most commonly used procedure: LEEP) to be associated with increased obstetrical morbidity. Some studies also suggest that this is also true for ablative therapies [Wright TC, 2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ]. National management guidelines were therefore recently revised to allow "either observation for up to 24 months or treatment" for adolescents and young females with CIN 2,3. This approach puts a heavy burden on our health care system as there are an estimated 200,000 female adolescents/young women diagnosed with CIN2,3 in the US each year. Many of these women will now need tracking and close clinical follow up. Further, delayed treatment of growing lesions might lead to the need for deeper/wider excisions for removal. To begin to address this important issue over the next two years, we will: Aim one: define specific promoter region CpGs and chromatin modifications central to development of ICC by mapping methylation and histone marks of DAPK1, IGSF4, PAX1, TIMP3 and TFPI2 present in stored biopsies of ICC, CIS and normal cervical tissues; Aim two: enroll 100 16-25 year old women with biopsy confirmed CIN 2-3 and define the status of the promoter region CpGs and chromatin modifications identified in Aim 1 in their biopsies and same day
exfoliated cell samples. Aim 3: Follow enrolled women every 6 months (for up to 18 months) by colposcopy and collection of exfoliated cell samples for cytology and testing to determine whether changes in methylation status and/or the pattern of chromatin marks associated with TWIST1, DAPK1, IGSF4, PAX1, TIMP3 and TFPI2 occur over time, and further, whether such changes are associated with colposcopic and cytologic changes.
Chromatin structure of two genomic sites for targeted transgene integration in induced pluripotent stem cells and hematopoietic stem cells.
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