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1.  Complex Hyperplasia With and Without Atypia: Clinical Outcomes and Implications of Progestin Therapy 
Obstetrics and gynecology  2010;116(2 Pt 1):365-373.
Limited data exist to inform clinicians and patients as to the likelihood of long-term endometrial hyperplasia response to progestin therapy, especially for atypical hyperplasia. We evaluated women with complex and atypical endometrial hyperplasia, comparing those prescribed progestin to those not prescribed progestin.
This retrospective cohort study was conducted in 1985–2005 among women aged 18–88 years at an integrated health plan in Washington State. Women were ineligible if they achieved an outcome (endometrial carcinoma, hysterectomy, or both) within 8 weeks of hyperplasia diagnosis. Exposure was progestin use for at least 14 days, by duration and recency. Outcomes included rate of: 1) endometrial carcinoma; and/or 2) hysterectomy. Analyses performed included Kaplan Meier, incident rate ratios, and Cox proportional hazard ratios.
One thousand four hundred forty-three eligible women were identified. One thousand two hundred one had complex (n=164 no progestin) and 242 had atypical hyperplasia (n=62 no progestin). During follow-up, median 5.3 years (range 8 weeks to 20.8 years), 71 women were diagnosed with endometrial carcinoma (35 complex, 36 atypia) and 323 underwent hysterectomy (216 complex, 107 atypia). Among women with complex and atypical hyperplasia, rates of endometrial carcinoma among progestin users were 3.6 and 20.5 per 1,000 woman-years, respectively (compared with without progestin, 10.8 and 101.4). Among women with complex and atypical hyperplasia, rates of hysterectomy among progestin users were 23.3 and 61.4 per 1,000 woman-years, respectively (compared with without progestin, 55.1 and 297.3).
Endometrial carcinoma risk is diminished approximately 3- to 5-fold in women diagnosed with complex or atypical endometrial hyperplasia and dispensed progestin; hysterectomy risk is also decreased.
PMCID: PMC2949551  PMID: 20664397
2.  Hypermethylation of CCND2 May Reflect a Smoking-Induced Precancerous Change in the Lung 
Journal of Oncology  2011;2011:950140.
It remains unknown whether tobacco smoke induces DNA hypermethylation as an early event in carcinogenesis or as a late event, specific to overt cancer tissue. Using MethyLight assays, we analyzed 316 lung tissue samples from 151 cancer-free subjects (121 ever-smokers and 30 never-smokers) for hypermethylation of 19 genes previously observed to be hypermethylated in nonsmall cell lung cancers. Only APC (39%), CCND2 (21%), CDH1 (7%), and RARB (4%) were hypermethylated in >2% of these cancer-free subjects. CCND2 was hypermethylated more frequently in ever-smokers (26%) than in never-smokers (3%). CCND2 hypermethylation was also associated with increased age and upper lobe sample location. APC was frequently hypermethylated in both ever-smokers (41%) and never-smokers (30%). BVES, CDH13, CDKN2A (p16), CDKN2B, DAPK1, IGFBP3, IGSF4, KCNH5, KCNH8, MGMT, OPCML, PCSK6, RASSF1, RUNX, and TMS1 were rarely hypermethylated (<2%) in all subjects. Hypermethylation of CCND2 may reflect a smoking-induced precancerous change in the lung.
PMCID: PMC3090638  PMID: 21577262
3.  DNA Methylation in Tumor and Matched Normal Tissues from Non-Small Cell Lung Cancer Patients 
We used MethyLight assays to analyze DNA methylation status of 27 genes on 49 paired cancerous and noncancerous tissue samples from non-small cell lung cancer (NSCLC) patients who underwent surgical resection. Seven genes (RARB, BVES, CDKN2A, KCNH5, RASSF1, CDH13, and RUNX) were found to be methylated significantly more frequently in tumor tissues than in noncancerous tissues. Only methylation of CCND2 and APC was frequently detected in both cancerous and noncancerous tissues, supporting the hypothesis that the methylation of these two genes is a preneoplastic change and may be associated with tobacco smoking exposure. Methylation of any one of eight genes (RASSF1, DAPK1, BVES, CDH13, MGMT, KCNH5, RARB, or CDH1) was present in 80% of NSCLC tissues but only in 14% of noncancerous tissues. Detection of methylation of these genes in blood might have utility in monitoring and detecting tumor recurrence in early-stage NSCLC after curative surgical resection.
PMCID: PMC2798850  PMID: 18349282
4.  Examination of Oral Cancer Biomarkers by Tissue Microarray Analysis 
Oral squamous cell carcinoma (OSCC) is a major healthcare problem worldwide. Efforts in our laboratory and others focusing on the molecular characterization of OSCC tumors with the use of DNA microarrays have yielded heterogeneous results. To validate the DNA microarray results on a subset of genes from these studies that could potentially serve as biomarkers of OSCC, we elected to examine their expression by an alternate quantitative method and by assessing their protein levels.
Based on DNA microarray data from our lab and data reported in the literature, we identified six potential biomarkers of OSCC to investigate further. We employed quantitative, real-time polymerase chain reaction (qRT-PCR) to examine expression changes of CDH11, MMP3, SPARC, POSTN, TNC, TGM3 in OSCC and normal control tissues. We further examined validated markers on the protein level by immunohistochemistry (IHC) analysis of OSCC tissue microarray (TMA) sections.
qRT-PCR analysis revealed up-regulation of CDH11, SPARC, POSTN, and TNC gene expression, and decreased TGM3 expression in OSCC compared to normal controls. MMP3 was not found to be differentially expressed. In TMA IHC analyses, SPARC, periostin, and tenascin C exhibited increased protein expression in cancer compared to normal tissues, and their expression was primarily localized within tumor-associated stroma rather than tumor epithelium. Conversely, transglutaminase-3 protein expression was found only within keratinocytes in normal controls, and was significantly down-regulated in cancer cells.
Of six potential gene markers of OSCC, initially identified by DNA microarray analyses, differential expression of CDH11, SPARC, POSTN, TNC, and TGM3 were validated by qRT-PCR. Differential expression and localization of proteins encoded by SPARC, POSTN, TNC, and TGM3 were clearly shown by TMA IHC.
PMCID: PMC2578846  PMID: 18490578

Results 1-4 (4)