Publications by authors named "Hannah Lui Park"

32 Publications

Factors Associated with Women's Unwillingness to Decrease Alcohol Intake to Decrease Breast Cancer Risk.

J Prim Care Community Health 2021 Jan-Dec;12:21501327211000211

University of California, Irvine School of Medicine, Irvine, CA, USA.

Objective: Alcohol intake is a known risk factor for breast cancer. National organizations recommend that women consume no more than one serving of alcohol per day, if at all; however, many women exceed this recommendation, and some are unwilling to decrease consumption. Our study sought to identify factors associated with women's unwillingness to decrease their alcohol intake to decrease their breast cancer risk.

Methods: 942 women in a screening mammography cohort were asked questions about their demographics, personal and family health history, lifestyle factors, and willingness/unwillingness to decrease alcohol intake to decrease their breast cancer risk. Univariate and multivariate analyzes of their responses were performed.

Results: 13.2% of women in our cohort indicated they were unwilling to decrease their alcohol intake to reduce their breast cancer risk. After adjusting for potential confounders, women who were 60 years and older were more than twice as unwilling to decrease their alcohol intake compared to their younger counterparts ( = .0002). Women who had an annual household income of more than $200,000 were 1.75 times more unwilling to decrease their alcohol intake compared to their less affluent counterparts ( = .033). Unwillingness was not significantly associated with race/ethnicity, education, having a first-degree family member with cancer, health perception, breast cancer risk perception, or BMI.

Conclusions: Levels of unwillingness to decrease alcohol intake differed by age and household income. An opportunity is present to potentially decrease breast cancer risk in the community by educating women, especially older and more affluent women, about alcohol as a risk factor for breast cancer and the importance of limiting one's alcohol intake.
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http://dx.doi.org/10.1177/21501327211000211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983428PMC
March 2021

Breast Cancer Risk Prediction in Korean Women: Review and Perspectives on Personalized Breast Cancer Screening.

J Breast Cancer 2020 Aug 6;23(4):331-342. Epub 2020 Jul 6.

Department of Epidemiology, School of Medicine, University of California, Irvine, CA, USA.

Due to an increasing proportion of older individuals and the adoption of a westernized lifestyle, the incidence rate of breast cancer is expected to rapidly increase within the next 10 years in Korea. The National Cancer Screening Program (NCSP) of Korea recommends biennial breast cancer screening through mammography for women aged 40-69 years old and according to individual risk and preference for women above 70 years old. There is an ongoing debate on how to most effectively screen for breast cancer, with many proponents of personalized screening, or screening according to individual risk, for women under 70 years old as well. However, to accurately stratify women into risk categories, further study using more refined personalized characteristics, including potentially incorporating a polygenic risk score (PRS), may be needed. While most breast cancer risk prediction models were developed in Western countries, the Korean Breast Cancer Risk Assessment Tool (KoBCRAT) was developed in 2013, and several other risk models have been developed for Asian women specifically. This paper reviews these models compared to commonly used models developed using primarily Caucasian women, namely, the modified Gail, Breast Cancer Surveillance Consortium, Rosner and Colditz, and Tyrer-Cuzick models. In addition, this paper reviews studies in which PRS is included in risk prediction in Asian women. Finally, this paper discusses and explores strategies toward development and implementation of personalized screening for breast cancer in Korea.
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http://dx.doi.org/10.4048/jbc.2020.23.e40DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462811PMC
August 2020

Organophosphate Pesticide Exposure and Breast Cancer Risk: A Rapid Review of Human, Animal, and Cell-Based Studies.

Int J Environ Res Public Health 2020 07 13;17(14). Epub 2020 Jul 13.

Department of Epidemiology, School of Medicine, University of California, Irvine, CA 92697, USA.

Background: Organophosphate pesticides (OPs) are one of the most commonly used classes of insecticides in the U.S., and metabolites of OPs have been detected in the urine of >75% of the U.S.

Population: While studies have shown that OP exposure is associated with risk of neurological diseases and some cancers, the relationship between OP exposure and breast cancer risk is not well understood.

Methods: The aim of this rapid review was to systematically evaluate published literature on the relationship between OP exposure and breast cancer risk, including both epidemiologic and laboratory studies. Twenty-seven full-text articles were reviewed by searching on Pubmed, EMBASE, and Cochrane databases.

Results: Some human studies showed that malathion, terbufos, and chlorpyrifos were positively associated with human breast cancer risk, and some laboratory studies demonstrated that malathion and chlorpyrifos have estrogenic potential and other cancer-promoting properties. However, the human studies were limited in number, mostly included agricultural settings in several geographical areas in the U.S., and did not address cumulative exposure.

Conclusions: Given the mixed results found in both human and laboratory studies, more research is needed to further examine the relationship between OP exposure and breast cancer risk, especially in humans in non-agricultural settings.
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http://dx.doi.org/10.3390/ijerph17145030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399930PMC
July 2020

Rationale, Study Design, and Cohort Characteristics for the Markers for Environmental Exposures (MEE) Study.

Int J Environ Res Public Health 2020 03 9;17(5). Epub 2020 Mar 9.

Department of Epidemiology, University of California, Irvine, CA 92697, USA.

Environmental factors have been linked to many diseases and health conditions, but reliable assessment of environmental exposures is challenging. Developing biomarkers of environmental exposures, rather than relying on self-report, will improve our ability to assess the association of such exposures with disease. Epigenetic markers, most notably DNA methylation, have been identified for some environmental exposures, but identification of markers for additional exposures is still needed. The rationale behind the Markers for Environmental Exposures (MEE) Study was to (1) identify biomarkers, especially epigenetic markers, of environmental exposures, such as pesticides, air/food/water contaminants, and industrial chemicals that are commonly encountered in the general population; and (2) support the study of potential relationships between environmental exposures and health and health-related factors. The MEE Study is a cross-sectional study with potential for record linkage and follow-up. The well-characterized cohort of 400 postmenopausal women has generated a repository of biospecimens, including blood, urine, and saliva samples. Paired data include an environmental exposures questionnaire, a breast health questionnaire, dietary recalls, and a food frequency questionnaire. This work describes the rationale, study design, and cohort characteristics of the MEE Study. In addition to our primary research goals, we hope that the data and biorepository generated by this study will serve as a resource for future studies and collaboration.
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http://dx.doi.org/10.3390/ijerph17051774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084413PMC
March 2020

Epigenetic Biomarkers for Environmental Exposures and Personalized Breast Cancer Prevention.

Authors:
Hannah Lui Park

Int J Environ Res Public Health 2020 02 13;17(4). Epub 2020 Feb 13.

Department of Epidemiology, UC Irvine School of Medicine, Irvine, CA 92617, USA.

Environmental and lifestyle factors are believed to account for >80% of breast cancers; however, it is not well understood how and when these factors affect risk and which exposed individuals will actually develop the disease. While alcohol consumption, obesity, and hormone therapy are some known risk factors for breast cancer, other exposures associated with breast cancer risk have not yet been identified or well characterized. In this paper, it is proposed that the identification of blood epigenetic markers for personal, in utero, and ancestral environmental exposures can help researchers better understand known and potential relationships between exposures and breast cancer risk and may enable personalized prevention strategies.
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http://dx.doi.org/10.3390/ijerph17041181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068429PMC
February 2020

Effective risk communication to promote behavioral change in patients at elevated risk for breast cancer based on the Health Belief Model.

Breast J 2018 11 6;24(6):1097-1098. Epub 2018 Aug 6.

Department of Epidemiology, School of Medicine, University of California, Irvine, California.

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http://dx.doi.org/10.1111/tbj.13086DOI Listing
November 2018

Beyond Serendipity to an Algorithmic Approach.

Plast Reconstr Surg Glob Open 2018 Feb 6;6(2):e1675. Epub 2018 Feb 6.

VasculoTox, Inc., New York, N.Y.; Department of Plastic Surgery, Kaiser Permanente, Irvine, Calif.; and Department of Epidemiology, University of California Irvine, School of Medicine, Irvine, Calif.

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http://dx.doi.org/10.1097/GOX.0000000000001675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865940PMC
February 2018

Trends in Treatment Patterns and Clinical Outcomes in Young Women Diagnosed With Ductal Carcinoma In Situ.

Clin Breast Cancer 2018 04 10;18(2):e179-e185. Epub 2017 Aug 10.

Department of Epidemiology, University of California, Irvine, School of Medicine, Irvine, CA.

Background: Although it is known that the risk of a second breast cancer event among young women diagnosed with ductal carcinoma in situ (DCIS) is higher than in older women, the effect of current treatment options on long-term outcomes in this subgroup of women remains poorly defined. We aimed to evaluate national treatment trends and determine their effect on second breast cancer risk and overall survival among young women diagnosed with DCIS.

Materials And Methods: Surveillance, Epidemiology, and End Results data from 1998 to 2011 were used to analyze 3648 DCIS patients younger than age 40 years.

Results: Among all treatment options, breast-conserving surgery (BCS) with radiation therapy (BCS + RT) was the most prevalent (36.1%) followed by mastectomy (MTX) without contralateral prophylactic MTX (CPM; 25.8%), BCS alone (22.2%), and MTX with CPM (15.8%). Risk of a second ipsilateral event was > 5-fold and > 2-fold lower within 2 years and 5 years of initial DCIS diagnosis, respectively, in women who received BCS + RT compared with BCS alone; and overall survival was 3-fold higher in women who received BCS + RT. However, MTX with or without CPM did not show an increase in overall survival compared with BCS + RT. In addition, although the percentage of young women who receive MTX with CPM has increased in recent years, MTX with CPM did not show an increased benefit in survival compared with MTX without CPM.

Conclusion: The results of our study suggest that more aggressive treatments do not offer survival benefits over BCS + RT; thus, clinical treatment options in young women with DCIS should be carefully considered.
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http://dx.doi.org/10.1016/j.clbc.2017.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817367PMC
April 2018

Novel polymorphisms in caspase-8 are associated with breast cancer risk in the California Teachers Study.

BMC Cancer 2016 Jan 12;16:14. Epub 2016 Jan 12.

Department of Epidemiology, University of California, Irvine, School of Medicine, 224 Irvine Hall, Irvine, CA, 92697, USA.

Background: The ability of tamoxifen and raloxifene to decrease breast cancer risk varies among different breast cancer subtypes. It is important to determine one's subtype-specific breast cancer risk when considering chemoprevention. A number of single nucleotide polymorphisms (SNPs), including one in caspase-8 (CASP8), have been previously associated with risk of developing breast cancer. Because caspase-8 is an important protein involved in receptor-mediated apoptosis whose activity is affected by estrogen, we hypothesized that additional SNPs in CASP8 could be associated with breast cancer risk, perhaps in a subtype-specific manner.

Methods: Twelve tagging SNPs of CASP8 were analyzed in a nested case control study (1,353 cases and 1,384 controls) of non-Hispanic white women participating in the California Teachers Study. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each SNP using all, estrogen receptor (ER)-positive, ER-negative, human epidermal growth factor receptor 2 (HER2)-positive, and HER2-negative breast cancers as separate outcomes.

Results: Several SNPs were associated with all, ER-positive, and HER2-positive breast cancers; however, after correcting for multiple comparisons (i.e., p < 0.0008), only rs2293554 was statistically significantly associated with HER2-positive breast cancer (OR = 1.98, 95% CI 1.34-2.92, uncorrected p = 0.0005).

Conclusions: While our results for CASP8 SNPs should be validated in other cohorts with subtype-specific information, we conclude that some SNPs in CASP8 are associated with subtype-specific breast cancer risk. This study contributes to our understanding of CASP8 SNPs and breast cancer risk by subtype.
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http://dx.doi.org/10.1186/s12885-015-2036-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4711015PMC
January 2016

Self-recalled Youth Physical Activity and Postmenopausal Cardiovascular Disease.

Health Behav Policy Rev 2014 Nov;1(6):472-483

Department of Epidemiology, University of California, Irvine, Irvine, CA.

Objectives: To evaluate the association between childhood physical activity and incident cardiovascular disease (CVD) during postmenopausal years.

Methods: Proportional hazards and logistic regression were used describe the association between self-reported childhood physical activity and CVD incidence and mortality in 36,741 postmenopausal women.

Results: Older women, African-Americans, or nondrinkers or past drinkers self-reported the highest levels of youth physical activity and women with a history of diabetes, hypertension, overweight or obesity, or current smoking reported the highest youth physical activity dose. Youth physical activity was not associated with CVD incidence (HR=1.11; 0.93, 1.34) or mortality (HR=1.2; 0.9, 1.73).

Conclusions: Self-reported youth activity was not associated with postmenopausal CVD incidence or mortality.
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http://dx.doi.org/10.14485/HBPR.1.6.5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627784PMC
November 2014

Human Nail Clippings as a Source of DNA for Genetic Studies.

Open J Epidemiol 2015 Feb;5(1):41-50

Department of Epidemiology, Genetic Epidemiology Research Institute, University of California, Irvine, CA, USA.

Blood samples have traditionally been used as the main source of DNA for genetic analysis. However, this source can be difficult in terms of collection, transportation, and long-term storage. In this study, we investigated whether human nail clippings could be used as a source of DNA for SNP genotyping, null-allele detection, and whole-genome amplification. From extracted nail DNA, we achieved amplicons up to a length of ~400 bp and >96% concordance for SNP genotyping and 100% concordance for null-allele detection compared to DNA derived from matched blood samples. For whole-genome amplification, OmniPlex performed better than Multiple Displacement Amplification with a success rate of 89.3% and 76.8% for SNP genotyping and null-allele detection, respectively. Concordance was ~98% for both methods. When combined with OmniPlex whole-genome amplification, human nail clippings could potentially be used as an alternative to whole blood as a less invasive and more convenient source of DNA for genotyping studies.
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http://dx.doi.org/10.4236/ojepi.2015.51006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4499506PMC
February 2015

Prospective analysis of association between statin use and breast cancer risk in the women's health initiative.

Cancer Epidemiol Biomarkers Prev 2013 Oct 23;22(10):1868-76. Epub 2013 Aug 23.

Authors' Affiliations: Weill Cornell Medical College, New York, New York; Wayne State University; Barbara Ann Karmanos Cancer Institute, Detroit, Michigan; Los Angeles Biomedical Research Institute at Harbor, University of California, Los Angeles Medical Center, Los Angeles; University of California, Irvine, Irvine, California; Stony Brook University Medical Center, Stony Brook, New York; Harvard School of Public Health, Boston, Massachusetts; Fred Hutchinson Cancer Research Center, Seattle, Washington; George Washington University, Washington, District of Columbia; NorthShore University Health System, Evanston, Illinois; Albert Einstein College of Medicine, New York; University at Buffalo, The State University of New York, Buffalo, New York; Henry Ford Health Systems, Detroit, Michigan; Lakeland Regional Medical Center, St. Joseph, Michigan; West Virginia University, Morgantown, West Virginia; and University of Tennessee Health Science Center, Memphis, Tennessee.

Background: Statins are a class of cholesterol-lowering drugs that affect many intracellular pathways that may have implications for chemoprevention against cancer. Epidemiologic data on statins and breast cancer are conflicting. We analyzed updated data from the Women's Health Initiative (WHI) to assess the relationship between statins and breast cancer risk.

Methods: The population included 154,587 postmenopausal women ages 50 to 79 years, with 7,430 pathologically confirmed cases of breast cancer identified over an average of 10.8 (SD, 3.3) years. Information on statins was collected at baseline and years one, three, six, and nine. Self- and interviewer-administered questionnaires were used to collect information on risk factors. Cox proportional hazards regression was used to calculate HRs with 95% confidence intervals (CI) to evaluate the relationship between statin use and cancer risk. Statistical tests were two-sided.

Results: Statins were used by 11,584 (7.5%) women at baseline. The annualized rate of breast cancer was 0.42% among statin users and 0.42% among nonusers. The multivariable adjusted HR of breast cancer for users versus nonusers was 0.94 (95% CI, 0.83-1.06). In the multivariable-adjusted, time-dependent model, the HR for simvastatin was 0.87 (95% CI, 0.71-1.07). There was no significant trend by overall duration of use (P value for trend 0.68). There was no effect of tumor stage, grade, or hormone receptor status.

Conclusion: Overall, statins were not associated with breast cancer risk.

Impact: Our study is one of the largest prospective observational studies on this topic, and substantially adds to the literature suggesting no relationship between statins and breast cancer risk.
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http://dx.doi.org/10.1158/1055-9965.EPI-13-0562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3889164PMC
October 2013

Cysteine dioxygenase 1 is a tumor suppressor gene silenced by promoter methylation in multiple human cancers.

PLoS One 2012 27;7(9):e44951. Epub 2012 Sep 27.

Department of Otolaryngology, Head and Neck Cancer Research Division, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

The human cysteine dioxygenase 1 (CDO1) gene is a non-heme structured, iron-containing metalloenzyme involved in the conversion of cysteine to cysteine sulfinate, and plays a key role in taurine biosynthesis. In our search for novel methylated gene promoters, we have analyzed differential RNA expression profiles of colorectal cancer (CRC) cell lines with or without treatment of 5-aza-2'-deoxycytidine. Among the genes identified, the CDO1 promoter was found to be differentially methylated in primary CRC tissues with high frequency compared to normal colon tissues. In addition, a statistically significant difference in the frequency of CDO1 promoter methylation was observed between primary normal and tumor tissues derived from breast, esophagus, lung, bladder and stomach. Downregulation of CDO1 mRNA and protein levels were observed in cancer cell lines and tumors derived from these tissue types. Expression of CDO1 was tightly controlled by promoter methylation, suggesting that promoter methylation and silencing of CDO1 may be a common event in human carcinogenesis. Moreover, forced expression of full-length CDO1 in human cancer cells markedly decreased the tumor cell growth in an in vitro cell culture and/or an in vivo mouse model, whereas knockdown of CDO1 increased cell growth in culture. Our data implicate CDO1 as a novel tumor suppressor gene and a potentially valuable molecular marker for human cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0044951PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459978PMC
March 2013

Effects of a dietary intervention and weight change on vasomotor symptoms in the Women's Health Initiative.

Menopause 2012 Sep;19(9):980-8

Division of Research, Kaiser Permanente, Oakland, CA, USA.

Objective: The aim of this study was to determine whether a dietary intervention designed to reduce fat intake and increase intake of fruit, vegetables, and whole grains, and weight loss, reduces vasomotor symptoms (VMS; ie, hot flashes or night sweats) in postmenopausal women.

Methods: We included 17,473 postmenopausal US women, ages 50 to 79 years, at baseline who participated in the Women's Health Initiative Dietary Modification trial and were not taking menopausal hormone therapy. Logistic regression was used to evaluate associations.

Results: In multivariate-adjusted analyses, with simultaneous adjustment for the intervention and weight change, assignment to the dietary intervention versus the control arm was significantly (odds ratio [OR], 1.14; 95% CI, 1.01-1.28) related to a higher likelihood of symptom elimination among women with VMS at baseline. In addition, women with symptoms at baseline who lost 10 lb or more (OR, 1.23; 95% CI, 1.05-1.46) or lost 10% or more of their baseline body weight (OR, 1.56; 95% CI, 1.21-2.02) between baseline and year 1 were significantly more likely to eliminate VMS compared with those who maintained weight. Upon examining the joint effect of the dietary modification and weight loss, compared with women in the control arm who maintained weight, women who lost substantial weight (≥ 10%) as a part of the intervention (OR, 1.89; 95% CI, 1.39-2.57) but not as part of the control arm (OR, 1.40; 95% CI, 0.92-2.13) were significantly more likely to end VMS, although these two groups did not differ significantly from each other. Large weight loss (>22 lb), but not dietary changes, was related to the elimination of moderate/severe VMS.

Conclusions: Weight loss as part of a healthy dietary modification may help eliminate VMS among postmenopausal women.
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http://dx.doi.org/10.1097/gme.0b013e31824f606eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428489PMC
September 2012

Promoter DNA methylation of oncostatin m receptor-beta as a novel diagnostic and therapeutic marker in colon cancer.

PLoS One 2009 Aug 7;4(8):e6555. Epub 2009 Aug 7.

Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.

In addition to genetic changes, the occurrence of epigenetic alterations is associated with accumulation of both genetic and epigenetic events that promote the development and progression of human cancer. Previously, we reported a set of candidate genes that comprise part of the emerging "cancer methylome". In the present study, we first tested 23 candidate genes for promoter methylation in a small number of primary colon tumor tissues and controls. Based on these results, we then examined the methylation frequency of Oncostatin M receptor-beta (OSMR) in a larger number of tissue and stool DNA samples collected from colon cancer patients and controls. We found that OSMR was frequently methylated in primary colon cancer tissues (80%, 80/100), but not in normal tissues (4%, 4/100). Methylation of OSMR was also detected in stool DNA from colorectal cancer patients (38%, 26/69) (cut-off in TaqMan-MSP, 4). Detection of other methylated markers in stool DNA improved sensitivity with little effect on specificity. Promoter methylation mediated silencing of OSMR in cell lines, and CRC cells with low OSMR expression were resistant to growth inhibition by Oncostatin M. Our data provide a biologic rationale for silencing of OSMR in colon cancer progression and highlight a new therapeutic target in this disease. Moreover, detection and quantification of OSMR promoter methylation in fecal DNA is a highly specific diagnostic biomarker for CRC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0006555PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2717211PMC
August 2009

Pharmacologic unmasking of epigenetically silenced genes in breast cancer.

Clin Cancer Res 2009 Feb;15(4):1184-91

Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins School of Medicine, Baltimore, MD 21231, USA.

Purpose: Aberrant promoter hypermethylation of several known or putative tumor suppressor genes occurs frequently during the pathogenesis of various cancers including breast cancer. Many epigenetically inactivated genes involved in breast cancer development remain to be identified. Therefore, in this study we used a pharmacologic unmasking approach in breast cancer cell lines with 5-aza-2'-deoxycytidine (5-aza-dC) followed by microarray expression analysis to identify epigenetically inactivated genes in breast cancer.

Experimental Design: Breast cancer cell lines were treated with 5-aza-dC followed by microarray analysis to identify epigenetically inactivated genes in breast cancer. We then used bisulfite DNA sequencing, conventional methylation-specific PCR, and quantitative fluorogenic real-time methylation-specific PCR to confirm cancer-specific methylation in novel genes.

Results: Forty-nine genes were up-regulated in breast cancer cells lines after 5-aza-dC treatment, as determined by microarray analysis. Five genes (MAL, FKBP4, VGF, OGDHL, and KIF1A) showed cancer-specific methylation in breast tissues. Methylation of at least two was found at high frequency only in breast cancers (40 of 40) as compared with normal breast tissue (0 of 10; P<0.0001, Fisher's exact test).

Conclusions: This study identified new cancer-specific methylated genes to help elucidate the biology of breast cancer and as candidate diagnostic markers for the disease.
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http://dx.doi.org/10.1158/1078-0432.CCR-08-1304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3082476PMC
February 2009

Genome-wide promoter analysis uncovers portions of the cancer methylome.

Cancer Res 2008 Apr;68(8):2661-70

Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins School of Medicine, Baltimore, Maryland 21231, USA.

DNA methylation has a role in mediating epigenetic silencing of CpG island genes in cancer and other diseases. Identification of all gene promoters methylated in cancer cells "the cancer methylome" would greatly advance our understanding of gene regulatory networks in tumorigenesis. We previously described a new method of identifying methylated tumor suppressor genes based on pharmacologic unmasking of the promoter region and detection of re-expression on microarray analysis. In this study, we modified and greatly improved the selection of candidates based on new promoter structure algorithm and microarray data generated from 20 cancer cell lines of 5 major cancer types. We identified a set of 200 candidate genes that cluster throughout the genome of which 25 were previously reported as harboring cancer-specific promoter methylation. The remaining 175 genes were tested for promoter methylation by bisulfite sequencing or methylation-specific PCR (MSP). Eighty-two of 175 (47%) genes were found to be methylated in cell lines, and 53 of these 82 genes (65%) were methylated in primary tumor tissues. From these 53 genes, cancer-specific methylation was identified in 28 genes (28 of 53; 53%). Furthermore, we tested 8 of the 28 newly identified cancer-specific methylated genes with quantitative MSP in a panel of 300 primary tumors representing 13 types of cancer. We found cancer-specific methylation of at least one gene with high frequency in all cancer types. Identification of a large number of genes with cancer-specific methylation provides new targets for diagnostic and therapeutic intervention, and opens fertile avenues for basic research in tumor biology.
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http://dx.doi.org/10.1158/0008-5472.CAN-07-5913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3102297PMC
April 2008

DCC promoter hypermethylation in esophageal squamous cell carcinoma.

Int J Cancer 2008 Jun;122(11):2498-502

Department of Otolaryngology, Division of Head and Neck Cancer Research, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.

Deleted in Colorectal Cancer (DCC) is a putative tumor suppressor gene, whose loss has been implicated in colorectal tumorigenesis. Decreased or loss of DCC expression has been demonstrated in a number of human cancers, including esophageal cancer. In this study, we analyzed esophageal squamous cell carcinoma (ESCC) cell lines and primary ESCCs as well as normal esophageal tissues for DCC methylation by bisulfite sequencing, methylation-specific PCR (MSP) and/or quantitative methylation-specific PCR (qMSP). When a qMSP cut-off value for positivity was set to 1.0, DCC methylation was detected in 10 of 12 ESCC cell lines tested, 74% of primary ESCCs (n = 70), 0% of corresponding normal esophageal tissues (n = 20) and 0% of normal esophagus from healthy individuals (n = 19). DCC expression was undetectable in the majority of ESCC cell lines, and treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine reactivated gene expression. DCC overexpression suppressed colony formation in ESCC cell lines, suggesting that DCC may function as a tumor suppressor gene in the esophagus. However, DCC methylation was not associated with any clinical or pathologic parameters measured. We have demonstrated that DCC methylation is a frequent and cancer-specific event in primary ESCCs, suggesting that DCC and associated pathways may represent a new diagnostical therapeutic target.
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http://dx.doi.org/10.1002/ijc.23434DOI Listing
June 2008

HOP/OB1/NECC1 promoter DNA is frequently hypermethylated and involved in tumorigenic ability in esophageal squamous cell carcinoma.

Mol Cancer Res 2008 Jan;6(1):31-41

Department of Otolaryngology, Head and Neck Cancer Research Division, Johns Hopkins University, Baltimore, MD 21231, USA.

Promoter DNA hypermethylation with gene silencing is a common feature of human cancer, and cancer-prone methylation is believed to be a landmark of tumor suppressor genes (TSG). Identification of novel methylated genes would not only aid in the development of tumor markers but also elucidate the biological behavior of human cancers. We identified several epigenetically silenced candidate TSGs by pharmacologic unmasking of esophageal squamous cell carcinoma (ESCC) cell lines by demethylating agents (5-aza-2'-deoxycitidine and trichostatin A) combined with ESCC expression profiles using expression microarray. HOP/OB1/NECC1 was identified as an epigenetically silenced candidate TSG and further examined for (a) expression status, (b) methylation status, and (c) functional involvement in cancer cell lines. (a) The HOP gene encodes two putative promoters (promoters A and B) associated with two open reading frames (HOPalpha and HOPbeta, respectively), and HOPalpha and HOPbeta were both down-regulated in ESCC independently. (b) Promoter B harbors dense CpG islands, in which we found dense methylation in a cancer-prone manner (55% in tumor tissues by TaqMan methylation-specific PCR), whereas promoter A does not harbor CpG islands. HOPbeta silencing was associated with DNA methylation of promoter B in nine ESCC cell lines tested, and reactivated by optimal conditions of demethylating agents, whereas HOPalpha silencing was not reactivated by such treatments. Forced expression of HOP suppressed tumorigenesis in soft agar in four different squamous cell carcinoma cell lines. More convincingly, RNA interference knockdown of HOP in TE2 cells showed drastic restoration of the oncogenic phenotype. In conclusion, HOP is a putative TSG that harbors tumor inhibitory activity, and we for the first time showed that the final shutdown process of HOP expression is linked to promoter DNA hypermethylation under the double control of the discrete promoter regions in cancer.
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http://dx.doi.org/10.1158/1541-7786.MCR-07-0213DOI Listing
January 2008

Alterations of GPI transamidase subunits in head and neck squamous carcinoma.

Mol Cancer 2007 Nov 21;6:74. Epub 2007 Nov 21.

Department of Otolaryngology- Head and Neck Surgery, Head and Neck Cancer Research Division, Johns Hopkins Medical Institutions, 601 N. Caroline Street, 6th Floor, Baltimore, MD 21287-0910, USA.

Background: GPI anchor attachment is catalyzed by the GPI transamidase (GPIT) complex. GAA1, PIG-T and PIG-U are the three of five GPIT subunits. Previous studies demonstrated amplification and overexpression of GPIT subunits in bladder and breast cancer with oncogenic function. We performed an analysis of these subunits in head and neck squamous cell carcinoma (HNSCC).

Results: To evaluate GAA1, PIG-T and PIG-U in HNSCC, we used quantitative PCR (QPCR) and quantitative RT-PCR (QRT-PCR) to determine the copy number of those genes in primary tumors and the matching lymphocytes in 28 patients with HNSCC and quantified RNA expression of those genes in 16 primary HNSCC patients and 4 normal control tissue samples. GAA1 showed a significant increase in normalized mRNA expression, 2.11 (95% CI: 1.43, 2.79), in comparison to that of normal controls, 0.43 (95% CI: -0.76, 1.61), p = 0.014 (Mann-Whitney test). The mean genomic copy number of GAA1 was significantly increased in HNSCC, 0.59 (95% CI: 0.50, 0.79), in comparison to lymphocyte DNA, 0.35 (95% CI: 0.30, 0.50), p = 0.001 (paired t-test).

Conclusion: An increased expression level and elevated copy number for GAA1 suggest a role for this GPI anchor subunit in HNSCC.
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http://dx.doi.org/10.1186/1476-4598-6-74DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2204038PMC
November 2007

A promoter methylation pattern in the N-methyl-D-aspartate receptor 2B gene predicts poor prognosis in esophageal squamous cell carcinoma.

Clin Cancer Res 2007 Nov;13(22 Pt 1):6658-65

Department of Otolaryngology, Head and Neck Cancer Research Division, Johns Hopkins University, 1550 Orleans Street, Baltimore, MD 21231, USA.

Purpose: To investigate whether the promoter methylation pattern in N-methyl-d-aspartate receptor 2B (NMDAR2B) is correlated with clinical features of human esophageal squamous cell carcinoma (ESCC), the methylation status of the gene was examined at three different sites (P1, P2, and P3) where two CpG islands reside within 1 kb upstream of the transcription start site.

Experimental Design: Three independent modalities for methylation analysis (bisulfite sequencing, combined bisulfite restriction analysis, and TaqMan methylation-specific PCR) were done to analyze total 67 ESCC tissues that included 43 primary tumors with well-characterized clinicopathologic variables including patient outcome.

Results: Using an optimized cutoff value based on quantitative methylation-specific PCR, we found that patients with higher NMDAR2B methylation ratio in the proximal region (P1) showed a worse 5-year disease-specific survival rate than those without NMDAR2B methylation (P < 0.006). A significant correlation was also seen between NMDAR2B promoter methylation and the presence of vascular permeation (P = 0.03).

Conclusion: NMDAR2B promoter methylation could be a clinically applicable marker in ESCC.
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http://dx.doi.org/10.1158/1078-0432.CCR-07-1178DOI Listing
November 2007

Quantitative hypermethylation of NMDAR2B in human gastric cancer.

Int J Cancer 2007 Nov;121(9):1994-2000

Department of Otolaryngology, Division of Head and Neck Cancer Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

NMDA receptor Type 2B (NMDAR2B) is a candidate TSG first identified in esophageal squamous cell carcinoma (ESCC). To evaluate NMDAR2B methylation in gastric cancer progression, we performed quantitative methylation-specific PCR (MSP), RT-PCR and immnunohistochemistry (IHC) in primary gastric tissues and colony formation assays in gastric cancer cell lines. We found that the expression of NMDAR2B was reactivated by the demethylating agent, 5-aza-2'-deoxycytidine, with or without trichostatin A in gastric cancer cell lines. Moreover, inactivation of NMDAR2B was found to be closely correlated with promoter methylation status in gastric cell lines and primary gastric tumors. IHC data also showed that NMDAR2B was specifically expressed in gastric epithelial cells and its expression was diminished or absent in gastric cancer epithelium. Quantitative analysis of NMDAR2B promoter methylation showed 61% (17/28) hypermethylation in primary gastric tumors versus 5% (1/20) in normal gastric tissues from nongastric cancer patients. Forced over-expression of NMDAR2B in gastric cancer cell lines significantly inhibited cell colony formation. Taken together, the above results suggest that NMDAR2B methylation is a common and important biologically relevant event in gastric cancer progression.
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http://dx.doi.org/10.1002/ijc.22934DOI Listing
November 2007

A p53-type response element in the GDF15 promoter confers high specificity for p53 activation.

Biochem Biophys Res Commun 2007 Mar 25;354(4):913-8. Epub 2007 Jan 25.

Department of Otolaryngology, Head and Neck Cancer Research Division, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

GDF15 is a transcriptional target gene for p53 and its family members, p63 and p73. Its promoter region contains two p53-type response elements, RE1 and RE2, and RE2 confers p53-specific transactivation. RE2 contains several mismatches from the canonical p53 response element (RRRCWWGYYY). Two mismatches in the RRR span and T base of the RE2 core sequence in the most 3' quarter-site are critical for inhibiting the binding affinity to p63 and p73 and corresponding promoter activity. Our results strongly suggest that differential DNA-binding affinities between p53 family member proteins act, at least in part, to confer specific target gene activation.
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http://dx.doi.org/10.1016/j.bbrc.2007.01.089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1975780PMC
March 2007

Increased plasma DNA integrity index in head and neck cancer patients.

Int J Cancer 2006 Dec;119(11):2673-6

Department of Otolaryngology-Head and Neck Surgery, Head and Neck Cancer Research Division, Johns Hopkins Medical Institutions, Baltimore, MA, USA.

Analysis of the length of circulating DNA in plasma has been reported as a marker for solid tumor detection. We assessed the sensitivity and specificity of increased plasma DNA length to identify patients with head and neck squamous cell carcinoma (HNSCC) and monitor posttreatment disease status. Fifty-eight HNSCC patients with paired pre- and postoperative plasma and 47 plasma samples from control subjects were analyzed using quantitative PCR to determine plasma DNA integrity index. We found that the mean DNA integrity index was significantly greater in the plasma from HNSCC patients, 0.24 (95% CI: 0.11, 0.38), when compared to plasma from the control subjects, -2.24 (95% CI: -2.92, -1.56), p < 0.0001 using multivariate analysis. The optimal sensitivity (the value for which sensitivity equals specificity) was found at a plasma DNA integrity index of 0.82: sensitivity, 84.5%; specificity, 83%. However, there was no significant difference noted between pre- and postoperative DNA integrity index in plasma samples from HNSCC patients. This study shows that DNA integrity index in the plasma of the patients with HNSCC is increased in comparison with that in the plasma from non-HNSCC control subjects. Lack of normalization of plasma DNA integrity index after surgical resection implies the persistence of a population of cells with an altered pattern of DNA degradation despite removal of malignancy.
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http://dx.doi.org/10.1002/ijc.22250DOI Listing
December 2006

PGP9.5 methylation in diffuse-type gastric cancer.

Cancer Res 2006 Apr;66(7):3921-7

Department of Otolaryngology, Division of Head and Neck Cancer Research, Johns Hopkins University, 720 Rutland Avenue, Baltimore, MD 21205, USA.

Diffuse-type gastric cancer (DGC) is the most deadly form of gastric cancer and is frequently accompanied by peritoneal dissemination and metastasis. The specific molecular events involved in DGC pathogenesis remain elusive. Accumulating evidence of epigenetic inactivation in tumor suppressor genes led us to conduct a comprehensive screen to identify novel methylated genes in human cancers using pharmacologic unmasking and subsequent microarray analysis. We compared differential RNA expression profiles of DGC and intestinal-type gastric cancer (IGC) cell lines treated with 5-aza-2'-deoxycytidine using microarrays containing 22,284 genes. We identified 16 methylated genes, including many novel genes, in DGC cell lines and studied PGP9.5 with particular interest. In primary gastric cancers, PGP9.5 was found to be more frequently methylated in DGCs (78%) than in IGCs (36%; DGC versus IGC, P < 0.05). Furthermore, real-time methylation-specific PCR analysis of PGP9.5 showed relatively higher methylation levels in DGC than in IGC. Our data thus implicate a molecular event common in the DGC phenotype compared with IGC.
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http://dx.doi.org/10.1158/0008-5472.CAN-05-1511DOI Listing
April 2006

N-methyl-D-aspartate receptor type 2B is epigenetically inactivated and exhibits tumor-suppressive activity in human esophageal cancer.

Cancer Res 2006 Apr;66(7):3409-18

Department of Otolaryngology, Head and Neck Cancer Research Division, Institute of Cell Engineering, Johns Hopkins University School of Medicine, 818 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA.

Promoter hypermethylation accompanied by gene silencing is a common feature of human cancers. We identified previously several new tumor suppressor genes based on pharmacologic unmasking of the promoter region and detection of reexpression on microarray analysis. In this study, we modified the selection of candidates from our previous microarray data by excluding genes that showed basal expression in cancer cell lines. With the new method, we found novel methylated genes with 90% accuracy. Among these 33 novel methylated genes that we identified in esophageal squamous cell carcinoma (ESCC) cell lines, N-methyl-D-aspartate receptor type 2B (NMDAR2B) was of particular interest. NMDAR2B was methylated in 95% of primary human ESCC tissue specimens and 12 ESCC cell lines by sequence analysis. NMDAR2B expression was silenced in all 12 ESCC cell lines and was reactivated by the demethylating agent 5-aza-2'-deoxycytidine. Moreover, reintroduction of the gene was accompanied by marked Ca(2+)-independent apoptosis in ESCC cell lines, suggesting that NMDAR2B can suppress tumor growth. Thus, NMDAR2B promoter methylation is common in ESCC, abrogating gene transcription and leading to cellular resistance to apoptosis.
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http://dx.doi.org/10.1158/0008-5472.CAN-05-1608DOI Listing
April 2006

A novel response element confers p63- and p73-specific activation of the WNT4 promoter.

Biochem Biophys Res Commun 2006 Jan 5;339(4):1120-8. Epub 2005 Dec 5.

Department of Otolaryngology, Head and Neck Cancer Research Division, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

The p53 tumor suppressor gene family consists of three genes, p53, p63, and p73. p53 family proteins share high homology in their DNA-binding domains but exhibit diverse biological functions. In this study, we demonstrated differential target gene activation by specific p53, p63, and p73 induction in Saos2 cells by oligonucleotide microarray expression analysis. We further analyzed the WNT4 promoter, which was induced by p63 and p73 but not p53, in order to clarify the mechanism of differential target gene activation between the three family members. Luciferase analysis showed that the WNT4 promoter harbors two p63/p73 response elements, designated RE1 and RE2. RE1 resembles the canonical p53 response element (tandem repeats of RRRCWWGYYY), located between -141 and -121, while RE2 consists of a GC-rich sequence further downstream. Neither response element alone was able to confer transcriptional activity. It is thus likely that both RE1 and RE2 are necessary in rendering p63/p73-specific activation of the WNT4 promoter.
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http://dx.doi.org/10.1016/j.bbrc.2005.11.118DOI Listing
January 2006

Differential recognition of response elements determines target gene specificity for p53 and p63.

Mol Cell Biol 2005 Jul;25(14):6077-89

Department of Otolaryngology, Division of Head and Neck Surgery, Johns Hopkins University School of Medicine, 818 Ross Research Building, 720 Rutland Avenue, Baltimore, Maryland 21205, USA.

p63 is a member of the p53 tumor suppressor gene family, which regulates downstream target gene expression by binding to sequence-specific response elements similar to those of p53. By using oligonucleotide expression microarray analysis and analyzing the promoters of p63-induced genes, we have identified novel p63-specific response elements (p63-REs) in the promoter regions of EVPL and SMARCD3. These p63-REs exhibit characteristic differences from the canonical p53-RE (RRRCWWGYYY) in both the core-binding element (CWWG) as well as the RRR and/or YYY stretches. Luciferase assays on mutagenized promoter constructs followed by electromobility shift analysis showed that p53 preferentially activates and binds to the RRRCATGYYY sequence, whereas p63 preferentially activates RRRCGTGYYY. Whereas EVPL protein is highly expressed in epithelial cells of the skin and pharynx in the p63+/+ mouse, it is undetectable in these tissues in the p63-/- mouse. Our results indicate that p63 can regulate expression of specific target genes such as those involved in skin, limb, and craniofacial development by preferentially activating distinct p63-specific response elements.
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http://dx.doi.org/10.1128/MCB.25.14.6077-6089.2005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1168821PMC
July 2005

p63-specific activation of the BPAG-1e promoter.

J Invest Dermatol 2005 Jul;125(1):52-60

Department of Otolaryngology, Division of Head and Neck Cancer Research, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

p63, a member of the p53 superfamily, is an essential cell fate determinant for stratified epithelium. Deficiency of p63 leads to lack of differentiated epithelium from the skin and the presence of trace undifferentiated cells left in the dermis. We found that transcriptionally active isoforms of p63, TAp63beta and TAp63gamma, activated the skin-specific promoter of bullous pemphigoid antigen 1 (BPAG-1). The p63-response element was localized between bases -177 and -153 upstream of exon 1 in the BPAG-1e promoter, whereas regions surrounding the response element suppressed transcriptional responses to p53 and TAp73beta, resulting in p63-specific activation of the promoter. This represents a novel molecular mechanism by which target gene induction by p63 is distinguished from induction by other p53 family members.
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http://dx.doi.org/10.1111/j.0022-202X.2005.23801.xDOI Listing
July 2005