52 results on '"Sharon N. Edmiston"'
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2. Region of Interest Detection in Melanocytic Skin Tumor Whole Slide Images - Nevus & Melanoma.
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Yi Cui, Yao Li, Jayson R. Miedema, Sharon N. Edmiston, Sherif Farag, J. S. Marron, and Nancy E. Thomas
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- 2024
- Full Text
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3. Methylation of nonessential genes in cutaneous melanoma – Rule Out hypothesis
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Ivan P. Gorlov, Kathleen Conway, Sharon N. Edmiston, Eloise A. Parrish, Honglin Hao, Christopher I. Amos, Spiridon Tsavachidis, Olga Y. Gorlova, Colin Begg, Eva Hernando, Chao Cheng, Ronglai Shen, Irene Orlow, Li Luo, Marc S. Ernstoff, Pei Fen Kuan, David W. Ollila, Yihsuan S. Tsai, Marianne Berwick, and Nancy E. Thomas
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Cancer Research ,Oncology ,Dermatology - Published
- 2023
4. Supplementary Figures S1-3, Tables S1-4 from Racial Variation in Breast Tumor Promoter Methylation in the Carolina Breast Cancer Study
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Theresa Swift-Scanlan, Ryan May, Eloise A. Parrish, Brionna Y. Hair, Pei Fen Kuan, Christopher Bryant, Chiu-Kit Tse, Sharon N. Edmiston, and Kathleen Conway
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Supplementary Figures S1-3, Tables S1-4. Supplemental Figure S1. Racial differences in breast tumor methylation at candidate CpG probes when race is self-reported or defined by AIMs markers. Supplemental Figure S2. Methylation detected at KCNK4 and DSC2 by the GoldenGate Cancer Panel I array or quantitative methylation-specific PCR. Supplemental Figure S3. Kaplan-Meier plots showing disease-specific survival in AAs and non-AAs according to tumor methylation level for the top probes varying by race. Cases were divided into three methylation groups (high, intermediate, low) based on beta values in the combined dataset, and Kaplan-Meier plots were generated within AAs and non-AAs. Log-rank p-values are given for differences according to methylation level within each racial group. Supplemental Table S1. Reported genomic variants overlapping CpG probes and their frequencies by ancestry Supplemental Table S2. CpGs significantly differentially methylated by race in HR+ or HR- breast tumors Supplemental Table S3. Correlation between 450K CpG methylation and gene expression in TCGA breast tumors for genes showing differential methylation by race in CBCS Supplemental Table S4. Comparison of methylation in lymphoblastoid cell lines from African Americans and Caucasian Americans
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- 2023
5. Data from Racial Variation in Breast Tumor Promoter Methylation in the Carolina Breast Cancer Study
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Theresa Swift-Scanlan, Ryan May, Eloise A. Parrish, Brionna Y. Hair, Pei Fen Kuan, Christopher Bryant, Chiu-Kit Tse, Sharon N. Edmiston, and Kathleen Conway
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Background: African American (AA) women are diagnosed with more advanced breast cancers and have worse survival than white women, but a comprehensive understanding of the basis for this disparity remains unclear. Analysis of DNA methylation, an epigenetic mechanism that can regulate gene expression, could help to explain racial differences in breast tumor clinical biology and outcomes.Methods: DNA methylation was evaluated at 1,287 CpGs in the promoters of cancer-related genes in 517 breast tumors of AA (n = 216) or non-AA (n = 301) cases in the Carolina Breast Cancer Study (CBCS).Results: Multivariable linear regression analysis of all tumors, controlling for age, menopausal status, stage, intrinsic subtype, and multiple comparisons [false discovery rate (FDR)], identified seven CpG probes that showed significant (adjusted P < 0.05) differential methylation between AAs and non-AAs. Stratified analyses detected an additional four CpG probes differing by race within hormone receptor–negative (HR−) tumors. Genes differentially methylated by race included DSC2, KCNK4, GSTM1, AXL, DNAJC15, HBII-52, TUSC3, and TES; the methylation state of several of these genes may be associated with worse survival in AAs. TCGA breast tumor data confirmed the differential methylation by race and negative correlations with expression for most of these genes. Several loci also showed racial differences in methylation in peripheral blood leukocytes (PBL) from CBCS cases, indicating that these variations were not necessarily tumor-specific.Conclusions: Racial differences in the methylation of cancer-related genes are detectable in both tumors and PBLs from breast cancer cases.Impact: Epigenetic variation could contribute to differences in breast tumor development and outcomes between AAs and non-AAs. Cancer Epidemiol Biomarkers Prev; 24(6); 921–30. ©2015 AACR.
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- 2023
6. Supplementary Table 1 from IL2 Inducible T-cell Kinase, a Novel Therapeutic Target in Melanoma
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Nancy E. Thomas, Kathleen Conway, Norman E. Sharpless, David W. Ollila, James E. Bear, C. Ryan Miller, David S. Rubenstein, Paula Berkowitz, Sara C. Hanna, Eloise Parrish, Virginia D. Alldredge, David C. Gibbs, Dennis A. Hopkinson, Jill S. Frank, Honglin Hao, Jamie L. Jordan, Keefe T. Chan, Shaily Pandey, Pei Fen Kuan, Xin Zhou, Pamela A. Groben, Nana Nikolaishvili-Feinberg, David B. Darr, Sharon N. Edmiston, Stergios J. Moschos, and Craig C. Carson
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Supplementary Table 1. Clinical and histologic characteristics of cutaneous melanocytic nevi, primary melanomas, and melanoma metastases and their relationship to ITK protein levels
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- 2023
7. Supplementary Figure legends from IL2 Inducible T-cell Kinase, a Novel Therapeutic Target in Melanoma
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Nancy E. Thomas, Kathleen Conway, Norman E. Sharpless, David W. Ollila, James E. Bear, C. Ryan Miller, David S. Rubenstein, Paula Berkowitz, Sara C. Hanna, Eloise Parrish, Virginia D. Alldredge, David C. Gibbs, Dennis A. Hopkinson, Jill S. Frank, Honglin Hao, Jamie L. Jordan, Keefe T. Chan, Shaily Pandey, Pei Fen Kuan, Xin Zhou, Pamela A. Groben, Nana Nikolaishvili-Feinberg, David B. Darr, Sharon N. Edmiston, Stergios J. Moschos, and Craig C. Carson
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Legends for Supplementary Figures 1 and 2
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- 2023
8. Data from Body Mass Index Is Associated with Gene Methylation in Estrogen Receptor–Positive Breast Tumors
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Kathleen Conway, Theresa Swift-Scanlan, Andrew F. Olshan, Michael C. Wu, Whitney R. Robinson, Eloise A. Parrish, Sharon N. Edmiston, Melissa A. Troester, and Brionna Y. Hair
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Background: Although obesity is associated with breast cancer incidence and prognosis, the underlying mechanisms are poorly understood. Identification of obesity-associated epigenetic changes in breast tissue may advance mechanistic understanding of breast cancer initiation and progression. The goal of this study, therefore, was to investigate associations between obesity and gene methylation in breast tumors.Methods: Using the Illumina GoldenGate Cancer I Panel, we estimated the association between body mass index (BMI) and gene methylation in 345 breast tumor samples from phase I of the Carolina Breast Cancer Study, a population-based case–control study. Multivariable linear regression was used to identify sites that were differentially methylated by BMI. Stratification by tumor estrogen receptor (ER) status was also conducted.Results: In the majority of the 935 probes analyzed (87%), the average beta value increased with obesity (BMI ≥ 30). Obesity was significantly associated with differential methylation (FDR q < 0.05) in just two gene loci in breast tumor tissue overall and in 21 loci among ER-positive tumors. Obesity was associated with methylation of genes that function in immune response, cell growth, and DNA repair.Conclusions: Obesity is associated with altered methylation overall, and with hypermethylation among ER-positive tumors in particular, suggesting that obesity may influence the methylation of genes with known relevance to cancer. Some of these differences in methylation by obese status may influence levels of gene expression within breast cells.Impact: If our results are validated, obesity-associated methylation sites could serve as targets for prevention and treatment research. Cancer Epidemiol Biomarkers Prev; 24(3); 580–6. ©2015 AACR.
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- 2023
9. Supplemental Table 1 from Body Mass Index Is Associated with Gene Methylation in Estrogen Receptor–Positive Breast Tumors
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Kathleen Conway, Theresa Swift-Scanlan, Andrew F. Olshan, Michael C. Wu, Whitney R. Robinson, Eloise A. Parrish, Sharon N. Edmiston, Melissa A. Troester, and Brionna Y. Hair
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Supplemental Table 1. Correlation between BMI-associated methylation sites (overall and among ER-positive tumors) and gene expression in breast tumors from The Cancer Genome Atlas (TCGA)
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- 2023
10. Supplementary Figure 2 from IL2 Inducible T-cell Kinase, a Novel Therapeutic Target in Melanoma
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Nancy E. Thomas, Kathleen Conway, Norman E. Sharpless, David W. Ollila, James E. Bear, C. Ryan Miller, David S. Rubenstein, Paula Berkowitz, Sara C. Hanna, Eloise Parrish, Virginia D. Alldredge, David C. Gibbs, Dennis A. Hopkinson, Jill S. Frank, Honglin Hao, Jamie L. Jordan, Keefe T. Chan, Shaily Pandey, Pei Fen Kuan, Xin Zhou, Pamela A. Groben, Nana Nikolaishvili-Feinberg, David B. Darr, Sharon N. Edmiston, Stergios J. Moschos, and Craig C. Carson
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Supplementary Figure 2. Ingenuity Pathway Analysis Results from RPPA assay and effects of ITK activity on specific cellular proteins by westerns and RPPA results.
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- 2023
11. Data from IL2 Inducible T-cell Kinase, a Novel Therapeutic Target in Melanoma
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Nancy E. Thomas, Kathleen Conway, Norman E. Sharpless, David W. Ollila, James E. Bear, C. Ryan Miller, David S. Rubenstein, Paula Berkowitz, Sara C. Hanna, Eloise Parrish, Virginia D. Alldredge, David C. Gibbs, Dennis A. Hopkinson, Jill S. Frank, Honglin Hao, Jamie L. Jordan, Keefe T. Chan, Shaily Pandey, Pei Fen Kuan, Xin Zhou, Pamela A. Groben, Nana Nikolaishvili-Feinberg, David B. Darr, Sharon N. Edmiston, Stergios J. Moschos, and Craig C. Carson
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Purpose: IL2 inducible T-cell kinase (ITK) promoter CpG sites are hypomethylated in melanomas compared with nevi. The expression of ITK in melanomas, however, has not been established and requires elucidation.Experimental Design: An ITK-specific monoclonal antibody was used to probe sections from deidentified, formalin-fixed paraffin-embedded tumor blocks or cell line arrays and ITK was visualized by IHC. Levels of ITK protein differed among melanoma cell lines and representative lines were transduced with four different lentiviral constructs that each contained an shRNA designed to knockdown ITK mRNA levels. The effects of the selective ITK inhibitor BI 10N on cell lines and mouse models were also determined.Results: ITK protein expression increased with nevus to metastatic melanoma progression. In melanoma cell lines, genetic or pharmacologic inhibition of ITK decreased proliferation and migration and increased the percentage of cells in the G0–G1 phase. Treatment of melanoma-bearing mice with BI 10N reduced growth of ITK-expressing xenografts or established autochthonous (Tyr-Cre/Ptennull/BrafV600E) melanomas.Conclusions: We conclude that ITK, formerly considered an immune cell–specific protein, is aberrantly expressed in melanoma and promotes tumor development and progression. Our finding that ITK is aberrantly expressed in most metastatic melanomas suggests that inhibitors of ITK may be efficacious for melanoma treatment. The efficacy of a small-molecule ITK inhibitor in the Tyr-Cre/Ptennull/BrafV600E mouse melanoma model supports this possibility. Clin Cancer Res; 21(9); 2167–76. ©2015 AACR.
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- 2023
12. Supplementary Table 6 from IL2 Inducible T-cell Kinase, a Novel Therapeutic Target in Melanoma
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Nancy E. Thomas, Kathleen Conway, Norman E. Sharpless, David W. Ollila, James E. Bear, C. Ryan Miller, David S. Rubenstein, Paula Berkowitz, Sara C. Hanna, Eloise Parrish, Virginia D. Alldredge, David C. Gibbs, Dennis A. Hopkinson, Jill S. Frank, Honglin Hao, Jamie L. Jordan, Keefe T. Chan, Shaily Pandey, Pei Fen Kuan, Xin Zhou, Pamela A. Groben, Nana Nikolaishvili-Feinberg, David B. Darr, Sharon N. Edmiston, Stergios J. Moschos, and Craig C. Carson
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Supplementary Table 6. Significant pathways identified by Ingenuity Pathway Analysis for Reverse Phase Protein Array (RPPA) results of RPMI 8322
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- 2023
13. Supplementary Tables 3 and 4 from IL2 Inducible T-cell Kinase, a Novel Therapeutic Target in Melanoma
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Nancy E. Thomas, Kathleen Conway, Norman E. Sharpless, David W. Ollila, James E. Bear, C. Ryan Miller, David S. Rubenstein, Paula Berkowitz, Sara C. Hanna, Eloise Parrish, Virginia D. Alldredge, David C. Gibbs, Dennis A. Hopkinson, Jill S. Frank, Honglin Hao, Jamie L. Jordan, Keefe T. Chan, Shaily Pandey, Pei Fen Kuan, Xin Zhou, Pamela A. Groben, Nana Nikolaishvili-Feinberg, David B. Darr, Sharon N. Edmiston, Stergios J. Moschos, and Craig C. Carson
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Supplementary Tables 3 and 4. Supplementary Table 3. ITK protein expression levels in cell lines by single fluorescent immunocytochemistry Supplementary Table 4. Statistical analysis of shRNA and BI 10N effects on the proliferation and motility rates of melanoma cell lines
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- 2023
14. Supplementary Figure 1 from IL2 Inducible T-cell Kinase, a Novel Therapeutic Target in Melanoma
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Nancy E. Thomas, Kathleen Conway, Norman E. Sharpless, David W. Ollila, James E. Bear, C. Ryan Miller, David S. Rubenstein, Paula Berkowitz, Sara C. Hanna, Eloise Parrish, Virginia D. Alldredge, David C. Gibbs, Dennis A. Hopkinson, Jill S. Frank, Honglin Hao, Jamie L. Jordan, Keefe T. Chan, Shaily Pandey, Pei Fen Kuan, Xin Zhou, Pamela A. Groben, Nana Nikolaishvili-Feinberg, David B. Darr, Sharon N. Edmiston, Stergios J. Moschos, and Craig C. Carson
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Supplementary Figure 1. IHC staining for co-localization of immune markers with cells expressing ITK and determining the presence of ITK in immune cell subtypes infiltrating the tumor and the effect of ITK ablation on the cell cycle of the melanoma cells
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- 2023
15. Landscape of mutations in early stage primary cutaneous melanoma: An InterMEL study
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Li, Luo, Ronglai, Shen, Arshi, Arora, Irene, Orlow, Klaus J, Busam, Cecilia, Lezcano, Tim K, Lee, Eva, Hernando, Ivan, Gorlov, Christopher, Amos, Marc S, Ernstoff, Venkatraman E, Seshan, Anne E, Cust, James, Wilmott, Richard A, Scolyer, Graham, Mann, Eduardo, Nagore, Pauline, Funchain, Jennifer, Ko, Peter, Ngo, Sharon N, Edmiston, Kathleen, Conway, Paul B, Googe, David, Ollila, Jeffrey E, Lee, Shenying, Fang, Judy R, Rees, Cheryl L, Thompson, Meg, Gerstenblith, Marcus, Bosenberg, Bonnie, Gould Rothberg, Iman, Osman, Yvonne, Saenger, Adam Z, Reynolds, Matthew, Schwartz, Tawny, Boyce, Sheri, Holmen, Elise, Brunsgaard, Paul, Bogner, Pei Fen, Kuan, Charles, Wiggins, Nancy E, Thomas, Colin B, Begg, and Marianne, Berwick
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Male ,Proto-Oncogene Proteins B-raf ,MicroRNAs ,Skin Neoplasms ,Oncology ,Mutation ,Humans ,Female ,Dermatology ,Melanoma ,General Biochemistry, Genetics and Molecular Biology ,Aged - Abstract
It is unclear why some melanomas aggressively metastasize while others remain indolent. Available studies employing multi-omic profiling of melanomas are based on large primary or metastatic tumors. We examine the genomic landscape of early-stage melanomas diagnosed prior to the modern era of immunological treatments. Untreated cases with Stage II/III cutaneous melanoma were identified from institutions throughout the United States, Australia and Spain. FFPE tumor sections were profiled for mutation, methylation and microRNAs. Preliminary results from mutation profiling and clinical pathologic correlates show the distribution of four driver mutation sub-types: 31% BRAF; 18% NRAS; 21% NF1; 26% Triple Wild Type. BRAF mutant tumors had younger age at diagnosis, more associated nevi, more tumor infiltrating lymphocytes, and fewer thick tumors although at generally more advanced stage. NF1 mutant tumors were frequent on the head/neck in older patients with severe solar elastosis, thicker tumors but in earlier stages. Triple Wild Type tumors were predominantly male, frequently on the leg, with more perineural invasion. Mutations in TERT, TP53, CDKN2A and ARID2 were observed often, with TP53 mutations occurring particularly frequently in the NF1 sub-type. The InterMEL study will provide the most extensive multi-omic profiling of early-stage melanoma to date. Initial results demonstrate a nuanced understanding of the mutational and clinicopathological landscape of these early-stage tumors.
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- 2022
16. InterMEL: An international biorepository and clinical database to uncover predictors of survival in early-stage melanoma
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Irene Orlow, Keimya D. Sadeghi, Sharon N. Edmiston, Jessica M. Kenney, Cecilia Lezcano, James S. Wilmott, Anne E. Cust, Richard A. Scolyer, Graham J. Mann, Tim K. Lee, Hazel Burke, Valerie Jakrot, Ping Shang, Peter M. Ferguson, Tawny W. Boyce, Jennifer S. Ko, Peter Ngo, Pauline Funchain, Judy R. Rees, Kelli O’Connell, Honglin Hao, Eloise Parrish, Kathleen Conway, Paul B. Googe, David W. Ollila, Stergios J. Moschos, Eva Hernando, Douglas Hanniford, Diana Argibay, Christopher I. Amos, Jeffrey E. Lee, Iman Osman, Li Luo, Pei-Fen Kuan, Arshi Aurora, Bonnie E. Gould Rothberg, Marcus W. Bosenberg, Meg R. Gerstenblith, Cheryl Thompson, Paul N. Bogner, Ivan P. Gorlov, Sheri L. Holmen, Elise K. Brunsgaard, Yvonne M. Saenger, Ronglai Shen, Venkatraman Seshan, Eduardo Nagore, Marc S. Ernstoff, Klaus J. Busam, Colin B. Begg, Nancy E. Thomas, and Marianne Berwick
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IntroductionWe are conducting a multicenter study to identify classifiers predictive of disease-specific survival in patients with primary melanomas. Here we delineate the unique aspects, challenges, and best practices for optimizing a study of generally small-sized pigmented tumor samples including primary melanomas of at least 1.05mm from AJTCC TNM stage IIA-IIID patients. This ongoing study will target 1,000 melanomas within the international InterMEL consortium. We also evaluated tissue-derived predictors of extracted nucleic acids’ quality and success in downstream testing.MethodsFollowing a pre-established protocol, participating centers ship formalin-fixed paraffin embedded (FFPE) tissue sections to Memorial Sloan Kettering Cancer Center for the centralized handling, dermatopathology review and histology-guided coextraction of RNA and DNA. Samples are distributed for evaluation of somatic mutations using next gen sequencing (NGS) with the MSK-IMPACT™ assay, methylation-profiling (array), and miRNA expression (Nanostring nCounter).ResultsSufficient material was obtained for screening of miRNA expression in 683/685 (99%) eligible melanomas, methylation in 467 (68%), and somatic mutations in 560 (82%). In 446/685 (65%) cases, aliquots of RNA/DNA were sufficient for testing with all three platforms. Among samples evaluated by the time of this analysis, the mean NGS coverage was 249x, 59 (18.6%) samples had coverage below 100x, and 41/414 (10%) failed methylation QC due to low intensity probes or insufficient Meta-Mixed Interquartile (BMIQ)- and single sample (ss)- Noob normalizations. Six of 683 RNAs (1%) failed Nanostring QC due to the low proportion of probes above the minimum threshold. Age of the FFPE tissue blocks (pConclusionOur experience with many archival tissues demonstrates that with careful management of tissue processing and quality control it is possible to conduct multi-omic studies in a complex multi-institutional setting for investigations involving minute quantities of FFPE tumors, as in studies of early-stage melanoma.
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- 2022
17. Targeting the IL-2 inducible kinase in melanoma; a phase 2 study of ibrutinib in systemic treatment-refractory distant metastatic cutaneous melanoma: preclinical rationale, biology, and clinical activity (NCI9922)
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George Ansstas, Anastasia Ivanova, Elizabeth Claire Dees, Karen P. McKinnon, Nancy Garrett-Mead, Christy Arrowood, S. Percy Ivy, Gino K. In, Lokesh Agrawal, Zeynep Eroglu, Frances A. Collichio, Peng Wang, Glenn Liu, Stergios J. Moschos, Hsing-Hui Wang, Kathleen Conway, Craig C. Carson, Nancy E. Thomas, Nana Nikolaishvilli-Feinberg, Nikhil I. Khushalani, David W. Ollila, Kari Kendra, Sharon N. Edmiston, Paul B. Googe, James L. Abbruzzese, and Jonathan S. Serody
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Adult ,Male ,0301 basic medicine ,Cancer Research ,Skin Neoplasms ,Phases of clinical research ,Ipilimumab ,Dermatology ,Peripheral blood mononuclear cell ,Article ,CD19 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Piperidines ,medicine ,Humans ,PTEN ,Melanoma ,Aged ,Aged, 80 and over ,biology ,Tumor-infiltrating lymphocytes ,Adenine ,Middle Aged ,medicine.disease ,030104 developmental biology ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Ibrutinib ,biology.protein ,Cancer research ,Interleukin-2 ,Female ,medicine.drug - Abstract
Background IL-2 inducible kinase (ITK) is highly expressed in metastatic melanomas and its inhibition suppresses melanoma cell proliferation. We hypothesize that ibrutinib has a direct antitumor effect in melanoma cell lines and that treatment of metastatic melanomas with ibrutinib induces antitumor responses. Methods We assessed the ibrutinib effect on melanoma cell proliferation, apoptosis, and motility. Patients with metastatic melanoma refractory to PD-1 and MAPK inhibitors (if BRAFV600-mutant) were treated with ibrutinib, 840 mg PO QD, as part of a phase II clinical trial (clinicaltrials.gov NCT02581930). Results Melanoma cell lines frequently express ITK, YES1, and EGFR. Ibrutinib suppressed cell motility and proliferation in most cell lines. Eighteen patients (13 male; median age 63.5 years, range 37-82; 12 with ipilimumab resistance) were enrolled. The most frequent side effects were fatigue (61%), anorexia (50%), hyponatremia (28%), nausea, and vomiting (22% each). No antitumor responses were seen. At a median follow-up of 6 months (0.3-35.8 months), the median progression-free survival was 1.3 months (range 0.2-5.5 months). Fifteen patients were discontinued from the study due to progression, and 14 patients had died from metastatic melanoma. All archived tumors expressed ITK, 41% had no expression of p16 and PTEN, and 61% had absent tumor-infiltrating lymphocytes (TILs). Ibrutinib significantly suppressed proliferating (Ki67+) CD19+ peripheral blood mononuclear cells and had no significant effect on other lymphocyte subsets. Conclusion Ibrutinib did not induce any meaningful clinical benefit. ITK expression may not be clinically relevant. Treatment-refractory metastatic melanomas have other fundamental defects (i.e. absent PTEN and p16 expression, absent TILs) that may contribute to an adverse prognosis.
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- 2021
18. Characterization of the CpG island hypermethylated phenotype (CIMP) subclass in primary melanomas
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David W. Ollila, Paul B. Googe, Eloise Parrish, Nancy E. Thomas, Honglin Hao, Kathleen Conway, Glynis Scott, Pei Fen Kuan, Joel S. Parker, Jill S. Frank, Sharon N. Edmiston, and Yihsuan S. Tsai
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Skin Neoplasms ,Dermatology ,Biochemistry ,Article ,Medicine ,PTEN ,Humans ,Lentigo maligna melanoma ,Molecular Biology ,neoplasms ,Melanoma ,biology ,CpG Island Methylator Phenotype ,business.industry ,Tumor-infiltrating lymphocytes ,Cell Biology ,DNA Methylation ,medicine.disease ,Prognosis ,Phenotype ,CpG site ,Cutaneous melanoma ,DNA methylation ,biology.protein ,Cancer research ,CpG Islands ,business - Abstract
Cutaneous melanoma can be lethal even if detected at an early stage. Epigenetic profiling may facilitate the identification of aggressive primary melanomas with unfavorable outcomes. We performed clustering of whole-genome methylation data to identify subclasses that were then assessed for survival, clinical features, methylation patterns, and biological pathways. Among 89 cutaneous primary invasive melanomas, we identified three methylation subclasses exhibiting low methylation, intermediate methylation, or hypermethylation of CpG islands, known as the CpG island methylator phenotype (CIMP). CIMP melanomas occurred as early as tumor stage 1b and, compared with low-methylation melanomas, were associated with age at diagnosis ≥65 years, lentigo maligna melanoma histologic subtype, presence of ulceration, higher American Joint Committee on Cancer stage and tumor stage, and lower tumor-infiltrating lymphocyte grade (all P0.05). Patients with CIMP melanomas had worse melanoma-specific survival (hazard ratio = 11.84; confidence interval = 4.65‒30.20) than those with low-methylation melanomas, adjusted for age, sex, American Joint Committee on Cancer stage, and tumor-infiltrating lymphocyte grade. Genes hypermethylated in CIMP compared with those in low-methylation melanomas included PTEN, VDR, PD-L1, TET2, and gene sets related to development/differentiation, the extracellular matrix, and immunity. CIMP melanomas exhibited hypermethylation of genes important in melanoma progression and tumor immunity, and although present in some early melanomas, CIMP was associated with worse survival independent of known prognostic factors.
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- 2021
19. Disease-Associated Risk Variants in
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Danielle R, Davari, Irene, Orlow, Peter A, Kanetsky, Li, Luo, Sharon N, Edmiston, Kathleen, Conway, Eloise A, Parrish, Honglin, Hao, Klaus J, Busam, Ajay, Sharma, Anne, Kricker, Anne E, Cust, Hoda, Anton-Culver, Stephen B, Gruber, Richard P, Gallagher, Roberto, Zanetti, Stefano, Rosso, Lidia, Sacchetto, Terence, Dwyer, David W, Ollila, Colin B, Begg, Marianne, Berwick, and Nancy E, Thomas
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Male ,Proto-Oncogene Proteins B-raf ,Skin Neoplasms ,Membrane Proteins ,Middle Aged ,Article ,GTP Phosphohydrolases ,Lymphocytes, Tumor-Infiltrating ,Mutation ,Humans ,Female ,Melanoma ,Aged ,Cyclin-Dependent Kinase Inhibitor p15 ,Genome-Wide Association Study - Abstract
BACKGROUND: Genome-wide association studies have reported that genetic variation at ANRIL (CDKN2B-AS1) is associated with risk of several chronic diseases including coronary artery disease, coronary artery calcification, myocardial infarction, and type 2 diabetes mellitus. ANRIL is located at the CDKN2A/B locus, which encodes multiple melanoma tumor suppressors. We investigated the association of these variants with melanoma prognostic characteristics. METHODS: The Genes, Environment, and Melanoma Study enrolled 3,285 European origin participants with incident invasive primary melanoma. For each of ten disease-associated single-nucleotide polymorphisms (SNPs) at or near ANRIL, we used linear and logistic regression modeling to estimate, respectively, the per allele mean changes in log of Breslow thickness and odds ratios (ORs) for presence of ulceration and tumor-infiltrating lymphocytes (TILs). We also assessed effect modification by tumor NRAS/BRAF mutational status. RESULTS: Rs518394, rs10965215, and rs564398 passed false discovery and were each associated (P ≤ 0.005) with TILs, although only rs564398 was independently associated (P = 0.0005) with TILs. Stratified by NRAS/BRAF mutational status, rs564398*A was significantly positively associated with TILs among NRAS/BRAF mutant, but not wildtype, cases. We did not find SNP associations with Breslow thickness or ulceration. CONCLUSIONS: ANRIL rs564398 was associated with TIL presence in primary melanomas, and this association may be limited to NRAS/BRAF mutant cases. IMPACT: Pathways related to ANRIL variants warrant exploration in relationship to TILs in melanoma, especially given the impact of TILs on immunotherapy and survival.
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- 2021
20. Inherited Genetic Variants Associated with Melanoma BRAF/NRAS Subtypes
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Nancy E. Thomas, Sharon N. Edmiston, Irene Orlow, Peter A. Kanetsky, Li Luo, David C. Gibbs, Eloise A. Parrish, Honglin Hao, Klaus J. Busam, Bruce K. Armstrong, Anne Kricker, Anne E. Cust, Hoda Anton-Culver, Stephen B. Gruber, Richard P. Gallagher, Roberto Zanetti, Stefano Rosso, Lidia Sacchetto, Terence Dwyer, David W. Ollila, Colin B. Begg, Marianne Berwick, Kathleen Conway, Colin Begg, Pampa Roy, Anne Reiner, Siok Leong, Sergio Corrales Guerrero, Keimya Sadeghi, Tawny W. Boyce, Alison Venn, Paul Tucker, Loraine D. Marrett, Lynn From, Shu-Chen Huang, Pamela A. Groben, Eloise Parrish, Jill S. Frank, Timothy R. Rebbeck, Julia Lee Taylor, and Sasha Madronich
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Adult ,Male ,Proto-Oncogene Proteins B-raf ,Risk ,0301 basic medicine ,Oncology ,Neuroblastoma RAS viral oncogene homolog ,medicine.medical_specialty ,Skin Neoplasms ,Genotype ,endocrine system diseases ,Clinical Sciences ,Oncology and Carcinogenesis ,Single-nucleotide polymorphism ,Genome-wide association study ,Dermatology ,Polymorphism, Single Nucleotide ,Biochemistry ,Article ,GTP Phosphohydrolases ,Group VI Phospholipases A2 ,03 medical and health sciences ,Polymorphism (computer science) ,Internal medicine ,medicine ,Humans ,SNP ,Melanoma ,neoplasms ,Molecular Biology ,Genetic Association Studies ,Aged ,business.industry ,Dermatology & Venereal Diseases ,Membrane Proteins ,GEM Study Group ,Cell Biology ,Odds ratio ,Middle Aged ,medicine.disease ,digestive system diseases ,030104 developmental biology ,Interferon Regulatory Factors ,Mutation ,Female ,business - Abstract
BRAF and NRAS mutations arise early in melanoma development, but their associations with low-penetrance melanoma susceptibility loci remain unknown. In the Genes, Environment and Melanoma Study, 1,223 European-origin participants had their incident invasive primary melanomas screened for BRAF/NRAS mutations and germline DNA genotyped for 47 single-nucleotide polymorphisms identified as low-penetrant melanoma-risk variants. We used multinomial logistic regression to simultaneously examine each single-nucleotide polymorphism's relationship to BRAF V600E, BRAF V600K, BRAF other, and NRAS+ relative to BRAF-/NRAS- melanoma adjusted for study features. IRF4 rs12203592*T was associated with BRAF V600E (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.43-0.79) and V600K (OR = 0.65, 95% CI = 0.41-1.03), but not BRAF other or NRAS+ melanoma. A global test of etiologic heterogeneity (Pglobal = 0.001) passed false discovery (Pglobal = 0.0026). PLA2G6 rs132985*T was associated with BRAF V600E (OR = 1.32, 95% CI = 1.05-1.67) and BRAF other (OR = 1.82, 95% CI = 1.11-2.98), but not BRAF V600K or NRAS+ melanoma. The test for etiologic heterogeneity (Pglobal) was 0.005. The IRF4 rs12203592 associations were slightly attenuated after adjustment for melanoma-risk phenotypes. The PLA2G6 rs132985 associations were independent of phenotypes. IRF4 and PLA2G6 inherited genotypes may influence melanoma BRAF/NRAS subtype development.
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- 2018
21. Relationship of Chromosome Arm 10q Variants to Occurrence of Multiple Primary Melanoma in the Population-Based Genes, Environment, and Melanoma (GEM) Study
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Jonathan A. Miles, Irene Orlow, Peter A. Kanetsky, Li Luo, Anne E. Cust, Bruce K. Armstrong, Anne Kricker, Hoda Anton-Culver, Stephen B. Gruber, Richard P. Gallagher, Roberto Zanetti, Stefano Rosso, Lidia Sacchetto, Terence Dwyer, David C. Gibbs, Klaus J. Busam, Vikram Mavinkurve, David W. Ollila, Colin B. Begg, Marianne Berwick, Nancy E. Thomas, Colin Begg, Pampa Roy, Siok Leong, Sergio Corrales-Guerrero, Keimya Sadeghi, Anne Reiner, Tawny W. Boyce, Alison Venn, Paul Tucker, Agnes Lai, Loraine D. Marrett, Lynn From, Shu-Chen Huang, Kathleen Conway, Pamela A. Groben, Sharon N. Edmiston, Honglin Hao, Eloise Parrish, Jill S. Frank, Timothy R. Rebbeck, Julia Lee Taylor, and Sasha Madronich
- Subjects
Genetics ,Linkage disequilibrium ,business.industry ,Melanoma ,Chromosome ,Cancer ,Single-nucleotide polymorphism ,Cell Biology ,Dermatology ,medicine.disease ,Biochemistry ,Minor allele frequency ,Chromosome Arm ,Cutaneous melanoma ,Medicine ,business ,Molecular Biology - Published
- 2019
22. Inherited Melanoma Risk Variants Associated with Histopathologically Amelanotic Melanoma
- Author
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David Corley Gibbs, Irene Orlow, Steven Vernali, Helen B. Powell, Peter A. Kanetsky, Li Luo, Klaus J. Busam, Ajay Sharma, Anne Kricker, Bruce K. Armstrong, Anne E. Cust, Hoda Anton-Culver, Stephen B. Gruber, Richard P. Gallagher, Roberto Zanetti, Stefano Rosso, Lidia Sacchetto, Terence Dwyer, David W. Ollila, Colin B. Begg, Marianne Berwick, Nancy E. Thomas, Colin Begg, Pampa Roy, Emily La Pilla, Sarah Yoo, Jaipreet Rayar, Anne Reiner, Tawny W. Boyce, Alison Venn, Paul Tucker, Loraine D. Marrett, Lynn From, Shu-Chen Huang, Kathleen Conway, Pamela A. Groben, Sharon N. Edmiston, Honglin Hao, Eloise Parrish, Jill S. Frank, David C. Gibbs, Timothy R. Rebbeck, Julia Lee Taylor, and Sasha Madronich
- Subjects
Male ,Skin Neoplasms ,business.industry ,Melanoma ,Single-nucleotide polymorphism ,Melanoma, Amelanotic ,Cell Biology ,Dermatology ,Odds ratio ,DNA, Neoplasm ,Biology ,medicine.disease ,Biochemistry ,Polymorphism, Single Nucleotide ,Article ,Text mining ,medicine ,Cancer research ,SNP ,Humans ,Female ,Genetic Predisposition to Disease ,Amelanotic melanoma ,business ,Molecular Biology - Published
- 2019
23. Identification of a robust methylation classifier for cutaneous melanoma diagnosis
- Author
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Daniel C. Zedek, Matthew D. Wilkerson, Nancy E. Thomas, Yi-Hsuan Tsai, Pamela A. Groben, Glynis Scott, Sharon N. Edmiston, Xiaobei Zhao, Stergios J. Moschos, Eloise Parrish, Nathaniel A. Slater, Honglin Hao, Craig C. Carson, David W. Ollila, Michelle V. Pearlstein, Kathleen Conway, Pei Fen Kuan, Joel S. Parker, and Jill S. Frank
- Subjects
0301 basic medicine ,Oncology ,Epigenomics ,Male ,medicine.medical_specialty ,Skin Neoplasms ,Dermatology ,Biochemistry ,Article ,Epigenesis, Genetic ,Diagnosis, Differential ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Biomarkers, Tumor ,Nevus ,Humans ,Epigenetics ,Molecular Biology ,neoplasms ,Melanoma ,Retrospective Studies ,Skin ,Receiver operating characteristic ,business.industry ,Cell Biology ,Methylation ,DNA Methylation ,Middle Aged ,medicine.disease ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,ROC Curve ,030220 oncology & carcinogenesis ,Cutaneous melanoma ,DNA methylation ,CpG Islands ,Female ,business ,Classifier (UML) ,Algorithms - Abstract
Early diagnosis improves melanoma survival, yet the histopathological diagnosis of cutaneous primary melanoma can be challenging even for expert dermatopathologists. Analysis of epigenetic alterations, such as DNA methylation, that occur in melanoma can aid in its early diagnosis. Using a genome-wide methylation screen, we assessed CpG methylation in a diverse set of 89 primary invasive melanomas, 73 nevi, and 41 melanocytic proliferations of uncertain malignant potential, classified based on interobserver review by dermatopathologists. Melanomas and nevi were split into training and validation sets. Predictive modeling in the training set using ElasticNet identified a 40-CpG classifier distinguishing 60 melanomas from 48 nevi. High diagnostic accuracy (area under the receiver operator characteristics (ROC) curve (AUC)=0.996, sensitivity=96.6%, and specificity=100.0%) was independently confirmed in the validation set (29 melanomas, 25 nevi) and other published sample sets. The 40-CpG melanoma classifier included homeobox transcription factors and genes with roles in stem cell pluripotency or the nervous system. Application of the 40-CpG melanoma classifier to the diagnostically uncertain samples assigned melanoma or nevus status, potentially offering a diagnostic tool to assist dermatopathologists. In summary, the robust, accurate 40-CpG melanoma classifier offers a promising assay for improving primary melanoma diagnosis.
- Published
- 2018
24. Utility of TERT Promoter Mutations for Cutaneous Primary Melanoma Diagnosis
- Author
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Eloise Parrish, Jill S. Frank, David W. Ollila, Sharon N. Edmiston, Honglin Hao, Yihsuan S. Tsai, Paul B. Googe, Michelle V. Pearlstein, Nancy E. Thomas, Nathaniel A. Slater, Kathleen Conway, Klaus J. Busam, Daniel C. Zedek, Pei Fen Kuan, Joel S. Parker, and Glynis Scott
- Subjects
Adult ,Male ,Skin Neoplasms ,Dermatology ,Tert promoter ,Article ,Pathology and Forensic Medicine ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Medicine ,Nevus ,Humans ,Telomerase reverse transcriptase ,Tert promoter mutation ,Promoter Regions, Genetic ,Melanoma diagnosis ,Melanoma ,Telomerase ,Aged ,Nevus, Pigmented ,business.industry ,General Medicine ,Melanocytic neoplasm ,Middle Aged ,medicine.disease ,Predictive value ,Mutation ,Cancer research ,Female ,business - Abstract
Telomerase reverse transcriptase (TERT) promoter mutations are commonly found in malignant melanomas but rare in melanocytic nevi. To assess its potential diagnostic utility for the distinction of melanoma from nevus, we determined the TERT promoter mutation status of 86 primary melanomas, 72 melanocytic nevi, and 40 diagnostically problematic melanocytic proliferations. Of the 86 melanomas, 67 (77.9%) were TERT-positive, defined as harboring a hotspot TERT promoter mutation at positions -124C>T, -124_125CC>TT, -138_139CC>TT, or -146C>T. Of the 72 nevi, only 1 (1.4%) was TERT-positive. Of the 40 diagnostically uncertain melanocytic proliferations, 2 (5.0%) were TERT-positive. TERT positivity as a test for melanoma versus nevus had an accuracy of 87.3% [95% confidence interval (CI), 81.1-92.1], a sensitivity of 77.9% (95% CI, 68.9-85.4), a specificity of 98.6% (95% CI, 95.8-100), a positive predictive value of 98.5% (95% CI, 95.6-100), and a negative predictive value of 78.9% (95% CI, 72.6-85.4). Our results indicate that hotspot TERT promoter mutation status may be a useful ancillary parameter for the diagnosis of melanoma. In particular, the high specificity of these mutations for melanoma indicates the presence of a TERT promoter mutation in a melanocytic neoplasm associated with diagnostic controversy, or uncertainty should increase concern for a melanoma.
- Published
- 2018
25. Body Mass Index Is Associated with Gene Methylation in Estrogen Receptor–Positive Breast Tumors
- Author
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Kathleen Conway, Sharon N. Edmiston, Eloise Parrish, Michael C. Wu, Brionna Y. Hair, Theresa Swift-Scanlan, Andrew F. Olshan, Melissa A. Troester, and Whitney R. Robinson
- Subjects
Adult ,Oncology ,medicine.medical_specialty ,Epidemiology ,Population ,Estrogen receptor ,Breast Neoplasms ,Biology ,Article ,Body Mass Index ,Young Adult ,Breast cancer ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Obesity ,Epigenetics ,education ,Aged ,education.field_of_study ,Gene Expression Profiling ,Cancer ,Methylation ,DNA Methylation ,Middle Aged ,Prognosis ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Gene expression profiling ,Endocrinology ,Receptors, Estrogen ,DNA methylation ,Female - Abstract
Background: Although obesity is associated with breast cancer incidence and prognosis, the underlying mechanisms are poorly understood. Identification of obesity-associated epigenetic changes in breast tissue may advance mechanistic understanding of breast cancer initiation and progression. The goal of this study, therefore, was to investigate associations between obesity and gene methylation in breast tumors. Methods: Using the Illumina GoldenGate Cancer I Panel, we estimated the association between body mass index (BMI) and gene methylation in 345 breast tumor samples from phase I of the Carolina Breast Cancer Study, a population-based case–control study. Multivariable linear regression was used to identify sites that were differentially methylated by BMI. Stratification by tumor estrogen receptor (ER) status was also conducted. Results: In the majority of the 935 probes analyzed (87%), the average beta value increased with obesity (BMI ≥ 30). Obesity was significantly associated with differential methylation (FDR q < 0.05) in just two gene loci in breast tumor tissue overall and in 21 loci among ER-positive tumors. Obesity was associated with methylation of genes that function in immune response, cell growth, and DNA repair. Conclusions: Obesity is associated with altered methylation overall, and with hypermethylation among ER-positive tumors in particular, suggesting that obesity may influence the methylation of genes with known relevance to cancer. Some of these differences in methylation by obese status may influence levels of gene expression within breast cells. Impact: If our results are validated, obesity-associated methylation sites could serve as targets for prevention and treatment research. Cancer Epidemiol Biomarkers Prev; 24(3); 580–6. ©2015 AACR.
- Published
- 2015
26. Associations of MC1R genotype and patient phenotypes with BRAF and NRAS mutations in melanoma
- Author
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Nancy E. Thomas, Sharon N. Edmiston, Peter A. Kanetsky, Klaus J. Busam, Anne Kricker, Bruce K. Armstrong, Anne E. Cust, Hoda Anton-Culver, Stephen B. Gruber, Li Luo, Irene Orlow, Anne S. Reiner, Richard P. Gallagher, Roberto Zanetti, Stefano Rosso, Lidia Sacchetto, Terence Dwyer, Eloise A. Parrish, Honglin Hao, David C. Gibbs, Jill S. Frank, David W. Ollila, Colin B. Begg, Marianne Berwick, Kathleen Conway, Pampa Roy, Himali Patel, Susan Paine, Alison Venn, Paul Tucker, Loraine D. Marrett, Lynn From, Shu-Chen Huang, Pamela A. Groben, Eloise Parrish, Jennifer I. Bramson, Timothy R. Rebbeck, Julia Lee Taylor, and Sasha Madronich
- Subjects
0301 basic medicine ,Neuroblastoma RAS viral oncogene homolog ,Oncology ,Male ,Skin Neoplasms ,endocrine system diseases ,Biochemistry ,GTP Phosphohydrolases ,0302 clinical medicine ,Genotype ,Eye color ,skin and connective tissue diseases ,Melanoma ,education.field_of_study ,Middle Aged ,Phenotype ,030220 oncology & carcinogenesis ,Female ,Receptor, Melanocortin, Type 1 ,Proto-Oncogene Proteins B-raf ,Adult ,medicine.medical_specialty ,Population ,Clinical Sciences ,Oncology and Carcinogenesis ,Dermatology ,Biology ,Article ,03 medical and health sciences ,Internal medicine ,medicine ,Nevus ,Humans ,education ,Molecular Biology ,neoplasms ,Aged ,Dermatology & Venereal Diseases ,Australia ,Membrane Proteins ,Cell Biology ,Odds ratio ,GEM Study Group ,medicine.disease ,United States ,digestive system diseases ,Superficial spreading melanoma ,enzymes and coenzymes (carbohydrates) ,030104 developmental biology ,Mutation - Abstract
Associations of MC1R with BRAF mutations in melanoma have been inconsistent between studies. We sought to determine for 1,227 participants in the international population-based Genes, Environment, and Melanoma (GEM) study whether MC1R and phenotypes were associated with melanoma BRAF/NRAS subtypes. We used logistic regression adjusted by age, sex, and study design features and examined effect modifications. BRAF+ were associated with younger age, blond/light brown hair, increased nevi, and less freckling, and NRAS+ with older age relative to the wild type (BRAF-/NRAS-) melanomas (all P < 0.05). Comparing specific BRAF subtypes to the wild type, BRAF V600E was associated with younger age, blond/light brown hair, and increased nevi and V600K with increased nevi and less freckling (all P < 0.05). MC1R was positively associated with BRAF V600E cases but only among individuals with darker phototypes or darker hair (Pinteraction < 0.05) but inversely associated with BRAF V600K (Ptrend = 0.006) with no significant effect modification by phenotypes. These results support distinct etiologies for BRAF V600E, BRAF V600K, NRAS+, and wild-type melanomas. MC1R's associations with BRAF V600E cases limited to individuals with darker phenotypes indicate that MC1R genotypes specifically provide information about BRAF V600E melanoma risk in those not considered high risk based on phenotype. Our results also suggest that melanin pathways deserve further study in BRAF V600E melanomagenesis.
- Published
- 2017
27. Breast tumor DNA methylation patterns associated with smoking in the Carolina Breast Cancer Study
- Author
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Christopher Bryant, Kathleen Conway, Pei Fen Kuan, Sharon N. Edmiston, Eloise Parrish, Chiu Kit Tse, Theresa Swift-Scanlan, and Lauren E. McCullough
- Subjects
0301 basic medicine ,Oncology ,Adult ,Cancer Research ,medicine.medical_specialty ,Breast Neoplasms ,Tobacco smoke ,Article ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Breast cancer ,Risk Factors ,Internal medicine ,medicine ,Humans ,Epigenetics ,Risk factor ,Promoter Regions, Genetic ,Aged ,business.industry ,Smoking ,Cancer ,Methylation ,DNA, Neoplasm ,DNA Methylation ,Middle Aged ,medicine.disease ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Gene Ontology ,CpG site ,030220 oncology & carcinogenesis ,DNA methylation ,CpG Islands ,Female ,business ,Transcriptome - Abstract
Tobacco smoking is a risk factor in several cancers, yet its roles as a putative etiologic exposure or poor prognostic factor in breast cancer are less clear. Altered DNA methylation contributes to breast cancer development and may provide a mechanistic link between smoking and gene expression changes leading to cancer development or progression. Using a cancer-focused array, we examined methylation at 933 CpGs in 517 invasive breast tumors in the Carolina Breast Cancer Study to determine whether methylation patterns differ by exposure to tobacco smoke. Multivariable generalized linear regression models were used to compare tumor methylation profiles between smokers and never smokers, overall, or stratified on hormone receptor (HR) status. Modest differences in CpG methylation were detected at p
- Published
- 2016
28. FAK overexpression and p53 mutations are highly correlated in human breast cancer
- Author
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Chad A. Livasy, Dominic T. Moore, Robert C. Millikan, Chiu Kit Tse, Vita M. Golubovskaya, William G. Cance, Amy A. Lark, Sharon N. Edmiston, and Kathleen Conway-Dorsey
- Subjects
Adult ,Cancer Research ,Tumor suppressor gene ,Population ,Breast Neoplasms ,Biology ,medicine.disease_cause ,Article ,White People ,Breast cancer ,North Carolina ,medicine ,Humans ,Registries ,education ,Aged ,education.field_of_study ,Mutation ,Cancer ,Middle Aged ,medicine.disease ,Immunohistochemistry ,Up-Regulation ,Black or African American ,Gene Expression Regulation, Neoplastic ,Oncology ,Case-Control Studies ,Focal Adhesion Kinase 1 ,Cancer research ,Female ,Breast disease ,Tumor Suppressor Protein p53 ,Carcinogenesis - Abstract
Focal Adhesion Kinase (FAK) is overexpressed in a number of tumors, including breast cancer. Another marker of breast cancer tumorigenesis is the tumor suppressor gene p53 that is frequently mutated in breast cancer. In the present study, our aim was to find a correlation between FAK overexpression, p53 expression and mutation status in a population-based series of invasive breast cancer tumors from the Carolina Breast Cancer Study. Immunohistochemical analyses of 622 breast cancer tumors revealed that expression of FAK and p53 were highly correlated (P = 0.0002) and FAK positive tumors were 1.8 times more likely to be p53 positive compared to FAK negative tumors [odds ratio (OR) = 1.8; 95% Confidence Interval (CI) 1.2 – 2.8, adjusted for age, race and stage at diagnosis]. Tumors positive for p53 expression showed higher intensity of FAK staining (P
- Published
- 2009
29. Number of Nevi and Early-Life Ambient UV Exposure Are Associated with BRAF-Mutant Melanoma
- Author
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Dawn Tolbert, Pamela A. Groben, Colin B. Begg, Nancy E. Thomas, Sharon N. Edmiston, Chiu Kit Tse, Marianne Berwick, Audrey Alexander, Klaus J. Busam, Robert C. Millikan, Amanda J. Hummer, Honglin Hao, David W. Ollila, Dianne Mattingly, Julia Lee-Taylor, and Kathleen Conway
- Subjects
Male ,Proto-Oncogene Proteins B-raf ,Neuroblastoma RAS viral oncogene homolog ,Oncology ,medicine.medical_specialty ,Pathology ,Skin Neoplasms ,Ultraviolet Rays ,Epidemiology ,DNA Mutational Analysis ,Population ,medicine.disease_cause ,Risk Factors ,Internal medicine ,Confidence Intervals ,North Carolina ,Odds Ratio ,Humans ,Medicine ,Nevus ,Risk factor ,education ,Melanoma ,neoplasms ,Polymorphism, Single-Stranded Conformational ,Mutation ,education.field_of_study ,business.industry ,DNA, Neoplasm ,Sequence Analysis, DNA ,Odds ratio ,Middle Aged ,medicine.disease ,Confidence interval ,Genes, ras ,Phenotype ,Female ,business - Abstract
Malignant melanomas often contain BRAF or NRAS mutations, but the relationship of these mutations to ambient UV exposure in combination with phenotypic characteristics is unknown. In a population-based case series from North Carolina, 214 first primary invasive melanoma patients in the year 2000 were interviewed regarding their risk factors. Ambient solar UV exposures were estimated using residential histories and a satellite-based model. Cases were grouped on the basis of BRAF and NRAS somatic mutations, determined using single-strand conformation polymorphism analysis and radiolabeled DNA sequencing, and the risk profiles of these groups were compared. Mutually exclusive BRAF-mutant and NRAS-mutant cases occurred at frequencies of 43.0% and 13.6% with mean ages at diagnosis of 47.3 and 62.1 years, respectively. Tumors from patients with >14 back nevi were more likely to harbor either a BRAF mutation [age-adjusted odds ratio (OR), 3.2; 95% confidence interval (95% CI), 1.4-7.0] or an NRAS mutation (age-adjusted OR, 1.7; 95% CI, 0.6-4.8) compared with patients with 0 to 4 back nevi. However, BRAF-mutant and NRAS-mutant tumors were distinctive in that BRAF-mutant tumors were characteristic of patients with high early-life ambient UV exposure (adjusted OR, 2.6; 95% CI, 1.2-5.3). When ambient UV irradiance was analyzed by decadal age, high exposure at ages 0 to 20 years was associated with BRAF-mutant cases, whereas high exposure at ages 50 and 60 years was characteristic of NRAS-mutant cases. Our results suggest that although nevus propensity is important for the occurrence of both BRAF and NRAS-mutant melanomas, ambient UV irradiance influences risk differently based on the age of exposure. The association of BRAF mutations with early-life UV exposure provides evidence in support of childhood sun protection for melanoma prevention. (Cancer Epidemiol Biomarkers Prev 2007;16(5):991–7)
- Published
- 2007
30. Association Between NRAS and BRAF Mutational Status and Melanoma-Specific Survival Among Patients With Higher-Risk Primary Melanoma
- Author
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Eloise Parrish, Anne E. Cust, David W. Ollila, Li Luo, Anne Kricker, Jennifer I. Bramson, Anne S. Reiner, Sharon N. Edmiston, Colin B. Begg, Lynn From, Susan Paine, Kathleen Conway, Stefano Rosso, Stephen B. Gruber, Pamela A. Groben, Audrey Alexander, Hoda Anton-Culver, Lorraine D. Marrett, Honglin Hao, Nancy E. Thomas, Peter A. Kanetsky, Klaus J. Busam, Jill S. Frank, Richard P. Gallagher, Roberto Zanetti, Marianne Berwick, Irene Orlow, Bruce K. Armstrong, and Terence Dwyer
- Subjects
Neuroblastoma RAS viral oncogene homolog ,Oncology ,Male ,Cancer Research ,Pathology ,Skin Neoplasms ,Time Factors ,DNA Mutational Analysis ,Kaplan-Meier Estimate ,GTP Phosphohydrolases ,Gene Frequency ,Risk Factors ,Odds Ratio ,80 and over ,Tumor Microenvironment ,Lymphocytes ,Stage (cooking) ,Melanoma ,Cancer ,Aged, 80 and over ,education.field_of_study ,Tumor ,Middle Aged ,Phenotype ,Public Health and Health Services ,Female ,New South Wales ,Proto-Oncogene Proteins B-raf ,Adult ,medicine.medical_specialty ,Population ,Oncology and Carcinogenesis ,Risk Assessment ,Article ,Lymphocytes, Tumor-Infiltrating ,Clinical Research ,Internal medicine ,medicine ,Biomarkers, Tumor ,Humans ,Genetic Predisposition to Disease ,Tumor-Infiltrating ,education ,neoplasms ,Neoplasm Staging ,Proportional Hazards Models ,Aged ,Proportional hazards model ,business.industry ,Membrane Proteins ,Odds ratio ,GEM Study Group ,medicine.disease ,United States ,Cutaneous melanoma ,Multivariate Analysis ,Mutation ,Neoplasm Grading ,business ,Biomarkers - Abstract
ImportanceNRAS and BRAF mutations in melanoma inform current treatment paradigms, but their role in survival from primary melanoma has not been established. Identification of patients at high risk of melanoma-related death based on their primary melanoma characteristics before evidence of recurrence could inform recommendations for patient follow-up and eligibility for adjuvant trials.ObjectiveTo determine tumor characteristics and survival from primary melanoma by somatic NRAS and BRAF status.Design, setting, and participantsA population-based study with a median follow-up of 7.6 years (through 2007), including 912 patients from the United States and Australia in the Genes, Environment, and Melanoma (GEM) Study, with first primary cutaneous melanoma diagnosed in the year 2000 and analyzed for NRAS and BRAF mutations.Main outcomes and measuresTumor characteristics and melanoma-specific survival of primary melanoma by NRAS and BRAF mutational status.ResultsThe melanomas were 13% NRAS+, 30% BRAF+, and 57% with neither NRAS nor BRAF mutation (wildtype [WT]). In a multivariable model including clinicopathologic characteristics, relative to WT melanoma (with results reported as odds ratios [95% CIs]), NRAS+ melanoma was associated with presence of mitoses (1.8 [1.0-3.3]), lower tumor-infiltrating lymphocyte (TIL) grade (nonbrisk, 0.5 [0.3-0.8]; and brisk, 0.3 [0.5-0.7] [vs absent TILs]), and anatomic site other than scalp/neck (0.1 [0.01-0.6] for scalp/neck vs trunk/pelvis), and BRAF+ melanoma was associated with younger age (ages 50-69 years, 0.7 [0.5-1.0]; and ages >70 years, 0.5 [0.3-0.8] [vs
- Published
- 2015
31. IL2 Inducible T-cell Kinase, a Novel Therapeutic Target in Melanoma
- Author
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Kathleen Conway, David B. Darr, Keefe T. Chan, Sara C. Hanna, Nancy E. Thomas, Paula Berkowitz, Virginia D. Alldredge, David S. Rubenstein, Pamela A. Groben, Shaily Pandey, Nana Nikolaishvili-Feinberg, Honglin Hao, David C. Gibbs, Eloise Parrish, David W. Ollila, Dennis A. Hopkinson, Pei Fen Kuan, Stergios J. Moschos, Sharon N. Edmiston, Craig C. Carson, Jamie L. Jordan, C. Ryan Miller, James E. Bear, Xin Zhou, Jill S. Frank, and Norman E. Sharpless
- Subjects
Cancer Research ,Skin Neoplasms ,medicine.drug_class ,Blotting, Western ,Antineoplastic Agents ,Monoclonal antibody ,Article ,Small hairpin RNA ,Mice ,Cell Line, Tumor ,medicine ,Image Processing, Computer-Assisted ,PTEN ,Animals ,Humans ,Electrophoresis, Gel, Two-Dimensional ,neoplasms ,Melanoma ,Protein Kinase Inhibitors ,Oligonucleotide Array Sequence Analysis ,Gene knockdown ,biology ,Kinase ,Cancer ,Protein-Tyrosine Kinases ,medicine.disease ,Immunohistochemistry ,Xenograft Model Antitumor Assays ,Disease Models, Animal ,Oncology ,Cell culture ,Tissue Array Analysis ,Gene Knockdown Techniques ,Cancer research ,biology.protein - Abstract
Purpose: IL2 inducible T-cell kinase (ITK) promoter CpG sites are hypomethylated in melanomas compared with nevi. The expression of ITK in melanomas, however, has not been established and requires elucidation. Experimental Design: An ITK-specific monoclonal antibody was used to probe sections from deidentified, formalin-fixed paraffin-embedded tumor blocks or cell line arrays and ITK was visualized by IHC. Levels of ITK protein differed among melanoma cell lines and representative lines were transduced with four different lentiviral constructs that each contained an shRNA designed to knockdown ITK mRNA levels. The effects of the selective ITK inhibitor BI 10N on cell lines and mouse models were also determined. Results: ITK protein expression increased with nevus to metastatic melanoma progression. In melanoma cell lines, genetic or pharmacologic inhibition of ITK decreased proliferation and migration and increased the percentage of cells in the G0–G1 phase. Treatment of melanoma-bearing mice with BI 10N reduced growth of ITK-expressing xenografts or established autochthonous (Tyr-Cre/Ptennull/BrafV600E) melanomas. Conclusions: We conclude that ITK, formerly considered an immune cell–specific protein, is aberrantly expressed in melanoma and promotes tumor development and progression. Our finding that ITK is aberrantly expressed in most metastatic melanomas suggests that inhibitors of ITK may be efficacious for melanoma treatment. The efficacy of a small-molecule ITK inhibitor in the Tyr-Cre/Ptennull/BrafV600E mouse melanoma model supports this possibility. Clin Cancer Res; 21(9); 2167–76. ©2015 AACR.
- Published
- 2015
32. Tandem BRAF Mutations in Primary Invasive Melanomas
- Author
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Pamela A. Groben, Kathleen Conway, Dianne Mattingly, Eloise Parrish, Robert C. Millikan, Nancy E. Thomas, Sharon N. Edmiston, Marianne Berwick, Audrey Alexander, and David W. Ollila
- Subjects
Adult ,Male ,Proto-Oncogene Proteins B-raf ,MAPK/ERK pathway ,Skin Neoplasms ,DNA Mutational Analysis ,Molecular Sequence Data ,tandem mutation ,Dermatology ,Biology ,medicine.disease_cause ,Biochemistry ,BRAF ,03 medical and health sciences ,Exon ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Humans ,Point Mutation ,Allele ,Melanoma ,neoplasms ,Molecular Biology ,Aged ,030304 developmental biology ,Aged, 80 and over ,Cloning ,0303 health sciences ,Mutation ,Base Sequence ,Cell growth ,Exons ,Cell Biology ,Middle Aged ,medicine.disease ,3. Good health ,Proto-Oncogene Proteins c-raf ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,Female ,DNA - Abstract
The RAS/RAF/MAPK pathway likely mediates critical cell proliferation and survival signals in melanoma. BRAF mutations have been found in a high percentage of melanoma cell lines and metastases; however, only a few studies with a limited number of specimens have focused on primary melanomas. We examined BRAF exon 15 mutational status in 37 primary invasive melanomas of varying thicknesses, which had undergone a standardized pathology review. BRAF mutational status was determined using direct manual sequencing of PCR products, followed by resequencing separately amplified DNA aliquots to confirm each mutation. BRAF exon 15 mutations were found in 17 of 37 (46%) primary melanomas. Tumor-specific tandem mutations, encoding either V599K, V599R, or V599E, were found in 5 of 17 (29%) melanomas with BRAF exon 15 mutations. Cloning of BRAF double base-pair substitutions confirmed that both base changes were on the same allele and can result in a positive charge at codon 599. BRAF mutations, including tandem mutations, were frequently found in both thin and thick primary melanomas, implying that these mutations can occur early in the progression of melanoma. The finding of tandem mutations in thin melanomas makes it more likely that they arise as a simultaneous rather than sequential event.
- Published
- 2004
33. Racial variation in breast tumor promoter methylation in the Carolina Breast Cancer Study
- Author
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Chiu Kit Tse, Theresa Swift-Scanlan, Eloise Parrish, Kathleen Conway, Ryan May, Sharon N. Edmiston, Pei Fen Kuan, Brionna Y. Hair, and Christopher Bryant
- Subjects
Oncology ,medicine.medical_specialty ,Epidemiology ,Receptor, ErbB-2 ,Breast Neoplasms ,Biology ,White People ,Article ,Epigenesis, Genetic ,Immunoenzyme Techniques ,Breast cancer ,Internal medicine ,medicine ,Biomarkers, Tumor ,North Carolina ,Humans ,Neoplasm Invasiveness ,Epigenetics ,Promoter Regions, Genetic ,Neoplasm Staging ,Racial Groups ,Case-control study ,Cancer ,Promoter ,Methylation ,DNA Methylation ,Middle Aged ,medicine.disease ,Prognosis ,Black or African American ,CpG site ,Receptors, Estrogen ,Case-Control Studies ,DNA methylation ,Immunology ,CpG Islands ,Female ,Receptors, Progesterone ,Follow-Up Studies - Abstract
Background: African American (AA) women are diagnosed with more advanced breast cancers and have worse survival than white women, but a comprehensive understanding of the basis for this disparity remains unclear. Analysis of DNA methylation, an epigenetic mechanism that can regulate gene expression, could help to explain racial differences in breast tumor clinical biology and outcomes. Methods: DNA methylation was evaluated at 1,287 CpGs in the promoters of cancer-related genes in 517 breast tumors of AA (n = 216) or non-AA (n = 301) cases in the Carolina Breast Cancer Study (CBCS). Results: Multivariable linear regression analysis of all tumors, controlling for age, menopausal status, stage, intrinsic subtype, and multiple comparisons [false discovery rate (FDR)], identified seven CpG probes that showed significant (adjusted P < 0.05) differential methylation between AAs and non-AAs. Stratified analyses detected an additional four CpG probes differing by race within hormone receptor–negative (HR−) tumors. Genes differentially methylated by race included DSC2, KCNK4, GSTM1, AXL, DNAJC15, HBII-52, TUSC3, and TES; the methylation state of several of these genes may be associated with worse survival in AAs. TCGA breast tumor data confirmed the differential methylation by race and negative correlations with expression for most of these genes. Several loci also showed racial differences in methylation in peripheral blood leukocytes (PBL) from CBCS cases, indicating that these variations were not necessarily tumor-specific. Conclusions: Racial differences in the methylation of cancer-related genes are detectable in both tumors and PBLs from breast cancer cases. Impact: Epigenetic variation could contribute to differences in breast tumor development and outcomes between AAs and non-AAs. Cancer Epidemiol Biomarkers Prev; 24(6); 921–30. ©2015 AACR.
- Published
- 2014
34. DNA methylation Profiles in Primary Cutaneous Melanomas are Associated with Clinically Significant Pathologic Features
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Kathleen Conway, Pamela A. Groben, Marianne Berwick, Eloise Parrish, Xin Zhou, Stergios J. Moschos, Honglin Hao, David W. Ollila, Nathaniel A. Slater, Nancy E. Thomas, Craig C. Carson, Pei Fen Kuan, and Sharon N. Edmiston
- Subjects
Adult ,Male ,Skin Neoplasms ,Molecular Sequence Data ,Dermatology ,Biology ,Bioinformatics ,General Biochemistry, Genetics and Molecular Biology ,Article ,Breslow Thickness ,medicine ,Cluster Analysis ,Humans ,Clinical significance ,Promoter Regions, Genetic ,neoplasms ,Melanoma ,Aged ,Demography ,CpG Island Methylator Phenotype ,Cancer ,Reproducibility of Results ,Methylation ,DNA Methylation ,Middle Aged ,medicine.disease ,Phenotype ,Oncology ,CpG site ,Genetic Loci ,DNA methylation ,Cancer research ,CpG Islands ,Female - Abstract
Summary DNA methylation studies have elucidated a methylation signature distinguishing primary melanomas from benign nevi and provided new insights about genes that may be important in melanoma development. However, it is unclear whether methylation differences among primary melanomas are related to tumor pathologic features with known clinical significance. We utilized the Illumina GoldenGate Cancer Panel array to investigate the methylation profiles of 47 primary cutaneous melanomas. Arraywide methylation patterns revealed a positive association of methylation with Breslow thickness and mutated BRAF, a negative association with mitotic rate, and a weak association with ulceration. Hierarchical clustering on CpG sites exhibiting the most variable methylation (n = 235) divided the melanoma samples into three clusters, including a highly methylated cluster that was positively associated with Breslow thickness and an intermediately methylated cluster associated with Breslow thickness and mitotic rate. Our findings provide support for the existence of methylation-defined subsets in melanomas with increased methylation associated with Breslow thickness.
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- 2014
35. DNA methylation profiling in the Carolina Breast Cancer Study defines cancer subclasses differing in clinicopathologic characteristics and survival
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Sharon N. Edmiston, Theresa Swift-Scanlan, Joseph Geradts, Haitao Chu, Melissa A. Troester, Kathleen Conway, Ryan May, Chiu Kit Tse, Robert C. Millikan, Christopher Bryant, and Pei Fen Kuan
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Adult ,Microarray ,Population ,DNA Mutational Analysis ,Gene Expression ,Breast Neoplasms ,Kaplan-Meier Estimate ,Bioinformatics ,Young Adult ,Breast cancer ,medicine ,North Carolina ,Humans ,Epigenetics ,education ,Promoter Regions, Genetic ,Aged ,Proportional Hazards Models ,Medicine(all) ,education.field_of_study ,business.industry ,Carcinoma, Ductal, Breast ,Cancer ,Methylation ,Sequence Analysis, DNA ,DNA Methylation ,Middle Aged ,medicine.disease ,Prognosis ,3. Good health ,CpG site ,Multigene Family ,DNA methylation ,Multivariate Analysis ,Cancer research ,CpG Islands ,Female ,Tumor Suppressor Protein p53 ,business ,Research Article - Abstract
Introduction Breast cancer is a heterogeneous disease, with several intrinsic subtypes differing by hormone receptor (HR) status, molecular profiles, and prognosis. However, the role of DNA methylation in breast cancer development and progression and its relationship with the intrinsic tumor subtypes are not fully understood. Methods A microarray targeting promoters of cancer-related genes was used to evaluate DNA methylation at 935 CpG sites in 517 breast tumors from the Carolina Breast Cancer Study, a population-based study of invasive breast cancer. Results Consensus clustering using methylation (β) values for the 167 most variant CpG loci defined four clusters differing most distinctly in HR status, intrinsic subtype (luminal versus basal-like), and p53 mutation status. Supervised analyses for HR status, subtype, and p53 status identified 266 differentially methylated CpG loci with considerable overlap. Genes relatively hypermethylated in HR+, luminal A, or p53 wild-type breast cancers included FABP3, FGF2, FZD9, GAS7, HDAC9, HOXA11, MME, PAX6, POMC, PTGS2, RASSF1, RBP1, and SCGB3A1, whereas those more highly methylated in HR-, basal-like, or p53 mutant tumors included BCR, C4B, DAB2IP, MEST, RARA, SEPT5, TFF1, THY1, and SERPINA5. Clustering also defined a hypermethylated luminal-enriched tumor cluster 3 that gene ontology analysis revealed to be enriched for homeobox and other developmental genes (ASCL2, DLK1, EYA4, GAS7, HOXA5, HOXA9, HOXB13, IHH, IPF1, ISL1, PAX6, TBX1, SOX1, and SOX17). Although basal-enriched cluster 2 showed worse short-term survival, the luminal-enriched cluster 3 showed worse long-term survival but was not independently prognostic in multivariate Cox proportional hazard analysis, likely due to the mostly early stage cases in this dataset. Conclusions This study demonstrates that epigenetic patterns are strongly associated with HR status, subtype, and p53 mutation status and may show heterogeneity within tumor subclass. Among HR+ breast tumors, a subset exhibiting a gene signature characterized by hypermethylation of developmental genes and poorer clinicopathologic features may have prognostic value and requires further study. Genes differentially methylated between clinically important tumor subsets have roles in differentiation, development, and tumor growth and may be critical to establishing and maintaining tumor phenotypes and clinical outcomes. Electronic supplementary material The online version of this article (doi:10.1186/s13058-014-0450-6) contains supplementary material, which is available to authorized users.
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- 2013
36. Lack of association of rare alleles in the HRAS variable number of tandem repeats (VNTR) region with adult glioma
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Pengchin Chen, John K. Wiencke, Kathleen Conway, Sharon N. Edmiston, Rei Miike, and Margaret Wrensch
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Cancer Research ,Oncology ,Neurology (clinical) - Published
- 2000
37. Ha-ras rare alleles in breast cancer susceptibility
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Barbara S. Hulka, Edison T. Liu, Peter A. Garrett, Kathleen Conway, D. Fried, and Sharon N. Edmiston
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Genome instability ,Genetics ,Cancer Research ,Polymorphism, Genetic ,Mechanism (biology) ,Breast Neoplasms ,Minisatellite Repeats ,Biology ,medicine.disease ,Polymerase Chain Reaction ,Risk Assessment ,Genes, ras ,Breast cancer ,Oncology ,Polymorphism (computer science) ,Gene duplication ,medicine ,Humans ,Female ,Disease Susceptibility ,Risk factor ,Allele ,Gene ,Alleles - Abstract
Over the last several years, evidence has accumulated to support the idea that rare Ha-ras polymorphisms are associated with inherited susceptibility to certain human cancers. A recent epidemiologic study conducted at our institution found a significant association specifically with breast cancer, although the mechanism underlying this relationship remains unclear. We have proposed that rare Ha-ras alleles are markers of a genomic instability that predisposes to breast cancer. To address this hypothesis, we are investigating the relationship between the presence of rare alleles and another form of instability, gene amplification, and are developing new methodologies both to improve VNTR allele length detection and to characterize the internal repeat sequence variations of the various alleles. These studies should enable us to more clearly define the role of this region in cancer development by delineating VNTR structure and function and the mechanisms of rare allele generation. Ultimately, we hope to identify VNTR characteristics that will permit more accurate cancer risk assessment.
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- 1995
38. DNA-methylation profiling distinguishes malignant melanomas from benign nevi: Methylation profiling of melanomas and benign nevi
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David W Olilla, Zakaria S. Khondker, Pei Fen Kuan, Kathleen Conway, Pamela A. Groben, Nancy E. Thomas, Marianne Berwick, Sharon N. Edmiston, Haitao Chu, Honglin Hao, Xin Zhou, and Craig C. Carson
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0303 health sciences ,Microarray ,integumentary system ,Melanoma ,Dermatology ,Methylation ,Biology ,medicine.disease ,Bioinformatics ,General Biochemistry, Genetics and Molecular Biology ,3. Good health ,Gene expression profiling ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,CpG site ,030220 oncology & carcinogenesis ,DNA methylation ,Cancer research ,medicine ,Nevus ,Epigenetics ,skin and connective tissue diseases ,neoplasms ,030304 developmental biology - Abstract
DNA methylation, an epigenetic alteration typically occurring early in cancer development, could aid in the molecular diagnosis of melanoma. We determined technical feasibility for high-throughput DNA-methylation array-based profiling using formalin-fixed paraffin-embedded tissues for selection of candidate DNA-methylation differences between melanomas and nevi. Promoter methylation was evaluated in 27 common benign nevi and 22 primary invasive melanomas using a 1505 CpG site microarray. Unsupervised hierarchical clustering distinguished melanomas from nevi; 26 CpG sites in 22 genes were identified with significantly different methylation levels between melanomas and nevi after adjustment for age, sex, and multiple comparisons and with β-value differences of ≥0.2. Prediction analysis for microarrays identified 12 CpG loci that were highly predictive of melanoma, with area under the receiver operating characteristic curves of >0.95. Of our panel of 22 genes, 14 were statistically significant in an independent sample set of 29 nevi (including dysplastic nevi) and 25 primary invasive melanomas after adjustment for age, sex, and multiple comparisons. This first report of a DNA-methylation signature discriminating melanomas from nevi indicates that DNA methylation appears promising as an additional tool for enhancing melanoma diagnosis.
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- 2011
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39. Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation
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Sharon N. Edmiston, Jennifer J. Jordan, Lin Wu, Alberto Inga, Michael A. Resnick, Lisa A. Carey, and Kathleen Conway
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Transcriptional Activation ,Cancer Research ,Transcription, Genetic ,Mutant ,Mutation, Missense ,Breast Neoplasms ,Biology ,Response Elements ,Germline ,Article ,Transactivation ,Missense mutation ,Humans ,Genetic Predisposition to Disease ,Promoter Regions, Genetic ,Molecular Biology ,Gene ,Loss function ,Genetics ,Regulation of gene expression ,Carcinoma ,Galactose ,Phenotype ,Gene Expression Regulation, Neoplastic ,Oncology ,Cancer research ,Mutagenesis, Site-Directed ,Female ,Tumor Suppressor Protein p53 - Abstract
Mutations of the sequence-specific master regulator p53 that alter transactivation function from promoter response elements (RE) could result in changes in the strength of gene activation or spectra of genes regulated. Such mutations in this tumor suppressor might lead to dramatic phenotypic changes and diversification of cell responses to stress. We have determined “functional fingerprints” of sporadic breast cancer–related p53 mutants, many of which are also associated with familial cancer proneness such as the Li-Fraumeni syndrome and germline BRCA1/2 mutant-associated cancers. The ability of p53, wild-type and mutants, to transactivate from 11 human target REs has been assessed at variable expression levels using a cellular, isogenomic yeast model system that allows for the rapid analysis of p53 function using a qualitative and a quantitative reporter. Among 50 missense mutants, 29 were classified as loss of function. The remaining 21 retained transactivation toward at least one RE. At high levels of galactose-induced p53 expression, 12 of 21 mutants that retain transactivation seemed similar to wild-type. When the level of galactose was reduced, transactivation defects could be revealed, suggesting that some breast cancer–related mutants can have subtle changes in transcription. These findings have been compared with clinical data from an ongoing neoadjuvant chemotherapy treatment trial for locally advanced breast tumors. The functional and nonfunctional missense mutations may distinguish tumors in terms of demographics, appearance, and relapse, implying that heterogeneity in the functionality of specific p53 mutations could affect clinical behavior and outcome. Mol Cancer Res; 8(5); 701–16. ©2010 AACR.
- Published
- 2010
40. Relationship between Germline MC1R Variants and BRAF-Mutant Melanoma in a North Carolina Population-Based Study
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Honglin Hao, Colin B. Begg, Nancy E. Thomas, Pamela A. Groben, Marianne Berwick, Audrey Alexander, Klaus J. Busam, Sharon N. Edmiston, Peter A. Kanetsky, Kathleen Conway, and David W. Ollila
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Proto-Oncogene Proteins B-raf ,Skin Neoplasms ,Population ,Mutant ,Dermatology ,Biology ,Biochemistry ,Germline ,Article ,Germline mutation ,Risk Factors ,Genetic variation ,medicine ,North Carolina ,Humans ,education ,neoplasms ,Molecular Biology ,Melanoma ,Germ-Line Mutation ,Genetics ,education.field_of_study ,Genetic Variation ,Cell Biology ,medicine.disease ,Population based study ,Australian population ,Receptor, Melanocortin, Type 1 - Abstract
A few previous studies have examined the relationship between germline melanocortin-1 receptor (MC1R) status and somatic BRAF mutations in melanoma. Two publications reported strong associations in three independent populations (two from Italy and one from San Francisco) (Fargnoli et al., 2008; Landi et al., 2006), while a more recent publication found no association in an Australian population-based study (Hacker et al., 2009). We report our finding of no significant association between MC1R status and BRAF-mutant melanomas in a population-based study of malignant melanoma in North Carolina.
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- 2009
41. Risk factors for breast cancer characterized by the estrogen receptor alpha A908G (K303R) mutation
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Patricia G. Moorman, Robert C. Millikan, Kathleen Conway, Chiu Kit Tse, Beth Newman, Eloise Parrish, Dawn Tolbert, and Sharon N. Edmiston
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Adult ,medicine.medical_specialty ,medicine.drug_class ,Black People ,Estrogen receptor ,Alpha (ethology) ,Breast Neoplasms ,Biology ,Polymorphism, Single Nucleotide ,White People ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Risk Factors ,Surgical oncology ,Internal medicine ,medicine ,Humans ,Family ,skin and connective tissue diseases ,Estrogen receptor beta ,Aged ,030304 developmental biology ,Medicine(all) ,Menarche ,0303 health sciences ,Hyperplasia ,Estrogen Replacement Therapy ,Estrogen Receptor alpha ,Middle Aged ,medicine.disease ,3. Good health ,Endocrinology ,Amino Acid Substitution ,Risk factors for breast cancer ,Estrogen ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,Female ,Estrogen receptor alpha ,hormones, hormone substitutes, and hormone antagonists ,Contraceptives, Oral ,Research Article - Abstract
Introduction Estrogen is important in the development of breast cancer, and its biological effects are mediated primarily through the two estrogen receptors alpha and beta. A point mutation in the estrogen receptor alpha gene, ESR1, referred to as A908G or K303R, was originally identified in breast hyperplasias and was reported to be hypersensitive to estrogen. We recently detected this mutation at a low frequency of 6% in invasive breast tumors of the Carolina Breast Cancer Study (CBCS). Methods In this report, we evaluated risk factors for invasive breast cancer classified according to the presence or absence of the ESR1 A908G mutation in the CBCS, a population-based case-control study of breast cancer among younger and older white and African-American women in North Carolina. Of the 653 breast tumors evaluated, 37 were ESR1 A908G mutation-positive and 616 were mutation-negative. Results ESR1 A908G mutation-positive breast cancer was significantly associated with a first-degree family history of breast cancer (odds ratio [OR] = 2.69, 95% confidence interval [CI] = 1.15 to 6.28), whereas mutation-negative breast cancer was not. Comparison of the two case subgroups supported this finding (OR = 2.65, 95% CI = 1.15 to 6.09). There was also the suggestion that longer duration of oral contraceptive (OC) use (OR = 3.73, 95% CI = 1.16 to 12.03; Ptrend = 0.02 for use of more than 10 years) and recent use of OCs (OR = 3.63, 95% CI = 0.80 to 16.45; Ptrend = 0.10 for use within 10 years) were associated with ESR1 A908G mutation-positive breast cancer; however, ORs for comparison of the two case subgroups were not statistically significant. Hormone replacement therapy use was inversely correlated with mutation-negative breast cancer, but the effect on mutation-positive cancer was unclear due to the small number of postmenopausal cases whose tumors carried the mutation. Mutation-negative breast cancer was associated with several reproductive factors, including younger age at menarche (OR = 1.46, 95% CI = 1.09 to 1.94) and greater total estimated years of ovarian function (OR = 1.82, 95% CI = 1.21 to 2.74). Conclusion These preliminary results suggest that OCs may interact with the ESR1 A908G mutant receptor to drive the development of some breast tumors.
- Published
- 2007
42. IGF1 CA repeat polymorphisms, lifestyle factors and breast cancer risk in the Long Island Breast Cancer Study Project
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Susan L. Teitelbaum, Kathleen Conway, Sybil M. Eng, Rebecca J. Cleveland, Regina M. Santella, Marilie D. Gammon, Sharon N. Edmiston, Julie A. Britton, Alfred I. Neugut, and Mary Beth Terry
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Oncology ,Adult ,Cancer Research ,medicine.medical_specialty ,Genotype ,New York ,Breast Neoplasms ,Breast cancer ,Risk Factors ,Internal medicine ,Epidemiology ,medicine ,Humans ,Mass index ,Genetic Predisposition to Disease ,Allele ,Insulin-Like Growth Factor I ,Life Style ,Alleles ,Aged ,Cell Proliferation ,Polymorphism, Genetic ,business.industry ,Cell Differentiation ,General Medicine ,Odds ratio ,Middle Aged ,medicine.disease ,Endocrinology ,Cancer cell ,Median body ,Female ,business - Abstract
Insulin-like growth factor I (IGF-I) is an important regulator of growth and differentiation and is a potent mitogen for human breast cancer cells. Recent investigations suggest an association between cytosine-adenine dinucleotide (CA)n repeat polymorphisms of the IGF1 gene and IGF-I levels and further evidence indicates that genotype may influence breast cancer risk. We assessed the relation between IGF1 (CA)n repeats and breast cancer, and evaluated modification of genotype effects according to traditional breast cancer risk factors in 1028 breast cancer cases and 1086 controls. An increased risk of breast cancer was seen for genotypes that included alleles with fewer than (CA)19 repeats when compared to (CA)19 repeat carriers, an association that was particularly strong among premenopausal women [odds ratio (OR)=3.31; 95% confidence interval (CI)=1.47, 7.48]. No significant association was observed between an IGF1 genotype with no (CA)19 repeat compared to (CA)19 repeat genotypes in either pre- or postmenopausal women overall. However, when traditional breast cancer risk factors were considered, premenopausal women with genotypes that lacked a (CA)19 repeat had a nearly 60% increased risk of breast cancer among those who had ever used hormonal birth control, while never users had a significantly reduced risk (Pinteraction=0.01). Among postmenopausal women, those with genotypes lacking a (CA)19 repeat allele had significantly increased breast cancer risk among subjects with a lower than median body mass index (BMI) (OR=1.77 95% CI=1.09, 2.87), while no association for IGF1 genotype was seen among women with a higher than median BMI (Pinteraction=0.04). Our results demonstrate a role for alleles with fewer than (CA)19 repeats as a risk factor for breast cancer and also suggest that several traditional breast cancer risk factors modify the association of the IGF1 (CA)19 repeat genotype.
- Published
- 2005
43. The estrogen receptor-α A908G (K303R) mutation occurs at a low frequency in invasive breast tumors: results from a population-based study
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Eloise Parrish, Chiu Kit Tse, Sharon N. Edmiston, Beth Newman, Chad A. Livasy, Harsharan K. Singh, Joseph Geradts, Dawn Tolbert, Robert C. Millikan, and Kathleen Conway
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Pathology ,medicine.medical_specialty ,Population ,Black People ,Estrogen receptor ,Breast Neoplasms ,Biology ,Polymerase Chain Reaction ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Gene Frequency ,Surgical oncology ,North Carolina ,medicine ,Humans ,Neoplasm Invasiveness ,skin and connective tissue diseases ,education ,Polymorphism, Single-Stranded Conformational ,Estrogen receptor beta ,DNA Primers ,030304 developmental biology ,0303 health sciences ,education.field_of_study ,Point mutation ,Cell Cycle ,Estrogen Receptor alpha ,Exons ,Middle Aged ,medicine.disease ,3. Good health ,Amino Acid Substitution ,Case-Control Studies ,030220 oncology & carcinogenesis ,Mutation (genetic algorithm) ,Cancer research ,Female ,Estrogen receptor alpha ,Research Article - Abstract
Introduction Evidence suggests that alterations in estrogen signaling pathways, including estrogen receptor-α (ER-α), occur during breast cancer development. A point mutation in ER-α (nucleotide A908G), producing an amino acid change from lysine to arginine at codon 303 (K303R) results in receptor hypersensitivity to estrogen. This mutation was initially reported in one-third of hyperplastic benign breast lesions, although several recent studies failed to detect it in benign or malignant breast tissues. Methods We screened 653 microdissected, newly diagnosed invasive breast tumors from patients in the Carolina Breast Cancer Study, a population-based case-control study of breast cancer in African American and white women in North Carolina, for the presence of the ER-α A908G mutation by using single-strand conformational polymorphism (SSCP) analysis and 33P-cycle sequencing. Results We detected the ER-α A908G mutation in 37 of 653 (5.7%) breast tumors. The absence of this mutation in germline DNA confirmed it to be somatic. Three tumors exhibited only the mutant G base at nucleotide 908 on sequencing, indicating that the wild-type ER-α allele had been lost. The ER-α A908G mutation was found more frequently in higher-grade breast tumors (odds ratio (OR) 2.83; 95% confidence interval (CI) 1.09 to 7.34, grade II compared with grade I), and in mixed lobular/ductal tumors (OR 2.10; 95% CI 0.86 to 5.12) compared with ductal carcinomas, although the latter finding was not statistically significant. Conclusion This population-based study, the largest so far to screen for the ER-α A908G mutation in breast cancer, confirms the presence of the mutant in invasive breast tumors. The mutation was associated with higher tumor grade and mixed lobular/ductal breast tumor histology.
- Published
- 2005
44. Prevalence and spectrum of p53 mutations associated with smoking in breast cancer
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Kathleen, Conway, Sharon N, Edmiston, Lisa, Cui, S Scott, Drouin, Jingzhong, Pang, Mei, He, Chiu-Kit, Tse, Joseph, Geradts, Lynn, Dressler, Edison T, Liu, Robert, Millikan, and Beth, Newman
- Subjects
Adult ,DNA Mutational Analysis ,Smoking ,Breast Neoplasms ,Middle Aged ,Genes, p53 ,Risk Factors ,Case-Control Studies ,Mutation ,North Carolina ,Prevalence ,Humans ,Female ,Polymorphism, Single-Stranded Conformational ,Aged - Abstract
To explore the role of smoking in breast cancer, we undertook a population-based study to evaluate the prevalence and spectrum of p53 mutations in the breast tumors of smokers and nonsmokers. We evaluated 456 archival invasive breast tumors for mutations in exons 4-8 of the p53 gene, using single-strand conformational polymorphism analysis and manual sequencing. Statistical analyses were performed to determine the association of p53 mutations with clinical and smoking characteristics. Of 108 mutations identified, 77 (71%) were point mutations and 31 (29%) were deletions or insertions. A higher prevalence of p53 mutations was found in the breast tumors of current smokers (36.5%; P = 0.02) compared with never smokers (23.6%), whereas fewer mutations were found in former smokers (16.2%; P = 0.09). After adjustment for age, race, menopausal status, clinical stage, tumor size, and family history of breast cancer, current smokers were significantly more likely to harbor any p53 mutation [odds ratio (OR), 2.11; 95% confidence interval (CI), 1.17-3.78], p53 transversions (OR, 3.37; 95% CI, 1.03-11.06), and G:C--T:A transversions (OR, 10.53; 95% CI, 1.77-62.55) compared with never smokers. Stage at diagnosis did not account for the increase in p53 mutation-positive breast cancer among current smokers. Former smokers were also more likely than never smokers to harbor G:C--T:A transversions (OR, 2.43; 95% CI, 0.37-15.73), although this association was not statistically significant. Among former smokers, the prevalence of p53 mutations varied with time since quitting: former smokers who quit smoking for longer than 1 year had a lower prevalence of p53 mutations (10.5% for 1-5 years and 12.9% for5 years) than those who had stopped smoking within the year of their cancer diagnosis (26.3%). Our results indicate that cigarette smoking appears to modify the prevalence and spectrum of p53 mutations in breast tumors. Moreover, the difference in mutational spectra observed between smokers and nonsmokers is suggestive of the genotoxic effects of smoking in breast tissue.
- Published
- 2002
45. Coinfection with multiple strains of the Epstein-Barr virus in human immunodeficiency virus-associated hairy leukoplakia
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Nancy Raab-Traub, John W. Sixbey, Lionel Resnick, Dennis M. Walling, Mohamed Abdel-Hamid, and Sharon N. Edmiston
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Hairy leukoplakia ,Herpesvirus 4, Human ,viruses ,Molecular Sequence Data ,Restriction Mapping ,Biology ,medicine.disease_cause ,Polymerase Chain Reaction ,Virus ,law.invention ,law ,hemic and lymphatic diseases ,medicine ,Humans ,Cloning, Molecular ,Antigens, Viral ,Polymerase chain reaction ,Southern blot ,Multidisciplinary ,Base Sequence ,medicine.disease ,Epstein–Barr virus ,Virology ,Blotting, Southern ,Tumor Virus Infections ,Viral replication ,Epstein-Barr Virus Nuclear Antigens ,Oligodeoxyribonucleotides ,DNA, Viral ,Coinfection ,Mouth Neoplasms ,Viral disease ,Leukoplakia, Oral ,Research Article - Abstract
Epstein-Barr virus DNA was analyzed from specimens of hairy leukoplakia, an oral lesion that occurs in patients infected with the human immunodeficiency virus. The simultaneous presence of both type 1 and type 2 Epstein-Barr virus was demonstrated by Southern blot analysis and polymerase chain reaction assay. Restriction fragment length polymorphisms in the BamHI WYH region and in clones of the EcoRI C region suggested the presence of multiple strains of type 1 and type 2 viruses. The demonstration of multiple variably sized BamHI H fragments on Southern blot analysis and cloning of the EBNA-2 gene coding region also suggested the presence of multiple viral strains or variants coinfecting hairy leukoplakia. Recombination of the viral genome in and around the EBNA-2 gene apparently generated viral variants that replicated efficiently, one of which appeared to increase in abundance in a lesion over time. These data indicate that hairy leukoplakia involves coinfection with multiple strains of replicating Epstein-Barr virus and the endogenous generation of viral variants, some of which have mutations of the EBNA-2 gene.
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- 1992
46. P53 mutation and differential response to neoadjuvant chemotherapy in women with locally advanced breast cancer: Results from the I-SPY trial (CALGB 150007/1500012 and ACRIN 6657)
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Dominic T. Moore, Nola M. Hylton, E. Parrish, Sharon N. Edmiston, Lisa A. Carey, S. M. Pradhan, and Kathleen Conway
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Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,Predictive marker ,Taxane ,Anthracycline ,business.industry ,medicine.medical_treatment ,Locally advanced ,P53 Mutation ,medicine.disease ,Breast cancer ,Internal medicine ,P53 status ,medicine ,skin and connective tissue diseases ,business - Abstract
11099 Background: Independent of other factors, p53 status may influence sensitivity to anthracycline (A)- and taxane (T)-based chemotherapy. We investigated p53 as a predictive marker of differential neoadjuvant chemoresponse by examining change in MRI longest diameter (LD) during sequential A- then T-based chemotherapy in a prospective clinical trial. Methods: 171 patients (pts) with newly diagnosed locally advanced breast cancer received neoadjuvant A- then T-based chemotherapy. LD were obtained pretherapy, between regimens, and posttherapy but prior to surgery. P53 mutation analysis was performed on pretherapy tissue using gene chip technology, SSCP, and sequencing. Subtypes were by IHC: LumA (ER/PR+/HER2-), LumB (ER/PR+/HER2+), Basal (triple negative), HER2 (HER2+/ER/PR-). Results: 99 pts had p53 mutant (M) tumors and 72 were wildtype (WT). M and WT did not differ by age, menopausal status, or HER2. M were significantly more common among basal (71%) and HER2 (59%) than Lum A (24%). Anthracycline response did not differ between WT and M within subtypes. Within HER2, Basal, and LumB, WT had higher taxane- and overall responses than M; within LumB these were statistically significant (p=0.03 and 0.05 respectively). Conclusions: P53 mutation status may affect chemosensitivity even within hormone receptor/HER2 subsets. In this dataset response to anthracycline appeared independent of p53 status within subtypes, while WT tumors responded better to taxanes and overall in LumB, with a similar trend among basal and HER2. Mutational subset and correlative analyses with gene expression, molecular subtyping, and IHC data are ongoing and will be presented. [Table: see text] No significant financial relationships to disclose.
- Published
- 2009
47. Gene expression subtype and p53 mutational status are correlated among neoadjuvantly treated breast cancers in UNC LCCC9819 and I-SPY1 (CALGB 150007/ACRIN 6657)
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LJ Esserman, Dawn Tolbert, L. Sawyer, Sharon N. Edmiston, Kathleen Conway, Daniel S. Oh, Lisa A. Carey, Dominic T. Moore, Charles M. Perou, and Meredith Buxton
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Cancer Research ,Oncology ,Gene expression ,Cancer research ,Mutational status ,Biology ,P53 Mutation ,Bioinformatics ,stat - Abstract
10048 Background: LCCC9819 and I-SPY1 are designed to examine multiple potential predictive markers and assays simultaneously in biopsies from neoadjuvantly treated patients. Both p53 mutation status and molecular ‘intrinsic‘ subtype have been associated with chemosensitivity. In this preliminary analysis, we present the p53 mutation spectra by molecular subtype from patients enrolled in the combined LCCC 9819 and I-SPY1 datasets. Methods: Patients received neoadjuvant anthracycline-based chemotherapy with pre-therapy biopsies. p53 mutation analysis was performed by p53 GeneChip assay for point mutations/1 bp deletions followed by SSCP if GeneChip-negative. Abnormal GeneChip or SSCP were confirmed by sequencing. DNA microarrays used Agilent human microarrays and a common reference strategy approach. Results: 51 patients were treated on LCCC9819 and have available molecular analyses; 87 from I-SPY1. 111 patients have completed p53 mutation analysis, revealing a high proportion (42%) with abnormal p53. Of these, several were in known hotspots, including R175H (4 mutations), R248L (1), R273H (3), and R273C (2). Most were missense mutations (81%), however, there were 8 (17%) null and 1 (2%) silent mutations. Most (91%) mutations were in the DNA binding domain. Molecular subtypes are known on 111 tumors: 22% Luminal A, 22% Luminal B, 3% Normal-like, 23% HER2+/ER−, 27% Basal-like, and 3% unclassified. Among those with both assays complete, we found that p53 mutations differed by subtype (Table). Conclusions: P53 mutations are common in these independent neoadjuvant datasets, and differ in frequency between molecular subtypes, which may have implications for predictive factor identification. Future analyses will include aCGH, cell cycle protein analysis, proteomics, and clinical data including response to chemotherapy. (supported by UNC Breast SPORE-CA58223, NIH M01RR00046, DAMD 17–02–1-0521). [Table: see text] No significant financial relationships to disclose.
- Published
- 2006
48. Race, Breast Cancer Subtypes, and Survival in the Carolina Breast Cancer Study
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Sharon N. Edmiston, Joseph Geradts, Chiu Kit Tse, Lisa A. Carey, Patricia G. Moorman, Sandra L. Deming, Lynn G. Dressler, H. Shelton Earp, Kathleen Conway, Chad A. Livasy, Robert C. Millikan, Torsten O. Nielsen, Maggie C.U. Cheang, David Cowan, Gamze Karaca, Melissa A. Troester, and Charles M. Perou
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Adult ,Oncology ,medicine.medical_specialty ,Mitotic index ,Receptor, ErbB-2 ,Mammary gland ,Population ,Breast Neoplasms ,Breast cancer ,Internal medicine ,medicine ,Humans ,skin and connective tissue diseases ,education ,Aged ,Gynecology ,education.field_of_study ,Basal-like carcinoma ,business.industry ,Keratin-6 ,General Medicine ,Odds ratio ,Middle Aged ,medicine.disease ,Black or African American ,ErbB Receptors ,medicine.anatomical_structure ,Receptors, Estrogen ,Basal-Like Breast Carcinoma ,Keratin-5 ,Keratins ,Female ,Triple-Negative Breast Carcinoma ,Menopause ,Receptors, Progesterone ,business - Abstract
Context: Gene expression analysis has identified several breast cancer subtypes, including basal-like, human epidermal growth factor receptor-2 positive/estrogen receptor negative (HER2+/ER–), luminal A, and luminal B. Objectives: To determine population-based distributions and clinical associations for breast cancer subtypes. Design, Setting, and Participants: Immunohistochemical surrogates for each subtype were applied to 496 incident cases of invasive breast cancer from the Carolina Breast Cancer Study (ascertained between May 1993 and December 1996), a population based, case-control study that oversampled premenopausal and African American women. Subtype definitions were as follows: luminal A (ER+ and/or progesterone receptor positive [PR+], HER2−), luminal B (ER+ and/or PR+, HER2+), basal-like (ER−, PR−, HER2−, cytokeratin 5/6 positive, and/or HER1+), HER2+/ER− (ER−, PR−, and HER2+), and unclassified (negative for all 5 markers). Main Outcome Measures: We examined the prevalence of breast cancer subtypes within racial and menopausal subsets and determined their associations with tumor size, axillary nodal status, mitotic index, nuclear pleomorphism, combined grade, p53 mutation status, and breast cancer–specific survival. Results The basal-like breast cancer subtype was more prevalent among premenopausal African American women (39%) compared with postmenopausal African American women (14%) and non–African American women (16%) of any age (P
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- 2006
49. IGF1 CA repeat polymorphisms, lifestyle factors and breast cancer risk in the Long Island Breast Cancer Study Project.
- Author
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Rebecca J. Cleveland, Marilie D. Gammon, Sharon N. Edmiston, Susan L. Teitelbaum, Julie A. Britton, Mary Beth Terry, Sybil M. Eng, Alfred I. Neugut, Regina M. Santella, and Kathleen Conway
- Abstract
Insulin-like growth factor I (IGF-I) is an important regulator of growth and differentiation and is a potent mitogen for human breast cancer cells. Recent investigations suggest an association between cytosine–adenine dinucleotide (CA)n repeat polymorphisms of the IGF1 gene and IGF-I levels and further evidence indicates that genotype may influence breast cancer risk. We assessed the relation between IGF1 (CA)n repeats and breast cancer, and evaluated modification of genotype effects according to traditional breast cancer risk factors in 1028 breast cancer cases and 1086 controls. An increased risk of breast cancer was seen for genotypes that included alleles with fewer than (CA)19 repeats when compared to (CA)19 repeat carriers, an association that was particularly strong among premenopausal women [odds ratio (OR) = 3.31; 95% confidence interval (CI) = 1.47, 7.48]. No significant association was observed between an IGF1 genotype with no (CA)19 repeat compared to (CA)19 repeat genotypes in either pre- or postmenopausal women overall. However, when traditional breast cancer risk factors were considered, premenopausal women with genotypes that lacked a (CA)19 repeat had a nearly 60% increased risk of breast cancer among those who had ever used hormonal birth control, while never users had a significantly reduced risk (Pinteraction = 0.01). Among postmenopausal women, those with genotypes lacking a (CA)19 repeat allele had significantly increased breast cancer risk among subjects with a lower than median body mass index (BMI) (OR = 1.77 95% CI = 1.09, 2.87), while no association for IGF1 genotype was seen among women with a higher than median BMI (Pinteraction = 0.04). Our results demonstrate a role for alleles with fewer than (CA)19 repeats as a risk factor for breast cancer and also suggest that several traditional breast cancer risk factors modify the association of the IGF1 (CA)19 repeat genotype. [ABSTRACT FROM AUTHOR]
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- 2006
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50. EBV DNA Structure and Expression in EBV-Induced Proliferations
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Jian-Jing Chen, Nancy Raab-Traub, Kathryn Flynn, Sharon N. Edmiston, Kevin Gilligan, and Hiroshi Sato
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Biology ,medicine.disease ,Virology ,Virus ,Lymphoma ,Parotid gland ,Lymphatic system ,Immune system ,medicine.anatomical_structure ,Nasopharyngeal carcinoma ,hemic and lymphatic diseases ,medicine ,Carcinoma ,Immunodeficiency - Abstract
The Epstein-Barr virus (EBV) is implicated in a variety of diseases. We have detected EBV DNA in lymphoid tissue specimens from patients with Burkitt’s lymphoma (BL) and lymphoproliferations which have developed in patients with immune disorders including Wiskott-Aldrich syndrome (WA), Chediak-Higashi syndrome (CH), X-linked lymphoproliferative syndrome (XLP), and severe-combined immunodeficiency (SCID). We have also detected EBV DNA in epithelial tissues including nasopharyngeal carcinoma of all three histologic subtypes (NPC), carcinomas of the base of the tongue, and carcinoma of the parotid gland. In order to understand the pathogenetic diversity of infection with EBV, we sought to determine the state of viral infection and to compare viral expression in infected tissues from a variety of EBV infections.
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- 1989
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