Skip to main content
Grant Details

Grant Number: 5R01CA140311-05 Interpret this number
Primary Investigator: Umbricht, Christopher
Organization: Johns Hopkins University
Project Title: Multicenter Genetic, Epigenetic & Expression Analysis of Dcis Outcome Predictors
Fiscal Year: 2015


DESCRIPTION (provided by applicant): The goal of this project is to identify the molecular alterations that occur in the progression from ductal carcinoma in situ (DCIS) to invasive breast cancer. This is of critical importance because it is only after the milestone of tissue invasion has been achieved that a cancer has the potential to metastasize and kill a patient. Invasive breast cancers harbor multiple molecular alterations that were sequentially acquired during progression from ADH to ductal carcinoma in situ (DCIS) to invasive breast cancer. We will identify the genetic alterations that may be specific to DCIS or may be cumulative with increasing malignant potential. 7Rationale: While the cure rate for ductal carcinoma in situ (DCIS) is over 90%, this comes at the cost of considerable treatment-related morbidity. We urgently need the prognostic markers that would identify key genetic alterations predictive of the long-term outcome of DCIS, since most DCIS never become invasive carcinomas, presumably because they lack critical genetic changes, the replicative lifespan, or simply the time necessary to do so. Our experimental design exploits recent technological developments that permit genome- wide testing of DNA samples for genetic and epigenetic alterations, even in the very limited material available from archival DCIS samples. DCIS may represent a stage at which various pathways of clonal evolution are attempted, until a particular combination of genetic and/or epigenetic changes allows tissue invasion. Indications are that genetic mutations and epigenetic silencing may both be operative in carcinogenesis, and that these alternatives may be used interchangeably, even in a complementary fashion in the same cancer cell. Therefore, a combined analysis of both types of alterations is necessary. 7Design: This study is designed as multicenter, longitudinal, case-control study of DCIS. We have identified unique cohorts of pure DCIS cases with known outcomes to enable a multicenter genome-wide screening study of 100 cases and 100 controls, which will be initially limited to patients of Caucasian origin in order to obtain a homogenous patient population and maximize the probability of successfully validating our hypothesis that prognostic markers exist in DCIS. Candidate markers of interest will be further characterized by quantitative PCR methods, with the goal of creating a single, prognostic multiplex PCR signature that can be used on the limited clinical material typically obtained in the diagnostic phase of the evaluation of DCIS. We will then validate the assay in an independent test cohort of 100 cases of DCIS with progressive disease vs. 100 cases of DCIS that remain disease free, obtained from the population-based repository provided by the Iowa SEER residual tissue repository (RTR). We will also use an additional population-based repository located in Hawaii, to test if the prognostic signature developed from Caucasian samples can be used successfully in a different ethnic group. This will guide future work, particularly regarding the necessity of exploring the predictive power of the multiplex assay in different populations.


Characterization of human telomerase reverse transcriptase promoter methylation and transcription factor binding in differentiated thyroid cancer cell lines.
Authors: Avin B.A. , Wang Y. , Gilpatrick T. , Workman R.E. , Lee I. , Timp W. , Umbricht C.B. , Zeiger M.A. .
Source: Genes, chromosomes & cancer, 2019 Aug; 58(8), p. 530-540.
EPub date: 2019-02-10.
PMID: 30664813
Related Citations

Measuring DNA Copy Number Variation Using High-Density Methylation Microarrays.
Authors: Cho S. , Kim H.S. , Zeiger M.A. , Umbricht C.B. , Cope L.M. .
Source: Journal of computational biology : a journal of computational molecular cell biology, 2019 Apr; 26(4), p. 295-304.
EPub date: 2019-02-21.
PMID: 30789293
Related Citations

Young age at diagnosis is associated with worse prognosis in the Luminal A breast cancer subtype: a retrospective institutional cohort study.
Authors: Liu Z. , Sahli Z. , Wang Y. , Wolff A.C. , Cope L.M. , Umbricht C.B. .
Source: Breast cancer research and treatment, 2018 Dec; 172(3), p. 689-702.
EPub date: 2018-09-17.
PMID: 30225619
Related Citations

Validation of a personalized risk prediction model for contralateral breast cancer.
Authors: Chowdhury M. , Euhus D. , Arun B. , Umbricht C. , Biswas S. , Choudhary P. .
Source: Breast cancer research and treatment, 2018 Jul; 170(2), p. 415-423.
EPub date: 2018-03-24.
PMID: 29574637
Related Citations

Monitoring of Serum DNA Methylation as an Early Independent Marker of Response and Survival in Metastatic Breast Cancer: TBCRC 005 Prospective Biomarker Study.
Authors: Visvanathan K. , Fackler M.S. , Zhang Z. , Lopez-Bujanda Z.A. , Jeter S.C. , Sokoll L.J. , Garrett-Mayer E. , Cope L.M. , Umbricht C.B. , Euhus D.M. , et al. .
Source: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2017 Mar; 35(7), p. 751-758.
EPub date: 2016-11-21.
PMID: 27870562
Related Citations

Optimizing the Use of Gene Expression Profiling in Early-Stage Breast Cancer.
Authors: Kim H.S. , Umbricht C.B. , Illei P.B. , Cimino-Mathews A. , Cho S. , Chowdhury N. , Figueroa-Magalhaes M.C. , Pesce C. , Jeter S.C. , Mylander C. , et al. .
Source: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2016-12-20; 34(36), p. 4390-4397.
EPub date: 2016-10-31.
PMID: 27998227
Related Citations

A Validated Model for Identifying Patients Unlikely to Benefit From the 21-Gene Recurrence Score Assay.
Authors: Gage M.M. , Rosman M. , Mylander W.C. , Giblin E. , Kim H.S. , Cope L. , Umbricht C. , Wolff A.C. , Tafra L. .
Source: Clinical breast cancer, 2015 Dec; 15(6), p. 467-72.
EPub date: 2015-04-23.
PMID: 26072275
Related Citations

Subtype-specific overexpression of the Rac-GEF P-REX1 in breast cancer is associated with promoter hypomethylation.
Authors: Barrio-Real L. , Benedetti L.G. , Engel N. , Tu Y. , Cho S. , Sukumar S. , Kazanietz M.G. .
Source: Breast cancer research : BCR, 2014-09-24; 16(5), p. 441.
EPub date: 2014-09-24.
PMID: 25248717
Related Citations

Novel methylated biomarkers and a robust assay to detect circulating tumor DNA in metastatic breast cancer.
Authors: Fackler M.J. , Lopez Bujanda Z. , Umbricht C. , Teo W.W. , Cho S. , Zhang Z. , Visvanathan K. , Jeter S. , Argani P. , Wang C. , et al. .
Source: Cancer research, 2014-04-15; 74(8), p. 2160-70.
PMID: 24737128
Related Citations

Do breast cancer cell lines provide a relevant model of the patient tumor methylome?
Authors: Cope L.M. , Fackler M.J. , Lopez-Bujanda Z. , Wolff A.C. , Visvanathan K. , Gray J.W. , Sukumar S. , Umbricht C.B. .
Source: PloS one, 2014; 9(8), p. e105545.
EPub date: 2014-08-26.
PMID: 25157401
Related Citations

HOXB13 mediates tamoxifen resistance and invasiveness in human breast cancer by suppressing ERα and inducing IL-6 expression.
Authors: Shah N. , Jin K. , Cruz L.A. , Park S. , Sadik H. , Cho S. , Goswami C.P. , Nakshatri H. , Gupta R. , Chang H.Y. , et al. .
Source: Cancer research, 2013-09-01; 73(17), p. 5449-58.
EPub date: 2013-07-05.
PMID: 23832664
Related Citations

Genome-wide methylation analysis identifies genes specific to breast cancer hormone receptor status and risk of recurrence.
Authors: Fackler M.J. , Umbricht C.B. , Williams D. , Argani P. , Cruz L.A. , Merino V.F. , Teo W.W. , Zhang Z. , Huang P. , Visvananthan K. , et al. .
Source: Cancer research, 2011-10-01; 71(19), p. 6195-207.
EPub date: 2011-08-08.
PMID: 21825015
Related Citations

Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters.
Authors: Hung T. , Wang Y. , Lin M.F. , Koegel A.K. , Kotake Y. , Grant G.D. , Horlings H.M. , Shah N. , Umbricht C. , Wang P. , et al. .
Source: Nature genetics, 2011-06-05; 43(7), p. 621-9.
EPub date: 2011-06-05.
PMID: 21642992
Related Citations

Back to Top