Victor Levenson - Academia.edu (original) (raw)

Papers by Victor Levenson

Molecular biomarkers, personalized medicine and other buzzwords are getting into the mainstream, ... more Molecular biomarkers, personalized
medicine and other buzzwords are getting
into the mainstream, so it is appropriate
to take a look at the field and
make a reality check: what exactly has
been accomplished, where are the hot
areas, what novel directions are likely to
be ‘the next big thing’. The papers in
this issue of Expert Review of Molecular
Diagnostics will be of great interest to
investigators working in this area. In a
short overview, we have tried to provide
a certain scaffold; it is by no means
comprehensive and to a large degree
presents a personal view of what we see
now as the concept of personalized medicine
and molecular biomarkers.

Cell-free circulating DNA carries not only tumor-specific changes in its sequence but also distin... more Cell-free circulating DNA carries not only tumor-specific changes in its sequence but also distinctive epigenetic marks, namely DNA methylation, in certain GC-rich fragments. These fragments are usually located within the promoters and first exons of many genes, comprising CpG islands. Analysis of DNA methylation using cell-free circulating DNA can facilitate development of very accurate biomarkers for detection, diagnosis, prediction of response to therapy and prognosis of outcomes. Recent data suggest that benign and inflammatory diseases have very specific methylation patterns within cell-free circulating DNA, which are different from the pattern of a malignant tumor of the same organ. In addition, specific methylation patterns have been detected for cancers of different organs, so a differential diagnosis of site-specific cancer appears feasible. Currently, cancer-related applications dominate the field, although methylation-based biomarkers may also be possible for other diseases, including neurodegenerative and psychiatric disorders.

Abnormal DNA methylation is a feature of most types of cancer, which is reflected in cell-free ci... more Abnormal DNA methylation is a feature of most types of cancer, which is reflected in cell-free circulating DNA in plasma. It is,
however, unknown whether surgical removal of the tumor and subsequent therapy induces changes in plasma DNA
methylation, which can be used to monitor treatment. In this pilot study, methylation in cell-free plasma DNA of 20 breast
cancer patients was determined by the previously developed MethDet-56 technique. Samples at three time points were
analyzed—before surgery (baseline), after surgery (to evaluate the effects of resection) and after surgery on tamoxifen therapy
(to determine the effects of treatment). Methylation patterns of healthy controls were used as a reference for all comparisons.
Seven promoters were differentially methylated (p < 0.05) in at least one comparison; three changed after surgery; another
one changed after beginning of tamoxifen treatment; and four were differentially methylated in baseline versus combined
treatment samples. Increased methylation of PR PROX, MDGI, PAX 5 and RARb2 at baseline (presurgery) diminished toward
the healthy controls with the lowest methylation in the combined treatment group. Surgery alone decreased methylation in
PAX 5 and RARb2, whereas tamoxifen treatment changed methylation only in the B promoter of ESR1. Methylation patterns in
cell-free plasma DNA change after surgery and tamoxifen treatment, most significantly—after combined treatment. The
baseline (presurgery) patterns become similar to those of healthy controls, suggesting that methylation patterns in cell-free
plasma DNA may be used to monitor treatment.

An accurate biomarker for detection of ovarian cancer may reduce cancer-related mortality. Using... more An accurate biomarker for detection of ovarian cancer
may reduce cancer-related mortality. Using a previously
developed microarray-based technique, we
evaluated differences in DNA methylation profiles in
a panel of 56 genes using sections of serous papillary
adenocarcinomas and uninvolved ovaries (n 30)
from women in a high-risk group. Methylation profiles
were also generated for circulating DNA from blood of
patients (n 33) and healthy controls (n 33). Using
the most differentially methylated genes for naïve
Bayesian analysis, we identified ten of these profiles as
potentially informative in tissues. Various combinations
of these genes produced 69% sensitivity and
70% specificity for cancer detection as estimated under
a stratified, fivefold cross-validation protocol. In
plasma, five genes were identified as informative;
their combination had 85% sensitivity and 61% specificity
for cancer detection. These results suggest that
differential methylation profiling in heterogeneous
samples has the potential to identify components of
a composite biomarker that may detect ovarian cancer
in blood with significant accuracy.

International Journal of Cancer, 2014

Profiling of DNA methylation status of specific genes is a way to screen for colorectal cancer (C... more Profiling of DNA methylation status of specific genes is a way to screen for colorectal cancer (CRC) and pancreatic cancer (PC) in blood. The commonality of methylation status of cancer-related tumor suppressor genes between CRC and PC is largely unknown. Methylation status of 56 cancer-related genes was compared in plasma of patients in the following cohorts: CRC, PC and healthy controls. Cross validation determined the best model by area under ROC curve (AUC) to differentiate cancer methylation profiles from controls. Optimal preferential gene methylation signatures were derived to differentiate either cancer (CRC or PC) from controls. For CRC alone, a three gene signature (CYCD2, HIC and VHL) had an AUC 0.9310, sensitivity (Sens) 5 0.826, specificity (Spec) 5 0.9383. For PC alone, an optimal signature consisted of five genes (VHL, MYF3, TMS, GPC3 and SRBC), AUC 0.848; Sens 5 0.807, Spec 5 0.666. Combined PC and CRC signature or "combined cancer signature" was derived to differentiate either CRC and PC from controls (MDR1, SRBC, VHL, MUC2, RB1, SYK and GPC3) AUC 5 0.8177, Sens 5 0.6316 Spec 5 0.840. In a validation cohort, N 5 10 CRC patients, the optimal CRC signature (CYCD2, HIC and VHL) had AUC 0.900. In all derived signatures (CRC, PC and combined cancer signature) the optimal panel used preferential VHL methylation. In conclusion, CRC and PC differ in specific genes methylated in plasma other than VHL. Preferential methylation of VHL is shared in the optimal signature for CRC alone, PC alone and combined PC and CRC. Future investigations may identify additional methylation markers informative for the presence of both CRC and PC.

Gynecologic Oncology, 2011

Objective. Epithelial ovarian carcinoma (OvCa) is rarely detected early, and it is also difficult... more Objective. Epithelial ovarian carcinoma (OvCa) is rarely detected early, and it is also difficult to determine
whether an adnexal mass is benign or malignant. Previously, we noted differences in methylation patterns of
cell-free plasma DNA (cfpDNA) in women without disease compared to patients with OvCa. In this work, we
investigated whether methylation patterns of cfpDNA can differentiate between benign and malignant
tumors.
Methods. Methylation patterns in cfpDNA were determined in three cohorts (30 samples each) using a
microarray-based assay (MethDet 56). Principal component analysis, supervised clustering, linear
discrimination analysis, and 25 rounds of 5-fold cross-validation were used to determine informative
genes and assess the sensitivity and specificity of differentiating between OvCa vs. healthy control (HC),
benign ovarian disease (mostly serous cystadenoma, BOD) vs. HC, and OvCa vs. BOD samples.
Results. Differential methylation of three promoters (RASSF1A, CALCA, and EP300) differentiated between
OvCa vs. HC with a sensitivity of 90.0% and a specificity of 86.7%. Three different promoters (BRCA1, CALCA,
and CDKN1C) were informative for differentiating between BOD vs. HC, with a sensitivity of 90.0% and a
specificity of 76.7%. Finally, two promoters (RASSF1A and PGR-PROX) were informative for differentiating
between OvCa vs. BOD, with a sensitivity of 80.0% and a specificity of 73.3%.
Conclusions. This proof-of-principle data show that differential methylation of promoters in cfpDNA may
be a useful biomarker to differentiate between certain benign and malignant ovarian tumors.

The Journal of Molecular Diagnostics, 2008

Abnormal DNA methylation is well established for cancer cells, but a methylation-based diagnostic... more Abnormal DNA methylation is well established for cancer cells, but a methylation-based diagnostic test is yet to be developed. One of the problems is insufficient accuracy of cancer detection in heterogeneous clinical specimens when only a single gene is analyzed. A new technique was developed to produce a multigene methylation signature in each sample, and its potential for selection of informative genes was tested using DNA from formalin-fixed, paraffin-embedded breast cancer tissues. Fifty-six promoters were analyzed in each of 138 clinical specimens by a microarray-based modification of the previously developed technique. Specific methylation signatures were identified for atypical ductal hyperplasia, ductal carcinoma in situ, and invasive ductal carcinoma. Informative promoters selected by Fisher's exact test were used for composite biomarker design using naïve Bayes algorithm. All informative promoters were unmethylated in disease compared with normal tissue. Cross-validation showed 72.4% sensitivity and 74.7% specificity for detection of ductal carcinoma in situ and invasive ductal carcinoma, and 87.5% sensitivity and 95% specificity for detection of atypical ductal hyperplasia. These results indicate that informative cancer-specific methylation signatures can be detected in heterogeneous tissue specimens, suggesting that a diagnostic assay can then be developed

International Journal of Cancer, 2010

Abnormal DNA methylation is a feature of most types of cancer, which is reflected in cell-free ci... more Abnormal DNA methylation is a feature of most types of cancer, which is reflected in cell-free circulating DNA in plasma. It is, however, unknown whether surgical removal of the tumor and subsequent therapy induces changes in plasma DNA methylation, which can be used to monitor treatment. In this pilot study, methylation in cell-free plasma DNA of 20 breast cancer patients was determined by the previously developed MethDet-56 technique. Samples at three time points were analyzed—before surgery (baseline), after surgery (to evaluate the effects of resection) and after surgery on tamoxifen therapy (to determine the effects of treatment). Methylation patterns of healthy controls were used as a reference for all comparisons. Seven promoters were differentially methylated (p < 0.05) in at least one comparison; three changed after surgery; another one changed after beginning of tamoxifen treatment; and four were differentially methylated in baseline versus combined treatment samples. Increased methylation of PR PROX, MDGI, PAX 5 and RARβ2 at baseline (presurgery) diminished toward the healthy controls with the lowest methylation in the combined treatment group. Surgery alone decreased methylation in PAX 5 and RARβ2, whereas tamoxifen treatment changed methylation only in the B promoter of ESR1. Methylation patterns in cell-free plasma DNA change after surgery and tamoxifen treatment, most significantly—after combined treatment. The baseline (presurgery) patterns become similar to those of healthy controls, suggesting that methylation patterns in cell-free plasma DNA may be used to monitor treatment.

Cancer, 2010

BACKGROUND: Although patients with chronic pancreatitis (CP) have an increased risk of pancreatic... more BACKGROUND: Although patients with chronic pancreatitis (CP) have an increased risk of pancreatic cancer
(PanCa), the timely detection of PanCa often is difficult, because the symptoms of CP and PanCa are very similar.
Moreover, secondary inflammation may be identified in PanCa, further complicating diagnosis. To improve the survival
of patients with PanCa, a reliable test to differentiate CP from PanCa is needed. In this article, the authors describe a
methylation profile of cell-free plasma DNA that distinguished CP from PanCa with >90% accuracy. METHODS: Methylation
in cell-free, plasma DNA was compared among 30 samples from patients with CP, 30 samples from patients
with PanCa, and 30 samples from healthy controls (N) using a microarray-mediated methylation analysis of 56 fragments
in each sample (MethDet56). Statistical analysis was done by using the Fisher exact test, a naive Bayes algorithm,
and 25 rounds of 5-fold cross-validation. RESULTS: The MethDet56 methylation analysis technique identified 17
gene promoters as informative (8 for distinguishing N from CP and 14 for distinguishing CP from PanCa). It achieved
81.7% sensitivity and 78% specificity (P<.01) in the detection of CP (N vs CP) and 91.2% sensitivity and 90.8% specificity
(P<.01) in the differential detection of PanCa (PanCa vs CP). CONCLUSIONS: The current data suggested that,
among patients with pancreatic disease, the methylation profiles of inflammatory disease and cancer are different
and open a new venue for the development of biomarkers for differential diagnosis. Further investigation of diagnostic
biomarkers for pancreatic cancer based on methylation in cell-free, circulating DNA appears to be warranted.

Pharmacogenomics, 2004

While different markers for cancer diagnosis have been known for at least a decade, the systemati... more While different markers for cancer diagnosis have been known for at least a decade, the systematic search for biomarkers emerged only several years ago. In this article, I will concentrate on DNA methylation as a dynamic and robust platform for the development of cancer-specific biomarkers. Simultaneous analysis of a growing number of independent methylation events can create increasingly more precise and individualized diagnostics. The differential detection of methylated and unmethylated DNA can be accomplished through either chemical modification or digestion with methylation-sensitive restriction enzyme(s). The benefits and potential pitfalls of both these approaches for clinical sample analysis will be addressed.

Journal of Surgical Oncology, 2009

Background and Objectives: Detection of pancreatic cancer by blood-based test may improve outcome... more Background and Objectives: Detection of pancreatic cancer by blood-based test may improve outcomes.We sought to establish the feasibility of a blood-based detection of pancreatic cancer through multiplexed array-mediated analysis of DNA methylation.
Methods: Methylation was assessed in each plasma sample using a panel of 56 frequently methylated genes. Methylation profiles in patients with ductal cell adenocarcinoma of the pancreas (n¼30) and healthy gender and age-matched controls (n¼30) were compared. Methylation was determined as described previously; a composite biomarker was developed for classification of cancer and normal samples. Sensitivity and
specificity of the biomarker were estimated using 25 rounds of fivefold cross-validation.
Results: Five promoters were consistently selected for the classifier during cross-validation and comprised the final composite biomarker Fivefold cross-validation results indicate 76% sensitivity and 59% specificity of the biomarker, which included promoters of CCND2, SOCS1,
THBS1, PLAU, and VHL.
Conclusion: Differential methylation profiling of plasma DNA can detect ductal adenocarcinoma of the pancreas with significant accuracy and should be explored further. While additional improvement of biomarkers is necessary, the blood-based biomarker may be already useful as a firstline detection tool.

Journal of Molecular Diagnostics, 2008

Abnormal DNA methylation is well established for cancer cells, but a methylation-based diagnostic... more Abnormal DNA methylation is well established for cancer cells, but a methylation-based diagnostic test is yet to be developed. One of the problems is insufficient accuracy of cancer detection in heterogeneous clinical specimens when only a single gene is analyzed. A new technique was developed to produce a multigene methylation signature in each sample, and its potential for selection of informative genes was tested using DNA from formalin-fixed, paraffin-embedded breast cancer tissues. Fifty-six promoters were analyzed in each of 138 clinical specimens by a microarray-based modification of the previously developed technique. Specific methylation signatures were identified for atypical ductal hyperplasia, ductal carcinoma in situ, and invasive ductal carcinoma. Informative promoters selected by Fisher's exact test were used for composite biomarker design using naïve Bayes algorithm. All informative promoters were unmethylated in disease compared with normal tissue. Cross-validation showed 72.4% sensitivity and 74.7% specificity for detection of ductal car-cinoma in situ and invasive ductal carcinoma, and 87.5% sensitivity and 95% specificity for detection of atypical ductal hyperplasia. These results indicate that informative cancer-specific methylation signatures can be detected in heterogeneous tissue specimens, suggesting that a diagnostic assay can then be developed.

Biochimica Et Biophysica Acta-general Subjects, 2007

Early detection of breast cancer reduces the suffering and cost to society associated with the di... more Early detection of breast cancer reduces the suffering and cost to society associated with the disease. A sensitive assay to identify biomarkers that can accurately diagnose the onset of breast cancer using non-invasively collected clinical specimens is ideal for early detection. The earlier and more accurate the diagnostic biomarker can predict disease onset, the more valuable it becomes. Here, a brief review of existing and emerging approaches for breast cancer biomarker identification and analysis is presented. Those biomarkers found in biological fluids, blood in particular, apparently hold the best promise for fast development of screening assays. Autoantibodies and abnormal tumor-specific DNA methylation found in cell-free plasma DNA may provide the best opportunity for constructing multiplexed and highly redundant tests, which will be sufficiently specific and sensitive for early detection of breast cancer. It is expected that technologies developed for breast cancer detection will be useful for other types of cancer.

Nucleic Acids Research, 2005

Abnormal DNA methylation is observed in certain promoters of neoplastic cells, although the likel... more Abnormal DNA methylation is observed in certain promoters of neoplastic cells, although the likelihood of methylation for each individual promoter varies. Simultaneous analysis of many promoters in the same sample can allow use of statistical methods for identification of neoplasia. Here we describe an assay for such analysis, based on digestion of genomic DNA with methylation-sensitive restriction enzyme and multiplexed PCR with gene-specific primers (MSRE-PCR). MSRE-PCR includes extensive digestion of genomic DNA (uncut fragments cannot be identified by PCR), can be applied to dilute samples (<1 pg/ml), requires limited amount of starting material (42 pg or genomic equivalent of seven cells) and can identify methylation in a heterogeneous mix containing <2% of cells with methylated fragments. When applied to 53 promoters of breast cancer cell lines MCF-7, MDA-MB-231 and T47D, MSRE-PCR correctly identified the methylation status of genes analyzed by other techniques. For selected genes results of MSRE-PCR were confirmed by methylation-specific PCR and bisulfite sequencing. The assay can be configured for any number of desired targets in any user-defined set of genes.

Human Gene Therapy, 1998

To facilitate gene delivery into animal cells we developed and characterized a family of single-t... more To facilitate gene delivery into animal cells we developed and characterized a family of single-transcript vectors (STVs) with different selection markers expressed from the internal ribosomal entry site (IRES) of encephalomyocarditis virus (EMCV). Retroviral IRES-STVs (R-IRES-STVs) were assembled using an LNCX backbone (Miller and Rosman, 1989). In all of these constructs, a multiple cloning site (MCS) is located immediately downstream of the single promoter and is followed by the IRES sequence and a selectable marker. This configuration ensures that the MCS-inserted gene will be expressed in selected cells. The selectable markers of these vectors provide resistance to G418, puromycin, hygromycin B, histidinol D, and phleomycin. One STV contains green fluorescent protein (GFP) as a selectable marker, permitting FACS-mediated selection, which may prove useful in gene therapy applications. More than 70% of recipient cells could be infected with R-IRES-STVs after one round of infection. Up to 99% of infected cells expressed the reporter gene (GFP) after selection with an appropriate drug. When ecotropic receptor was delivered via R-IRES-STV into human HT1080 cells, populations of drug-selected cells as well as a majority of individual clones were found to be highly susceptible to infection by ecotropic retroviruses.

A combination of four genetic suppressor elements (GSEs), two of which are derived from putative ... more A combination of four genetic suppressor elements (GSEs), two of which are derived from putative transcriptional regulators, was previously found to increase resistance to drugs inhibiting DNA replication in HT1080 fibrosarcoma cells. In the present study, two GSE-transduced cell lines, isolated with and without cytotoxic selection, were found to be resistant to a diverse group of DNA-interactive agents, including aphidicolin, hydroxyurea, cytarabine, etoposide, doxorubicin, and mafosfamide. Changes in gene expression associated with GSE-induced drug resistance were analyzed by cDNA array hybridization and reverse transcription-PCR. Twenty genes were found to be up-regulated in both of the resistant cell lines. These include genes involved in DNA replication and repair (e.g., PCNA, XRCC1, B-MYB, and GADD45), transcriptional regulators associated with stress response, and cell cycle checkpoint control (e.g., YB-1, DBPA, and ATF4), and genes for signal transduction proteins (e.g., protein tyrosine phosphatase 1B and regulatory subunits ␣ and ␤ of cAMP-dependent protein kinase). The observed changes in gene expression may play a role in pleiotropic resistance to different classes of DNA-targeting drugs.

Pharmaceuticals, 2012

A recent expansion of our knowledge about epigenetic changes strongly suggests that epigenetic ra... more A recent expansion of our knowledge about epigenetic changes strongly suggests that epigenetic rather than genetic features better reflect disease development, and consequently, can become more conclusive biomarkers for the detection and diagnosis of different diseases. In this paper we will concentrate on the current advances in DNA methylation studies that demonstrate a direct link between abnormal DNA methylation and a disease. This link can be used to develop diagnostic biomarkers that will precisely identify a particular disease. It also appears that disease-specific DNA methylation patterns undergo unique changes in response to treatment with a particular drug, thus raising the possibility of DNA methylation-based biomarkers for the monitoring of treatment efficacy, for prediction of response to treatment, and for the prognosis of outcome. While biomarkers for oncology are the most obvious applications, other fields of medicine are likely to benefit as well. This potential is demonstrated by DNA methylation-based biomarkers for neurological and psychiatric diseases. A special requirement for a biomarker is the possibility of longitudinal testing. In this regard cell-free circulating DNA from blood is especially interesting because it carries methylation markers specific for a particular disease. Although only a few DNA methylation-based biomarkers have attained clinical relevance, the ongoing efforts to decipher disease-specific methylation patterns are likely to produce additional biomarkers for detection, diagnosis, and monitoring of different diseases in the near future.

Journal of the Neurological Sciences, 2010

Background: There is growing interest for identification of new targets for biomarker development... more Background: There is growing interest for identification of new targets for biomarker development in multiple sclerosis (MS). The goal of this study was to compare the concentration and the methylation patterns of cellfree plasma DNA (cfpDNA) in patients with relapsing-remitting multiple sclerosis (RRMS) and healthy individuals. Methods: Three 30-patient cohorts were examined: patients with RRMS, in either remission or exacerbation, and healthy individuals as controls. Concentration of cfpDNA was determined using a standard fluorometric assay. Patterns of methylation in 56 gene promoters were determined by a microarray-based assay (MethDet-56). The data were analyzed to identify statistically relevant differences among the study groups. Results: The concentration of cfpDNA in patients with RRMS was four to eight-fold higher compared to healthy controls. Significant differences in cfpDNA methylation patterns were detected in all three comparisons: RRMS patients in remission versus healthy controls were recognized with 79.2% sensitivity and 92.9% specificity; RRMS patients in exacerbation versus healthy controls were recognized with 75.9% sensitivity and 91.5% specificity; and RRMS patients in exacerbation versus those in remission were recognized with 70.8% sensitivity and 71.2% specificity. Conclusion: Based on our findings, we conclude that patients with RRMS display unique disease-and state-specific changes of cfpDNA. Our findings are of clinical significance as they could be used in the development of potentially new biomarkers for MS. This is the first report in our knowledge describing such changes of cfpDNA in patients with MS. (R. Balabanov), Victor_Levenson@rush.edu (V. Levenson).

Journal of the American College of Surgeons, 2012

International Journal of Cancer, 2014

Gynecologic Oncology, 2011

The Journal of Molecular Diagnostics, 2008

International Journal of Cancer, 2010

Abnormal DNA methylation is a feature of most types of cancer, which is reflected in cell-free ci... more Abnormal DNA methylation is a feature of most types of cancer, which is reflected in cell-free circulating DNA in plasma. It is, however, unknown whether surgical removal of the tumor and subsequent therapy induces changes in plasma DNA methylation, which can be used to monitor treatment. In this pilot study, methylation in cell-free plasma DNA of 20 breast cancer patients was determined by the previously developed MethDet-56 technique. Samples at three time points were analyzed—before surgery (baseline), after surgery (to evaluate the effects of resection) and after surgery on tamoxifen therapy (to determine the effects of treatment). Methylation patterns of healthy controls were used as a reference for all comparisons. Seven promoters were differentially methylated (p < 0.05) in at least one comparison; three changed after surgery; another one changed after beginning of tamoxifen treatment; and four were differentially methylated in baseline versus combined treatment samples. Increased methylation of PR PROX, MDGI, PAX 5 and RARβ2 at baseline (presurgery) diminished toward the healthy controls with the lowest methylation in the combined treatment group. Surgery alone decreased methylation in PAX 5 and RARβ2, whereas tamoxifen treatment changed methylation only in the B promoter of ESR1. Methylation patterns in cell-free plasma DNA change after surgery and tamoxifen treatment, most significantly—after combined treatment. The baseline (presurgery) patterns become similar to those of healthy controls, suggesting that methylation patterns in cell-free plasma DNA may be used to monitor treatment.

Cancer, 2010

Pharmacogenomics, 2004

Journal of Surgical Oncology, 2009

Journal of Molecular Diagnostics, 2008

Abnormal DNA methylation is well established for cancer cells, but a methylation-based diagnostic... more Abnormal DNA methylation is well established for cancer cells, but a methylation-based diagnostic test is yet to be developed. One of the problems is insufficient accuracy of cancer detection in heterogeneous clinical specimens when only a single gene is analyzed. A new technique was developed to produce a multigene methylation signature in each sample, and its potential for selection of informative genes was tested using DNA from formalin-fixed, paraffin-embedded breast cancer tissues. Fifty-six promoters were analyzed in each of 138 clinical specimens by a microarray-based modification of the previously developed technique. Specific methylation signatures were identified for atypical ductal hyperplasia, ductal carcinoma in situ, and invasive ductal carcinoma. Informative promoters selected by Fisher's exact test were used for composite biomarker design using naïve Bayes algorithm. All informative promoters were unmethylated in disease compared with normal tissue. Cross-validation showed 72.4% sensitivity and 74.7% specificity for detection of ductal car-cinoma in situ and invasive ductal carcinoma, and 87.5% sensitivity and 95% specificity for detection of atypical ductal hyperplasia. These results indicate that informative cancer-specific methylation signatures can be detected in heterogeneous tissue specimens, suggesting that a diagnostic assay can then be developed.

Biochimica Et Biophysica Acta-general Subjects, 2007

Nucleic Acids Research, 2005

Human Gene Therapy, 1998

Pharmaceuticals, 2012

Journal of the Neurological Sciences, 2010

Journal of the American College of Surgeons, 2012