| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Genetics Branch [O. K. G., L. M. R., K. N., J. J., J. C., C-J. H., I. R. K.] and Biometric Research Branch [R. S., G. W.], Center for Cancer Research, National Cancer Institute (NCI), and Division of Cancer Prevention [E. H.], NCI, Bethesda, Maryland 20892; Surgery Department, National Naval Medical Center, Bethesda, Maryland 20889 [J. D., P. S.]; Department of Gastrointestinal Oncology, University of Texas-M. D. Anderson Cancer Center, Houston, Texas 77030 [P. L., S. P.]; Department of Preventive Medicine, Creighton University, Omaha, Nebraska [H. L.]; University of Toronto, Toronto, Ontario, M5G 1X5 Canada [S. G.]; Clinical Oncology Research and Development, Pharmacia, Peapack, New Jersey 07977 [A. B.]; and Ovation Pharma, Lincolnshire, Illinois 60015 [G. G.]
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The proximal and distal colon have a different embryological origin: cecum, ascending colon, and the proximal two thirds of the transverse colon [proximal, or right colon (RC)] derive from embryonic midgut; the distal third of the transverse colon, descending colon, sigmoid colon and rectum [distal, or left colon (LC)] derive from hindgut (7) . Reflecting their origin, the proximal and distal colon also have a different vascular supply, with the right colon served by the superior mesenteric artery and the left colon by the inferior mesenteric artery. In addition, right colon and left colon differ in expression of several antigens, metabolism of glucose, polyamines and butyric acid, as well as in bile acid concentrations, and composition and density of the bacterial population (1 , 5 , 6) .
Thus, the differences in incidence of CRC and predilection to microsatellite stable (MSS) or microsatellite unstable (MSI) type of carcinogenesis may: (a) reflect different biological characteristics of proximal and distal colon cells, acquired in embryonic or postnatal development, which in turn determine different responses to common environmental factors; or (b) result from the presence of different procarcinogenic factors in proximal and distal colon (bile acids, bacteria), acting on similar mucosa; or (c) be a combination of a distinct environment and distinct target cells.
To begin our exploration of this issue, we asked whether colonic mucosal epithelium from the right side can be distinguished from colonic mucosal epithelium obtained from the left side of the colon. Our approach has been to define patterns of gene expression for each side of the colon, and compare the right and left colon to determine whether there is a significant difference in these patterns.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
RNA Extraction and Amplification.
Total RNA was isolated from flash-frozen specimens, homogenized with a Disposable Generator and Micro-H Omni Homogenizer in either lysis buffer RLT (Qiagen) or in Tri-Reagent (Molecular Research Center, Inc.), and purified using Qiagen’s RNeasy Mini Kit columns (Qiagen) according to the manufacturer’s instructions.
mRNA was amplified according to a modified Eberwine’s protocol (8) . SuperScript II reverse transcriptase (Life Technologies, Inc.) was used for first-strand cDNA synthesis, starting with 5 µg of total RNA. First-strand cDNA synthesis was performed with an oligo(dT24) primer containing 5'-T7 promoter-primer, and the second strand was synthesized with a mixture of RNase H, DNA polymerase, and DNA ligase.
cDNA was treated with a mixture of phenol-chloroform-isoamyl alcohol, ethanol-precipitated, washed with 80% ethanol, and dried in a Speed-Vac. Purified cDNA was transcribed in vitro with a T7 MEGAscript kit (Ambion) according to the manufacturer’s instructions, and aRNA was purified using RNeasy mini spin columns (Qiagen). Concentration of the eluted aRNA was determined by spectrophotometric measurement of absorbance at 260 nm.
Using this protocol, 50–100 µg of aRNA were obtained after starting with 5 µg of total RNA, indicating an approximately 1000-fold linear amplification of mRNA.
cDNA Labeling and Microarray Hybridization.
Fluorescent-labeled cDNA was synthesized by reverse transcription of colon aRNA and human testis aRNA [prepared from total testis RNA (Clontech, Inc.) as described for colon aRNA] with Superscript II reverse transcriptase (Invitrogen) and random oligonucleotide primers in the presence of Cy3-dUTP or Cy5-dUTP (Amersham Pharmacia Biotech), respectively. For each hybridization experiment, 5 µg of colon aRNA and 6 µg of testis aRNA (common reference) were used to prepare a mixture of labeled cDNAs. After alkaline lysis of aRNA, labeled cDNA was purified with AutoSeq G50 columns (Amersham) and QIAquick PCR purification columns (Qiagen). Purified labeled colon and testis cDNAs were mixed, ethanol precipitated, dried in a Speed-Vac, and dissolved in hybridization buffer containing 3.7x SSPE, 2.5x Denhardt’s Solution (Sigma), 0.5 µg/µl Poly(A)40–60 (Amersham Pharmacia Biotech), human C0t1 DNA (Invitrogen), and 0.125 µg/µl yeast tRNA (Sigma) in TE buffer, with or without 50% formamide. After denaturing at 100°C for 2 min., snap-cooling on ice, and warming to room temperature, 10% SDS was added to the hybridization mixture to a final concentration of 0.25%.
Microarrays containing cDNAs spotted on lysine-coated glass slides were obtained from the Advanced Technology Center (NCI). Three different versions of microarrays were used, containing 6500, 6400, and 9000 distinct cDNA clones supplied from Research Genetics, Inc. (Huntsville, AL). Detailed information and comparison of printed cDNA sets can be found on the mAdb web site.4 9k-microarrays contain 9120 sequence-verified cDNAs, including 8281 unique UniGene clusters, among which 7102 represent named genes and 1179 represent EST clusters.
Most of the experiments were performed by incubating slides at 65°C for 16–18 h in sealed hybridization chambers with 20 µl (for 6.5k- and 6.4k-microarrays) or 40 µl (for 9k-microarrays) of hybridization mixture (without formamide) placed under the coverslips. A small number of 6.4k-microarrays were prehybridized in 5x SSPE-5x Denhardt’s Solution-0.1% SDS at 42°C for 1 h, washed in distilled H2O for 4 min at room temperature, dehydrated in isopropanol for 1 min., and dried by centrifugation at 150 x g for 5 min at room temperature. Twenty µl of a hybridization mixture containing 50% formamide were placed under the coverslip, and slides were incubated in sealed hybridization chambers at 42°C for 16–18 h.
After hybridization, slides were washed at room temperature in 2x SSC-0.1% SDS (5 min), 2x SSC (2 min), 1x SSC (1 min), and 0.2x SSC (30 s), and were dipped in 0.05% SSC. Slides were dried by centrifugation at 150 x g for 5 min. at room temperature.
Data Acquisition and Analysis.
Microarrays were scanned with an Axon 4000 laser scanner, and primary image analysis was performed with GenePix Pro 3.0 Software (Axon Instruments, Inc.). Images were also visually inspected, and questionable spots were flagged and excluded from the analysis. Multidimensional scaling, clustering of genes and arrays, and class prediction of arrays were performed with the BRB-ArrayTools (version 2.1) software package developed by the Biometric Research Branch of the Division of Cancer Treatment and Diagnosis of the NCI and The EMMES Corporation (9)
.5
Briefly, background intensities were subtracted, and data were filtered for minimal spot intensity (500 units) in each of the two channels and for missing values (not more than in 20% of arrays). Fluorescence intensity-ratio data were log-transformed and normalized by subtracting the median log-ratio from all of the log-ratios on the array. Average linkage hierarchical clustering of genes and samples and multidimensional scaling of samples were performed by using one minus the Pearson correlation coefficient as a distance metric. Test of statistical significance of sample clustering was accessed when possible by using Euclidian distance as the metric, and the first three principal components as the axes, with the null hypothesis that data samples came from the same multivariate Gaussian distribution (10) .
The Class Prediction module of the BRB-ArrayTools and CCP (11, 12, 13) were used to determine whether the pattern of gene expression allowed classification of samples from proximal and distal colon. First, the t test was used to select genes that showed univariately statistically significant (P < 0.001) differences in expression between the two classes of samples. In batch analysis, each sample was considered as independent, and a t test was performed on average log-ratios of gene expression for two classes, whereas in paired analysis, average differences in gene expression log-ratios of pairs of samples (ascending colon and descending colon biopsies) from the same patient were analyzed by t test. Then a CCP was calculated as a linear combination of log-ratios (or log-ratio differences) weighted by univariate t values (13) . The CCP value was calculated for each sample (or pair of samples) and, as a classification threshold, the mean of the average CCP for two classes was used for batch analysis, and the sign (positive or negative) of the CCP was used for paired analysis. The misclassification rate was estimated by leave-one-out cross-validation. Specifically, a sample (or a pair of samples in case of paired analysis) was omitted and a CCP was developed from scratch using the included samples. This step included performing the t tests, recalculating the CCP and classification threshold for the remaining samples, and applying the new CCP values to classify the omitted sample (or pair of samples). This was done independently for each omitted sample (or pair of samples). The ratio of "samples incorrectly classified in cross-validation":"the total number of samples" yields the misclassification rate. Permutation P for the misclassification rate for the CCP was calculated by 2000 random permutations of class labels and a repeated cross-validation procedure for each permutation. The proportion of the random permutations that gave the same or smaller misclassification rate as was obtained with true class labels is presented as a (permutation) P for CCP, and a value of P < 0.0005 was reported when no random permutation of class label was found among 2000 with the same or smaller misclassification rate as for true class labeling.
For quality assurance purposes, real-time RT-PCR was used to study expression of several cDNA sequences present on our arrays. RT-PCR was performed in LightCycler with LightCycler-RNA Amplification Kit SYBR-Green I using gene-specific primers according to the manufacturer’s instructions (Roche). RT-PCR data on the relative expression of these cDNAs were in general agreement with microarray hybridization results.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Biopsies from 50 HNPCC patients were analyzed on a total of 118 microarrays (with sets of ascending-colon and descending-colon biopsies from two patients analyzed twice on 6.5/6.4k-arrays and from six patients analyzed on 6.5/6.4k- and 9k-arrays; on analysis, data for the same biopsies were averaged and considered as one sample). As shown, on analysis of 42 9k-microarray data files generated with biopsies from 21 HNPCC patients, there are reproducible and significant differences in the gene expression profile in ascending-colon and descending-colon biopsies. After filtering, 744 of 7810 genes showed statistically significant (P < 0.001) differences in expression (Fig. 1
; Supplementary Table 1).1
All of the biopsies were correctly classified in leave-one-out cross-validation.
|
Analysis on 9k-arrays of 26 colon biopsies from 13 patients without predisposition to colon cancer (non-HNPCC patients) also showed differences in gene expression between the ascending and descending colon. Of 8818 genes that met the analysis criteria, 658 genes showed statistically significant (P < 0.001) differences in expression between ascending-colon and descending-colon biopsies (Supplementary Fig. S1; Supplementary Table 2).1 In cross-validation, the corresponding CCPs allowed correct classification of all of the samples (P < 0.0005).
A CCP that was built on 9k-array data for ascending-colon and descending-colon biopsies from HNPCC patients allowed correct classification of all ascending-colon and descending-colon biopsies from non-HNPCC patients (P < 0.0005), and a classifier built on samples from non-HNPCC patients predicted correctly 20 of 21 pairs of biopsies from HNPCC patients (P < 0.0005; data not shown). Thus, there are common differences in gene expression between the ascending and descending colon of HNPCC and non-HNPCC patients.
Samples from HNPCC and non-HNPCC patients, all hybridized on the same 9k-array platform, were then analyzed together (Fig. 2)
. In the combined set of all colon biopsies from HNPCC patients (42 ascending-colon and descending-colon biopsies) and non-HNPCC patients (26 biopsies), statistically significant differences between ascending-colon and descending-colon samples were found in the expression of 1336 genes (of 7994 genes that passed filtering criteria; Supplementary Fig. S2; Supplementary Table 3).1
Most of the genes that were found to be expressed differentially in ascending-colon and descending-colon biopsies in separate analyses of samples from HNPCC patients (93.7%) and from non-HNPCC patients (78.4%) were present in the list of 1336 genes obtained on analysis of the combined samples. All of the samples were classified correctly on cross-validation, with a pair of biopsies from a patient with a right hemicolectomy having the only borderline CCP value.
|
. Most of the genes (85%) that were found on the analysis of samples from patients without surgery were also identified as expressed differentially in the analysis of the combined group of patients, and vice versa.
|
To determine whether the differences in gene expression in adult ascending and descending colon are established in embryonic or postnatal development, 26 samples of embryonic colonic mucosal cells (13 paired samples from ascending and descending colon) were analyzed. Statistically significant differences between ascending colon and descending colon samples from the fetal colon were found in the expression of 87 genes (Fig. 3
; Supplementary Fig. S4; Supplementary Table 5).1
The probability of having, by chance, at least 87 of 9013 genes pass the filtering criteria, as defined by showing differences in expression at P = 0.001, is 0.005 by permutation analysis. Twenty-four of 26 samples are classified correctly by using the CCP (P < 0.0005). Twenty-four of these 87 genes are included in the list of CCP genes that showed differences in expression between ascending-colon and descending-colon samples from adult colon. However, only 11 of these 24 show the same directional (i.e., increased expression in right versus left colon and vice versa) differences in fetal and adult mucosa.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
. These include cell cycle, proliferation, cell death, response to external stimuli, stress response, and DNA replication and damage repair. Differentially expressed genes are implicated in major signaling pathways important for colon tumorigenesis, including EGF, TGFß, Wnt, Ras, insulin, and integrin signaling. For most of the functional groups, the relative number of genes that are expressed higher in the left compared with the right colon corresponds to a 2:1 ratio that is characteristic of the total set of the CCP genes, but for some groups the biases are more extreme. For example, 90% of the genes from cell cycle and DNA metabolism groups are overexpressed in the left colon (see below), whereas the number of overexpressed genes that are involved in cell death, Wnt, and Ras signaling is approximately the same in the ascending and the descending colon.
|
(16
, 17)
, Bak (18)
, cErbB2 (19)
, EGFR (20)
. These did not show variation in mRNA expression in the right and left colon segments in our experiments. c-Ha-ras was found to show differential right versus left expression in inflamed colon mucosa (21)
but did not emerge in our analysis of normal mucosa. A handful of other genes [Cdx2 (22)
and genes for gastric M1 and intestinal M3 antigens (23)
] were not included on our arrays.
Masys et al. (24)
have developed an approach to the interpretation of differences in gene expression through the analysis of associations between genes in a particular set and medical subject headings (MeSH) terms in published literature (e.g., presented in the Medline database), combined with an estimate of the probability of getting a number of associations by chance. We used the publicly available interface to the High-density Array Pattern Interpreter (HAPI) system6
to analyze genes expressed differently in the ascending and the descending colon. The analysis is somewhat hampered by the fact that only 
30% of genes in the Incyte UniGEM set of cDNAs printed on 9k-arrays have one or more linked citations (Ref. 24
; this is also true for the set of genes expressed differentially in right and left colon), and by the current limitations in the number of genes that can be analyzed (250) in one set. Nevertheless, a few conceptual associations were immediately evident when the set of 165 genes that showed a 
2-fold difference in expression in ascending-colon and descending-colon biopsies was analyzed. For example, there is a significant association of these genes with inorganic and organic chemicals subject areas. Separate analysis of genes overexpressed in right and left colon indicates that inorganic chemical subject area terms (ions, anions, and electrolytes) are associated mainly with genes overexpressed in the right colon, whereas organic chemical terms (carboxylic acids and acyclic acids) are linked to both sets of genes. These associations suggest differences in the physiology of the ascending and the descending colon. The large bowel is considered an appendage of the digestive tract with a relatively simple principal function in conservation of salt and water and disposal of waste material. The proximal colon is involved in the solidification of fecal contents through the absorption of water and electrolytes. The distal colon is used for transient storage of feces and is less involved in ion, anion, and electrolyte transport.
Genes overexpressed in the right colon are also associated with terms in heterocyclic compounds, polycyclic hydrocarbon, and steroids subject areas. Among these genes, several members of the cytochrome P450 family (CYP2C8, CYP2C18, and CYP4F12) are expressed 1.7- to 4.5-fold higher in the right colon, and so are genes for glutathione S-transferases Z1 (GST Z1, 1.2x), 3-ß-hydroxysteroid dehydrogenase 1 (HSD3C4, 1.7x) and hydroxysteroid (17ß) dehydrogenase (2.4x). This pattern of gene expression indicates that, if overexpression of genes is equally reflected in protein level and function, the right colon compared with the left colon may be better protected against procarcinogenic heterocyclic compounds in food. It is also possible that overexpression of these genes reflects greater exposure of the right colon to certain procarcinogenic compounds and concomitant induction of responsive genes rather than constitutive protection from such compounds. Better protection of the right colon against DNA damaging carcinogens is also evidenced in the lower level of O6-methylguanine in DNA of the proximal colon as compared with DNA derived from the distal colon (25) . On a population level, the higher level of expression of 3-ß-hydroxysteroid dehydrogenase also serves in protection against tumorigenesis, as was shown in a study of prostate cancer susceptibility (26) .
Most of the genes implicated in cell cycle control (notably genes encoding cyclins D1, D2, and G1; cyclin-dependent kinase 2; and PCNA), and all but three genes involved in DNA replication, DNA damage repair, and DNA-adduct metabolism, are overexpressed in the left colon. This suggests that control of cell proliferation and DNA damage repair may be different in the right and left colon, reflecting perhaps a higher proliferative activity in the distal colon (27) . Together with the differences in metabolism of procarcinogenic and carcinogenic compounds in the right and left colon mentioned above, these differences in cell cycle and DNA damage control may suggest a basis for the distinct susceptibilities of right versus left colon to certain pathways of tumorigenesis. It is provocative that several members of the cytochrome P450 and apolipoprotein families of genes whose polymorphic variants (with different enzymatic activities) have been shown to be associated with variations in colon cancer risk (28) show differential expression in ascending and descending colon.
Future studies of gene expression in the ascending and descending colons of patients from different geographic regions with different patterns (compared with this North American population) of CRC incidence, and different ratios of microsatellite-stable to microsatellite-unstable CRC may help to clarify the relevance of these observed differences in gene expression to colorectal carcinogenesis.
The number of genes expressed differentially in ascending and descending fetal colon is substantially smaller than the number of genes expressed differentially in adult colon, indicating that a more robust and distinctly different pattern between left and right colon is acquired during postnatal life. Three stages are distinguished in human colon development: appearance of stratified epithelium (8 to 10 weeks of gestation), conversion of this epithelium to a villous type with partially developed crypts (12 to 14 weeks), and establishment of the adult type crypt epithelium at 30 weeks of fetal development (29)
. Because gene expression was compared in 17–24-week-old fetuses, it is possible that the pattern of gene expression that is characteristic of adult right and left colon is established later, concurrent with the transformation to the adult type colonic epithelium at 30 weeks of gestation, or subsequently, in response to exposure of the gastrointestinal tract to food. The existence of a developmental program that leads to a distinct pattern of gene expression in ascending and descending colon is nevertheless suggested to be in place by 24 weeks of age.
This suggestion of a fetal developmental program creating distinct gene expression patterns in ascending and descending colon is based on a relatively few genes. We wished to gain an appreciation of whether such small differences might still be informative. To address this question, we compared patterns of gene expression in female versus male colon. Only 16 genes were found to be differentially expressed in a batch analysis of 28 female ascending-colon and descending-colon biopsies and 22 male colon biopsies, all from patients without surgery (the probability of getting at least 16 genes significant at the 0.001 level of 8296 filtered genes by chance is 0.088). Nevertheless, all 50 biopsies were classified correctly with the CCP (P < 0.0005). Eleven of 16 genes are localized on the sex chromosomes: 8 genes overexpressed in male colon are Y-chromosome linked, and 3 genes overexpressed in female colon are X-chromosome linked. The observed pattern offers some reassurance that even small differences in gene expression patterns between two distinct sample sets can be meaningful and informative.
An analysis of biopsies from patients with colon surgery indicates that the gene expression profile of colonic mucosal cells embryologically derived from right and left colon can be modulated after surgery to correspond to the new proximal (in case of right hemicolectomy) or distal (after left hemicolectomy) location. To what extent differences in gene expression in ascending and descending colon are programmed in development, and to what extent they are established postnatally and can be modified by interaction with aging and diet, or by surgery, is one area for future investigation.
|
Footnotes |
|---|
1 Please see Supplementary Data for this article at http://cebp.aacrjournals.org. 
2 To whom requests for reprints should be addressed, at Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda MD 20892. Fax: (301) 496-0047; E-mail: kirschi{at}exchange.nih.gov
3 The abbreviations used are: CRC, colorectal carcinoma; MSI-H, high level of microsatellite instability; NCI, National Cancer Institute; NNMC, National Naval Medical Center; HNPCC, hereditary nonpolyposis colorectal cancer; aRNA, antisense RNA; RT-PCR, reverse transcription-PCR; CCP, compound covariate predictor.
4 Internet address: http://nciarray.nci.nih.gov/.
5 Internet address: http://linus.nci.nih.gov/brb.
6 Internet address: http://array.ucsd.edu/.
Received 1/27/03; revised 4/17/03; accepted 4/27/03.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
and epidermal growth factor receptor in colonic mucosa in active and inactive inflammatory bowel disease. Growth Factors, 18: 79-91, 2000.[Medline]
, and EGF-R in human colorectal adenocarcinoma. Acta Oncol., 37: 285-289, 1998.[Medline]
This article has been cited by other articles:
|
|
 |
|
  L. C. LaPointe, R. Dunne, G. S. Brown, D. L. Worthley, P. L. Molloy, D. Wattchow, and G. P. Young Map of differential transcript expression in the normal human large intestine Physiol Genomics, March 10, 2008; 33(1): 50 - 64. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Bedard and K.-H. Krause The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology Physiol Rev, January 1, 2007; 87(1): 245 - 313. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Csillag, O. H. Nielsen, R. Borup, F. C. Nielsen, and J. Olsen Clinical phenotype and gene expression profile in Crohn's disease Am J Physiol Gastrointest Liver Physiol, January 1, 2007; 292(1): G298 - G304. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. K. Glebov, L. M. Rodriguez, P. Soballe, J. DeNobile, J. Cliatt, K. Nakahara, and I. R. Kirsch Gene Expression Patterns Distinguish Colonoscopically Isolated Human Aberrant Crypt Foci from Normal Colonic Mucosa. Cancer Epidemiol. Biomarkers Prev., November 1, 2006; 15(11): 2253 - 2262. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. M. Sodir, X. Chen, R. Park, A. E. Nickel, P. S. Conti, R. Moats, J. R. Bading, D. Shibata, and P. W. Laird Smad3 Deficiency Promotes Tumorigenesis in the Distal Colon of ApcMin/+ Mice. Cancer Res., September 1, 2006; 66(17): 8430 - 8438. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. K. Glebov, L. M. Rodriguez, P. Lynch, S. Patterson, H. Lynch, K. Nakahara, J. Jenkins, J. Cliatt, C.-J. Humbyrd, J. DeNobile, et al. Celecoxib treatment alters the gene expression profile of normal colonic mucosa. Cancer Epidemiol. Biomarkers Prev., July 1, 2006; 15(7): 1382 - 1391. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Ferretti, A. Felici, F. Cognetti, and M. Mandala Is there a right-sided shift for colorectal cancer in women compared with men? Cancer Epidemiol. Biomarkers Prev., May 1, 2006; 15(5): 1054 - 1054. [Full Text] [PDF]
|
|
|
|
|
|
K. Irby, W. F. Anderson, D. E. Henson, and S. S. Devesa Emerging and widening colorectal carcinoma disparities between blacks and whites in the United States (1975-2002). Cancer Epidemiol. Biomarkers Prev., April 1, 2006; 15(4): 792 - 797. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. P. Giacomini, S. Y. Leung, X. Chen, S. T. Yuen, Y. H. Kim, E. Bair, and J. R. Pollack A Gene Expression Signature of Genetic Instability in Colon Cancer Cancer Res., October 15, 2005; 65(20): 9200 - 9205. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. L. Pool-Zobel, V. Selvaraju, J. Sauer, T. Kautenburger, J. Kiefer, K. K. Richter, M. Soom, and S. Wolfl Butyrate may enhance toxicological defence in primary, adenoma and tumor human colon cells by favourably modulating expression of glutathione S-transferases genes, an approach in nutrigenomics Carcinogenesis, June 1, 2005; 26(6): 1064 - 1076. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. H. Olesen, L. L. Christensen, F. B. Sorensen, T. Cabezon, S. Laurberg, T. F. Orntoft, and K. Birkenkamp-Demtroder Human FK506 Binding Protein 65 Is Associated with Colorectal Cancer Mol. Cell. Proteomics, April 1, 2005; 4(4): 534 - 544. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K Birkenkamp-Demtroder, S H Olesen, F B Sorensen, S Laurberg, P Laiho, L A Aaltonen, and T F Orntoft Differential gene expression in colon cancer of the caecum versus the sigmoid and rectosigmoid Gut, March 1, 2005; 54(3): 374 - 384. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W.-Y. Huang, N. Chatterjee, S. Chanock, M. Dean, M. Yeager, R. E. Schoen, L.-F. Hou, S. I. Berndt, S. Yadavalli, C. C. Johnson, et al. Microsomal Epoxide Hydrolase Polymorphisms and Risk for Advanced Colorectal Adenoma Cancer Epidemiol. Biomarkers Prev., January 1, 2005; 14(1): 152 - 157. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. S. Patten, M. J. Adams, J. A. Dallimore, and M. Y. Abeywardena Depressed Prostanoid-Induced Contractility of the Gut in Spontaneously Hypertensive Rats (SHR) Is Not Affected by the Level of Dietary Fat J. Nutr., November 1, 2004; 134(11): 2924 - 2929. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention |
