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Carcinogenesis |
Centre Lorrain d’Etudes et de Recherches sur les Cancers Pulmonaires, Faculté de Médecine, 54505 Vandoeuvre-Lès-Nancy, France [N. M., G. F., T. L., H. F., R. V., E. P., D. L. F., J. S., J. B., T. B., J-M. V., Y. M.]; Hopital Universitaire, Service d’Epidémiologie, 54000 Nancy, France [F. A.]; Hopital Universitaire, Service de Biologie Moléculaire, 67098 Strasbourg, France [M-P. G.]; and Centre Jules Bordet, 1000 Bruxelles, Belgium [P. V.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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2 tests showed significant differences
(P < 0.05) when comparing the results
obtained from never smokers, smokers, squamous metaplasia,
dysplasia + in situ carcinoma, and tumors.
Microsatellite changes occurred frequently in all samples, but without
specificity for any group (P < 0.08–0.52). They were globally correlated with tobacco exposure
(P < 0.04), for which the
RAR-
marker appeared as a preferential target
(P < 0.004). Few reparation error
phenotypes were observed, mostly at the
RXR-
and RXR- markers for which combined
changes were also linearly increasing from never smokers to
dysplasia + in situ carcinoma
(P < 0.05 and P < 0.03). RAR-ß marker losses also increased from
the first to the last group studied (P < 0.01), with a concomitant decrease in RAR-ß protein expression and
correlated p53 increased immunoreactivity (P < 0.02). Losses at 3p14, 3p21, and
P16 were frequent, but no significant differences
between groups could be found. Unexpectedly, high constitutive
homozygosity was observed near the RAR- locus in
squamous cell lung cancer cases. RARs/RXRs form homodimers
or heterodimers involved in ligand binding. Their added alterations
could result in a state of functional vitamin A deficiency in the
affected bronchial cells. Further deletion events drawn from a limited
repertoire of specific regions such as 3p14–21 and
9p21 could subsequently drive the deficient cells to
invasive carcinoma. |
INTRODUCTION |
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Vitamin A and related retinoids are known to regulate normal lung
development, maturation, and maintenance of the bronchial epithelium.
Chronic vitamin A deficiency in hamsters results in the replacement of
normal tracheal epithelium by a pseudostratified squamous epithelium.
Reversal occurs when vitamin A is restored to the diet. A similar
phenomenon occurs in vitro in retinoid-deprived bronchial
cells (12)
. The control of gene expression by retinoids is
complex and depends on the nature of the ligand, the type of
ligand-binding proteins, and the interacting nuclear retinoid receptor
genes. They include two different families: the RAR and
RXR, with three subtypes for each (, ß, and ) and
several isoforms arising from promoter usage and alternate splicing. In
addition, the RARs/RXRs form homodimers and/or heterodimers that bind
to cis-acting response elements of retinoid target genes and
interact also with varied coactivators or corepressors. RXRs are
unusual because they bind to their response elements as homodimers.
They also associate with many other hydrophobic ligand receptors such
as the peroxisome proliferator-activated receptors. Thus, the retinoids
extend their function to cross-modulate specific cell surface receptor
signaling pathways (for review, see Ref. 13
).
Retinoids have been tested in cancer prevention, but with somewhat puzzling results (14 , 15) . RAR-ß is the best-studied member of the RAR family in the lung cancer process. It is believed to function as a tumor supressor gene (16 , 17) . By studying nucleic acids as well as the encoded proteins (18) , we reported that RAR/RXR had modified combined expression in lung tumors. The extension of the study to lung precursor lesions was difficult because tissue fixation is necessary for reliable identification and results in nucleic acid degradation. Moreover, the small size of the lesion precludes extensive immunohistochemistry screening. However, a microsatellite located near the RAR-ß gene (D3S1283) was found to be very useful in reflecting the gene status in lung tumors. Therefore, RARs/RXRs were targeted for more allelotyping studies testing RAR-ß protein expression in premalignant lesions in an effort to further define the early roles of RAR/RXR in lung cancer.
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MATERIALS AND METHODS |
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A control population without lung cancer was recruited from the archived samples of consecutive patients operated on at our institution between 1997 and 1999. It included patients who were either current smokers (n = 16) or lifelong never smokers (n = 8). As described above, an examination of the free resection margin was conducted.
Other sets of patients recruited at our institution were tested only
for their constitutional status at the RAR- and
RAR- markers as described in the DNA section. Set
1 consisted of 50 current smokers who were enrolled successively in
1999 for an ongoing smoking cessation program. They were paired in sex,
age (± 2 years), and tobacco consumption (±2 pack/year) with the
smoker population described above. Set 2 included the 40 patients with
squamous cell lung carcinoma who were described previously (2
, 18)
. Set 3 included 62 cases of pleural mesothelioma diagnosed
between 1988 and 1998 at our institution that have been confirmed by
the French Mesopath Panel. The patient and control populations are
described in Table 1
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DNA Purification.
Five to ten consecutive sections of each lung cancer precursor lesion
(n = 66), tumor (n = 4), and free resection margins from never smokers (n
= 8) and smokers (n = 16) were used to
separately collect all types of bronchial cells and paired normal
control cells whenever necessary (n = 44)
under the basal membrane by microdissection as described previously
(8)
. Normal healthy tissue and paired tumor
(macrodissected) obtained during surgery and kept frozen at -80°C
were also used for DNA preparation (n = 31)
with tissue proteinase K digestion for 24–72 h, phenol/chloroform
extraction, and further ethanol precipitations.
For the set 1 subjects, blood DNA was prepared with the Nucleon BACC3 kit from Pharmacia (Orsay, France). For sets 2 and 3, frozen normal lung tissue from patients with squamous cell lung carcinoma or microdissected (mesothelioma) normal tissue provided constitutional DNA.
DNA Amplification.
All of the reagents and the apparatus were from Pharmacia unless
otherwise specified. All sense primers were labeled in 5' with CY5. The
microsatellites were CA repeats chosen on the Genethon
site,4
where the sequences of the flanking primers were also found.
They were as follows: (a) at 17q12, D1751804
(RAR-); (b) at 3p24.2, DS1283
(RAR-ß); (c) at 12q13.13, D12S368
(RAR-); (d) at 9q34.3, D9S158
(RXR-); (e) at 6p21, D6273
(RXR-ß); (f) at 1q23, D1S2635
(RXR-); (g) at 3p14.2, D3S1300;
(h) at 3p21, D3S1582; and (i) at
9p21, D9S171 (P16). Microsatellite amplifications
were performed in a minithermocycler from MJ Research (Watertown, MA).
Duplex PCRs were accomplished in a 10-µl final volume including 0.20
µl of Taq polymerase, 0.8 µl of PCR mix, 0.8 µl of the four
deoxynucleotide triphosphate mixture (2
mM), 0.8 µl of each primer pair (10
pM), and 1 µl of DNA (10–50 ng). The PCR
cycles were as follows: (a) a 10-min hot start at 95°C;
(b) 38 cycles of 94°C for 35 s, 65°C for 1 min, and
70°C for 1 min; and (c) a final extension step at 70°C
for 10 min. At the end of the PCR, 4 µl of loading dye (Dextran 2000;
5 mg/ml in deionized formamide) were mixed with each reaction, and 9
µl of the mixture were heat-denatured and further electrophoresed on
7 M urea-acrylamide (6%) gels using an Alf
express sequencing machine fitted with short plates. CY5-labeled
molecular weight markers (100, 150, and 200 bp) were deposited on each
side of each gel. Duplex PCRs were always performed using the following
primer sets together: (a) 3p14/3p21;
(b) RAR-/RXR-; (c)
RAR-/P16; and/or (d)
RAR-ß/RAR-. PCRs for only one microsatellite at
a time were also performed with the same protocol. The results were
analyzed online with the Allele Links software. LOH was defined as a
complete disappearance of either microsatellite alleles in the
bronchial cells or in the tumors when compared with the heterozygous
paired normal sample. All patients were first screened for their
constitutional status for a given microsatellite before proceeding to
allelotyping of the sample. RER was present when, in a constitutional
heterozygous sample, the size of the paired lung cancer precursor
lesion or tumor alleles shifted. Whenever LOH or RER was
observed, the experiment was repeated for confirmation. Representative
data are shown on Fig. 1
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Microsatellite Changes.
The allelotyping results were broken down into five sample
"progression" groups: (a) never smokers; (b)
smokers; (c) squamous metaplasia; (d)
dysplasia + ISC; and (e) tumors. Because DNA was
not available for all experiments, the number of observed abnormalities
or microsatellite changes in each group and for a given microsatellite
is expressed as a percentage and as a ratio: LOH + RER number
in the samples:number of heterozygous paired samples. All of the data
are shown in Table 2
, in addition to the immunohistochemistry results of our previous
studies (2
, 18)
.
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2 test. ANOVA was realized with the
Kruskal-Wallis test, and mean comparisons were performed using the
Mann-Whitney test. Microsatellite changes from never smokers to tumors
and from never smokers to dysplasia + ISC were also tested
with a 2 test for trended linear progression.
The association of any microsatellite change with smoking, age, p53
immunohistochemistry results, and differences in the repartition of
constitutional heterozygous samples was considered for each
microsatellite and between groups. |
RESULTS |
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, microdissection was very efficient to
prepare separate specific DNAs with consequently complete rather than
near complete LOH in the specimens. The amplicon peak was often larger
for the remaining allele. Although tumors were carefully macrodissected
(70% of tumor cells), it is possible that LOHs have been hidden by the
stromal cells. RER by allele expansion (Fig. 1
, panel 6) was
observed once at the RAR- marker in sample 23P, three
times at the RXR- marker in samples 4T,
39T, and 18(g)P, once at 3p14 in 57 but 7 times
at the RXR- marker in samples 7T,
10T, 20P, 24P, 30T,
37P, and 61 with DNA prepared from either fixed or frozen tissue
(underlined sample numbers). There were neither global
(P < 0.63) nor individual
(P < 0.08–0.52) microsatellite change
differences between the five sample groups (Table 3)
. The overall
number of microsatellite changes was correlated to the level of tobacco
consumption (P < 0.04) but not to
the age of the patients (P < 0.82).
Microsatellite changes at the RAR- marker were rare in
most specimens, but the microsatellite informativity was low in
precursor lesions (22%) and tumors (23%). LOHs at the
RAR-ß marker were present in all types of precursor
lesions (35%) and tumors (60%) and were even seen in smokers (22%).
There was an increasing number of LOHs at this marker from group 1 to
group 5 (P < 0.01), with no significant
difference in the repartition of heterozygous samples in all groups
(P = 0.3). LOH at the RAR-
marker was common, but the microsatellite informativity was low in
premalignant specimens (28%) and tumors (29%). LOH at this locus was
strongly correlated with tobacco consumption expressed in pack/years
(P < 0.004). LOH or, more often, RER for
D9S158 (RXR-) was rarely observed in precursor specimens
(11%) and in smokers (29%) but was more frequently seen in tumors
(35%). However, the repartition of heterozygous samples in the five
groups was nonhomogenous (P = 0.2). LOH at
the RXR-ß marker was frequent, but with a low overall
microsatellite informativity in all groups. There was a significant
increase in the microsatellite changes for the RXR-
marker from groups 1 through 4 (P < 0.03).
Microsatellite changes for D3S1300 (3p14) were
frequent in all specimens, but with a linear decrease in the number of
heterozygous samples from groups 1 to 5. LOH at the 3p21
locus was also common, with a higher but not significant prevalence
seen in the dysplasia + ISC group. LOH at the P16
microsatellite was present in 40% of smokers, 44% of precursor
lesions, and 71% of tumors. Six patients had several premalignant
lesions for which the allelic losses were not similar. Moreover,
different microsatellite alleles were also lost in the different
specimens (patients 1, 6, and 12).
Lung cancer precursor lesions analyzed in this study (Table 2)
were
paired with nine tumors that were screened previously by
semiquantitative immunohistochemistry for the expression of
RAR-, RAR-ß, RXR-, and
RXR-ß and by quantitative reverse transcription-PCR for
RAR- expression in specimens 27T and 29T. The
allelotyping data are fully consistent with the immunohistochemistry
results: a decrease in RAR-ß is accompanied by LOH in heterozygous
samples; whereas increased or normal RAR- and
RXR- expression did not coincide with any microsatellite
change. With regard to the RXR-ß and RAR-
testing, the data are inconsistent. In premalignant specimens 12a, 14,
and 35, LOH at the RAR-ß marker and decreased RAR-ß
immunostaining were concomitant (Fig. 2
) whereas no decrease in RAR-ß expression and no change
for D3S1283 were seen in premalignant samples 12e, 23, and 24.
P53-positive staining was observed for only 35% of dysplasias but in
all ISCs and in all paired tumors (except for one case) and therefore
strongly correlated with the higher grade of lung cancer precursor
lesion (P < 0.001). RAR-ß LOH
was also correlated with P53-positive staining (P < 0.02).
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and RAR- markers: 40 more subjects (test 1
population), for a total of 66 squamous cell lung carcinoma cases; 48
more smokers (test 2 population) without lung cancer, for a total of 64
subjects and for comparison: 62 mesothelioma (test 3 population).
Patients with squamous cell lung carcinoma were less heterozygous than
expected for both the RAR- (36%) and RAR-
(29%) markers. Smokers were more heterozygous for the
RAR- microsatellite (58%) but were equally as homozygous
for the RAR- microsatellite (27%). The low rate of
heterozygosity at both loci persisted when the 18 additional
nonsquamous cell lung tumors were included (36% and 29%,
respectively). By contrast, in mesothelioma, 70% and 44% of subjects,
respectively, were found to be heterozygous. |
DISCUSSION |
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marker,
which is, in fact, close to the RAS gene, an oncogene known
to play a role in lung cancer, and to the fragile site FRA
12A. Interestingly, losses of this marker were correlated with
tobacco exposure. However genetic losses were not consistent with our
previous results in tumors 27 and 29. D6S273 has just been moved on the
Genethon map from 6p11 to 6p22, near to the
keratin gene cluster. High levels of homozygosity were found in all
studied samples, and hemiallelic losses did not match the previous
immunohistochemistry results. However, Virmani et al.
(19)
reported that 6p21 is a region of frequent
allelic losses in non-small cell lung cancer. Unfortunately, there were
no reliable RXR- antibodies to match the RXR- marker
allelotyping results. As shown in Table 2
, the allelotyping data of the
other microsatellites were mostly consistent with the previous tumor
immunohistochemistry screening. For the RAR- marker,
there was neither tumoral LOH nor decreased gene expression, but there
were too many homozygous samples. Immunohistochemistry performed on
five lung cancer precursor lesions with or without LOH for D3S1283
demonstrated decreased expression of the RAR-ß gene when
there was also a LOH. A similar concordance was found previously in
75–86% of 76 lung tumors (18)
. Allelic losses were
already present in smokers, but not in lifelong never smokers. However,
from so few cases, it is difficult to conclude any tobacco
carcinogen-specific action. Decreased RAR-ß quantity would impair
heterodimerization with RXR partners. In combination with other
RAR/RXR disruptions (promoter methylation), this could
result in a functional cellular retinoid deficiency. Similar events
have been described recently for RAR- and
RXR- in the skin as a consequence of UV irradiation
(20)
. Lung tumors were found to overexpress the RXR-
protein in combination with RAR-ß underexpression (18)
,
possibly as an adaptation to retinoid deficiency. Normal expression or
overexpression of RXR- has also been observed in breast tumors and
mouse skin tumors (21)
. Conflicting results placing
microsatellite instability in lung tumors between 0% and 60% have
been published previously (22
, 23)
. We recently
participated in extensive lung tumor allelotyping (18
, 24)
, and although different methodologies were used, the results
were consistent: RERs were rare. For the present study, fixed or
unfixed tissues were used, and, as found previously, RERs were rare.
The discrepancies might depend on: (a) the type of
polymorphic marker used (CA repeats versus trinucleotides or
tetranucleotides, for which the spontaneous rate of mutation can be
very high); (b) the criteria used to define RER as a
shifting of one or both alleles; and (c) microsatellite
instability as RER at one or several markers. Low polymorphism of
microsatellites at certain loci may be explained by the rather
conservative structure of the genes lying at such loci. In squamous
cell lung carcinoma, the frequency of homozygosity at D17S1804
(RAR-, 17q12) was unusual and was not found in
smokers or in patients with mesothelioma. However, higher rates of
homozygosity at D12S368 (RAR-, 12q13.13) were
found in both squamous cell lung carcinoma and smokers by comparison
with mesothelioma cases. The clinical and biological significance of
such homozygosities needs to be investigated carefully, even in
comparable ethnic populations, to eliminate a founder effect. Indeed,
homozygosities could favor altered DNA recombinations.
In general, it is thought that molecular damage incidence increases as
histopathological lung cancer precursor lesions progress from
hyperplasia to ISC. Identifying the genes targeted at each step would
reconstitute the natural history of squamous cell lung carcinoma.
However, comparisons between investigations are difficult because of
differences in methodology and in criteria for studying and scoring the
molecular disruptions. The systematic screening of lung tumors for
allelic losses led to the identification of multiple distinct regions
of recurrent deletions at 3p, 17p, 9q,
5q, 13q, 8p, and 11p
(approximately ranked by decreasing frequency), suggesting that these
regions contain unidentified genes involved in lung cancer
(24)
. Based on these findings, allelic losses have been
reported in lung cancer precursor lesions mainly on 3p and
9p regions (4
, 9, 10, 11
, 25)
. Four hot spots have
been identified in lung tumors at 3p12, 3p14,
3p21, and 3p25, and a candidate tumor supressor
gene at 3p14, fragile histidine triad (FHIT), has
been cloned (26)
. Whereas LOH at 3p14 has been
associated with the presence of aberrant transcripts that involve
partial deletions of this gene, other studies have suggested that LOH
can occur without abnormalities and is influenced by the proximity of
the FRA 3B region on which tobacco
exposure may be causal (27)
. This might also be the case
for the RAR- marker used here. Transfer of DNA fragments
from 3p21.3 into tumor cell lines suggested that the region
has tumor supressor gene activity (28)
. The protein
tyrosine phosphatase gene and a mitogen-activated protein kinase are
potential candidates located on 3p21, whereas others have
been eliminated (25)
. P16/CDKN2 is located on
9p21; a high percentage of alterations of this gene has been
observed in many tumors types, but the frequency of LOH found in lung
tumors is higher than the frequency of mutations, suggesting that other
tumor supressor genes reside on 9p (25)
. The
size of the lung cancer precursor lesion prevents fine mapping, but the
3p21 region remains a good candidate for tumor supressor
gene localization.
Allelotyping data have been obtained in current smokers, former smokers, and nonsmokers for normal and abnormal bronchial epithelium. Wistuba et al. (6) studied several microsatellites at the 3p14–21-24 loci and the retinoblastoma, P53, and P16 (D9S171) regions. No molecular changes were found in nonsmokers, but interpretation of the findings was potentially limited by the different age distribution of the nonsmokers, who were significantly younger than the smokers. Among the smokers, there was a modest correlation between the number of molecular changes/subject and smoking exposure, but the variation between current and former smokers was not significant. LOH occurred mainly at 3p (38%) and P16 (23%). At 3p21, LOH was detected in histologically normal epithelium, whereas 3p14 losses were detected only in dysplasia. RER was detected in smokers (64%), even in normal histological specimens. In addition, there was a loss of the same allele of a polymorphic marker in the same patient. By contrast, Mao et al. (5) found few 3p14 LOHs in nonsmokers (20%) but found more in current smokers (85%) than in former smokers (45%); premalignant lesions were also more frequent in current smokers. P16 losses were found in 23% of the specimens. P53 losses at 17p13 reached 18%, but no RER was reported. The alleles lost in the different biopsies for the studied polymorphic markers were different in the same patient. It is difficult to reach a consensus from these studies, but our results concerning the smokers are more in accordance with the latter work.
Several studies have repeatedly shown p53 increased immunoreactivity usually reflective of P53 mutations in premalignant lung lesions (2 , 29 , 30) . Other abnormalities, including an increased cellular proliferation rate (2) and c-myc (2) and bcl-2 overexpression with changes in the keratin pattern toward squamous epithelia, have also been described previously (31 , 32) .
Smoking prevention is the first tool against lung cancer prevention. For former smokers, early detection is necessary because lung cancer prognosis remains poor, despite several therapeutic improvements. Many efforts have been directed toward the identification of biomarkers for early detection of lung cancer (33) and chemoprevention (14 , 25) . This study and our previous study (18) suggest that retinoid deficiency may be among the first events contributing to lung tumorigenesis and imply that retinoids could be used in lung cancer chemoprevention. Aerosolized early on site, they could reverse the deficiency in stabilizing RAR/RXR expression for increased ligand binding to restore normal cellular differentiation. Early lung cancer detection could associate yeast functional assays of RAR-ß and P53 in shed bronchial cells and complementary testing of microsatellites, such as D3S1283, whose loss is correlated with decreased RAR-ß expression.
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FOOTNOTES |
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1 Supported by Action Integrée Franco/Belge
INSERM; Ligue contre le Cancer: Meuse, Moselle, and Vosges; and
Comité National Contre les Maladies Respiratoires et la
Tuberculose. 
2 To whom requests for reprints should be
addressed, at Centre Lorrain d’Etudes et de Recherches sur les Cancers
Pulmonaires, Faculté de Médecine, Bat AB, 9 Avenue de la
forêt de Haye, 54505, Vandoeuvre-Lès-Nancy, France. Phone:
03-83-59-27-57; Fax: 03-83-59-26-85; E-mail: martinet{at}facmed.u-nancy.fr
3 The abbreviations used are: ISC, in
situ carcinoma; RAR, retinoic acid receptor; RXR, retinoid X
receptor; LOH, loss of heterozygosity; RER, replication error
phenotype.
4 ftp://ftp.genethon.fr/pub/Gmap.
Received 7/ 6/99. Accepted 3/29/00.
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REFERENCES |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
-Tocopherol, ß-Carotene Cancer Prevention Study Group. The effect of vitamin E and ß carotene on the incidence of lung cancer and other cancers in male smokers. N. Engl. J. Med., 330: 1029-1035, 1996.
P., Welsh J. A., Trump B. F., Harris C. C. P53 protein accumulates frequently in early bronchial neoplasia. Cancer Res., 53: 4817-4822, 1993.This article has been cited by other articles:
|
|
 |
|
  H. Xiao, X. Hao, B. Simi, J. Ju, H. Jiang, B. S. Reddy, and C. S. Yang Green tea polyphenols inhibit colorectal aberrant crypt foci (ACF) formation and prevent oncogenic changes in dysplastic ACF in azoxymethane-treated F344 rats Carcinogenesis, January 1, 2008; 29(1): 113 - 119. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. E. Carpagnano, M. P. Foschino-Barbaro, G. Mule, O. Resta, S. Tommasi, A. Mangia, F. Carpagnano, G. Stea, A. Susca, G. Di Gioia, et al. 3p Microsatellite Alterations in Exhaled Breath Condensate from Patients with Non-Small Cell Lung Cancer Am. J. Respir. Crit. Care Med., September 15, 2005; 172(6): 738 - 744. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Shinozaki, D. S.B. Hoon, A. E. Giuliano, N. M. Hansen, H.-J. Wang, R. Turner, and B. Taback Distinct Hypermethylation Profile of Primary Breast Cancer Is Associated with Sentinel Lymph Node Metastasis Clin. Cancer Res., March 15, 2005; 11(6): 2156 - 2162. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Brabender, R. Metzger, D. Salonga, K. D. Danenberg, P. V. Danenberg, A. H. Holscher, and P. M. Schneider Comprehensive expression analysis of retinoic acid receptors and retinoid X receptors in non-small cell lung cancer: implications for tumor development and prognosis Carcinogenesis, March 1, 2005; 26(3): 525 - 530. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Vourlekis and E. Szabo Predicting Success in Cancer Prevention Trials J Natl Cancer Inst, February 5, 2003; 95(3): 178 - 179. [Full Text] [PDF]
|
|
|
|
|
|
J.-C. Soria, X. Xu, D. D. Liu, J. J. Lee, J. Kurie, R. C. Morice, F. Khuri, L. Mao, W. K. Hong, and R. Lotan Retinoic Acid Receptor {beta} and Telomerase Catalytic Subunit Expression in Bronchial Epithelium of Heavy Smokers J Natl Cancer Inst, January 15, 2003; 95(2): 165 - 168. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Cave-Riant, B. Cuillerier, M. Beau-Faller, N. Martinet, F. Alla, C. Bronner, A. Schneider, P. Oudet, and M. P. Gaub Association of Genetic Defects in Primary Resected Lung Adenocarcinoma Revealed by Targeted Allelic Imbalance Analysis Am. J. Respir. Cell Mol. Biol., October 1, 2002; 27(4): 495 - 502. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Brabender, K. D. Danenberg, R. Metzger, P. M. Schneider, R. V. Lord, S. Groshen, D. D. Tsao-Wei, J. Park, D. Salonga, A. H. Holscher, et al. The Role of Retinoid X Receptor Messenger RNA Expression in Curatively Resected Non-Small Cell Lung Cancer Clin. Cancer Res., February 1, 2002; 8(2): 438 - 443. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Lippman, J. J. Lee, D. D. Karp, E. E. Vokes, S. E. Benner, G. E. Goodman, F. R. Khuri, R. Marks, R. J. Winn, W. Fry, et al. Randomized Phase III Intergroup Trial of Isotretinoin to Prevent Second Primary Tumors in Stage I Non-Small-Cell Lung Cancer J Natl Cancer Inst, April 18, 2001; 93(8): 605 - 618. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. F. Gazdar, S. Zochbauer-Moller, A. Virmani, J. Kurie, J. D. Minna, and S. Lam RESPONSE: Re: Promoter Methylation and Silencing of the Retinoic Acid Receptor-{{beta}} Gene in Lung Carcinomas J Natl Cancer Inst, January 3, 2001; 93(1): 67 - 68. [Full Text] [PDF]
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