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Endocrinological Oncology |
Laboratoire d’Explorations Fonctionnelles Endocriniennes, Hôpital Trousseau (C.G., V. G., Y.L.B.), 75012 Paris; Clinique des Maladies Endocriniennes et Métaboliques (M.L.R.S., X.B., J.P.L.) and Service d’Anatomo-Pathologie (A.L.), Hôpital Cochin, and Clinique d’Hypertension Artérielle, Hôpital Broussais (P.F.P.), 75014 Paris; and Institut Gustave Roussy (M.S.), 94805 Villejuif, France
Address all correspondence and requests for reprints to: Dr. Christine Gicquel, Laboratoire d’Explorations Fonctionnelles Endocriniennes, Hôpital Trousseau, 26 Avenue Arnold Netter, 75012 Paris, France.
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Abstract |
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Abnormalities of the 11p15 region as LOH (loss of the maternal allele and duplication of the paternal allele) and/or IGF-II gene overexpression are frequent features of the malignant state and were found in 27 of 29 (93.1%) of the malignant tumors and in only 3 of 35 (8.6%) of the benign tumors. Tumors without abnormality of the 11p15 region (mainly benign tumors) did not exhibit pathological functional imprinting. In tumors with mosaicism for 11p15 LOH, biallelic expression of the IGF-II gene was constant in the tumor cell contingent not undergoing LOH. Abrogation of H19 expression correlated with the loss of the maternal allele (LOH or pathological imprinting), but did not always correlate with overexpression of the IGF-II gene.
These data indicate the involvement of dysregulation of the 11p15 region in late steps of adrenocortical tumorigenesis and provide us with new molecular markers for a better diagnostic and prognostic evaluation of adrenocortical tumors.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The adrenal gland produces an array of growth factors, including insulin-like growth factor II (IGF-II) (9, 10, 11, 12). The IGF-II gene maps to the chromosomal 11p15 region, which is subject to parental imprinting. The IGF-II gene is transcribed from the paternal allele (13, 14, 15). Other genes, H19 and p57KIP2, that also map to the 11p15.5 region are imprinted, but unlike the IGF-II gene, it is the maternally derived allele that is active (16, 17, 18). H19 encodes a ribonucleic acid (RNA) that cannot be translated into a protein (19) and might function as a tumor suppressor gene (20). p57KIP2 was recently described as a new cyclin-dependent kinase inhibitor, and its gene is a strong candidate suppressor gene (21). Recently, we showed that loss of the maternal allele with duplication of the paternal allele at the 11p15 locus was frequent in adrenocortical tumors, particularly those that are malignant (22, 23). This abnormality was frequently associated with a high overexpression of the IGF-II gene. This loss of heterozygosity (LOH) of the 11p15 region had previously been reported in embryonic tumors, including Wilms’ tumor, the most frequent tumor of the predisposing Beckwith-Wiedemann syndrome (see Refs. 24 and 25 for reviews). More recently, pathological functional imprinting with biallelic expression of the IGF-II gene was shown in Wilms’ tumors that had not lost heterozygosity at 11p (14, 15). In this model, relaxation of maternal allele was often associated with abrogation of H19 gene expression (26, 27). Deletion of the maternal H19 gene region in mice results in maternal IGF-II gene expression and in a growth advantage in mice inheriting the abnormal H19 gene from their mother (28). Thus, H19 could control the imprinting (and thus the expression) of the IGF-II gene.
Expression of both H19 and IGF-II genes is up-regulated by ACTH in human fetal adrenals (29). Abrogation of H19 gene expression was described in a few sporadic adrenocortical carcinomas, which also exhibited overexpression of the IGF-II gene (30). The details of the effect of 11p15 dysregulation on tumor proliferation are unknown, but it appears to be associated with the malignant phenotype. There is evidence that IGF-II is an important autocrine growth factor (31, 32, 33, 34). Recently, studies on uterine (35), lung (36), and testicular (37) tumors provided evidence that IGF-II genomic imprinting is relaxed not only in childhood tumors, but also in malignant adulthood tumors.
The aims of this study were to evaluate the frequency and distribution of 11p15 region abnormalities and IGF-II gene overexpression in a large series of well documented sporadic adrenocortical tumors and to assess the prognostic value of these molecular markers. To determine whether pathological functional imprinting is an earlier event in adrenocortical tumorigenesis, we tested for pathological functional imprinting of the 11p15 region in adrenocortical tumors exhibiting no or only partial (mosaicism) LOH.
Our data showed that abnormalities of the 11p15 region are late events associated with the transition from the benign to the malignant state. H19 expression status depends on the activity of the maternal allele, but does not always negatively correlate with the expression of the IGF-II gene.
These data show that dysregulation of the 11p15 region is a major event during adrenocortical tumorigenesis.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Eighty-two adults, 16–82 yr old (13 men and 69 women) with sporadic adrenocortical tumors were included in the study between 1989–1996. None of them had features of any tumor-predisposing syndrome (Beckwith-Wiedemann, McCune-Albright, multiple endocrine neoplasia type 1, or Li-Fraumeni syndromes).
Hormonal status and the stage of the tumor as localized, regional, or
metastatic were evaluated as previously described (38). Histological
features, including high mitotic rate, atypical mitoses, high nuclear
grade, low percentage of clear cells, necrosis, diffuse architecture of
tumor, capsular invasion, sinusoidal invasion, and venous invasion were
carefully gathered. Tumors without any of these histological features
were classified as benign. Localized tumors with one to three of these
histological features were classified as suspect. Tumors with more than
three of these features or with documentation of metastasis or
recurrence were classified as malignant tumors (2, 39). Pathological
and hormonal data are summarized in Table 1
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Eighteen patients were diagnosed as having suspect tumors (weight, 12–240 g), 14 of which were hormonally active.
Twenty-nine patients were initially diagnosed as having adrenocortical carcinomas (9 with metastases, 1 with local recurrence, 8 with regional invasion, and 11 with localized disease but histological data suggestive of malignancy). Eighty percent had secreting tumors. Tumors weights varied between 69–5000 g. For 1 patient with metastases, the primary adrenocortical tumor, metastatic, and adjacent nontumor liver samples were available. For another patient with metastases, only a lung metastasis sample was available for study.
Tissue fragments obtained at surgery were immediately frozen in liquid nitrogen and stored at -80 C until DNA and RNA extraction. Control leukocyte DNA for reference was available for all patients.
Isolation of nucleic acids
Isolation of nucleic acids was performed as previously described (22).
Southern blot analysis
Search for allelic losses at the 11p13–15 region. Allelic loss of the 11p13–15 region in tumors was investigated by Southern blot analysis using six human genomic or complementary DNA (cDNA) probes (insulin, IGF-II, H19, H-ras-1, catalase, and calcitonin) (22). Restriction endonucleases were chosen on the basis of the polymorphism of their digestion patterns: TaqI for insulin, H19, catalase, H-ras-1, and calcitonin probes, and AvaII for the IGF-II probe. The restriction pattern of tumor DNA was in all cases compared to the leukocyte DNA restriction pattern.
Parental analysis.
The IGF-II probe was used for parental
analysis. This probe is a 663-bp EcoRI fragment of the
IGF-II cDNA (40) that recognizes an AvaII polymorphism near
the 5'-part of exon 9 of the IGF-II gene (Fig. 1). In normal tissues,
the 5'-part of exon 9 of the maternal allele of the IGF-II gene is
specifically hypomethylated and thus completely disappears when
digested with AvaII and the methylation-sensitive enzyme
HpaII; the paternal allele is hypermethylated and is thus
not further digested by HpaII (Fig. 1, A and
B) (41).
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Tumor RNA contents were evaluated by dot blot and Northern blot analyses as previously described (22). Normal control adrenal RNA was obtained from glands surgically removed during large nephrectomy for kidney cancer. Placenta, which contains large amounts of IGF-II and H19 mRNA, was used as a positive control.
Hybridization signals were measured by densitometric analysis using a GS700 imaging densitometer and the molecular analyst data system (Bio-Rad, Richmond, CA). Each IGF-II and H19 mRNA signal was normalized to that for human ß-actin probe (Clontech, Palo Alto, CA).
Reverse transcription-PCR for analyzing allele-specific expression of the IGF-II gene
An ApaI-AvaII polymorphism in the
3'-untranslated region of the IGF-II gene (Fig. 1A
) was used to analyze
allele-specific expression (42). RNA samples (250 ng) were treated with
deoxyribonuclease (DNase) to eliminate any DNA contamination, reverse
transcribed at 70 C, and subsequently amplified using a thermostable
DNA polymerase (Perkin-Elmer, Norwalk, CT) (43). Sense and antisense
primers were, respectively, 5'-CTTGGACTTTGAGTCAAATTGG-3' (S1) and
5'-GGTCGTGCCAATTACATTTCA-3' (AS1; Fig. 1A) (36). The cycle, which
consisted of denaturation for 1 min at 94 C, annealing for 2 min at 55
C, and extension for 3 min at 72 C, was repeated 35 times. PCR products
were digested separately with ApaI or AvaII.
ApaI cleaves 1 of the polymorphic alleles, and
AvaII cleaves the other; therefore, spurious interpretation
due to partial digestion could be excluded. Control leukocyte and tumor
DNA samples were amplified in parallel, and their restriction patterns
were compared to the cDNA pattern. DNase-treated RNA PCR products were
used as a control for DNA contamination of the RNA samples. Products of
amplification and digestion were analyzed by electrophoresis on a 3%
Metaphor XR agarose gel (FMC Bioproducts, Rockland, ME).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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All patients were informative for one or more of the 11p13–15 markers, as detected by Southern blot analysis.
Thirty-eight tumors (46.3%) exhibited LOH, whereas all leukocyte DNA
gave normal heterozygous profiles (Figs. 1B and 2, A and
B). Allelic loss varied according to pathological data: 3 of 35 (8.6%)
in benign tumors, 11 of 18 (61.1%) in suspect localized tumors, and 24
of 29 (82.8%) in malignant tumors (Fig. 3A and Table 2).
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, patient 29, as an
example). Ten tumors gave mosaic patterns with allelic disproportion;
in these 10 tumors the percentage of cells with LOH (44) varied between
12–59% (Fig. 2A, patient 55).
Allele-specific methylation was investigated using the AvaII
with or without HpaII/IGF-II system in 15 patients. This
parental analysis showed that the lost allele was of maternal origin,
and the duplicated allele was of paternal origin in all (Fig. 2B, patient 72) except 1 patient with mosaicism who had partially lost the
paternal allele (Fig. 2B, patient 35).
Functional analysis of the IGF-II gene
IGF-II mRNA expression in adrenocortical tumors.
IGF-II mRNA
was measured by dot blot and Northern blot analyses. High levels of
IGF-II mRNA (between 10–582 times that in normal human adult
adrenocortical tissue) were found in 38 of 82 (46.3%) adrenocortical
tumors. The distribution of overexpression among the 3 groups of tumors
was similar to that of 11p15 LOH: 0% (0 of 35), 72.2% (13 of 18), and
86.2% (25 of 29) in benign, suspect, and malignant tumors,
respectively (Table 3 and Fig. 3, A and B).
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The distribution of IGF-II mRNA content according to pathological group
is shown in Fig. 4A.
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, patient 80, as an example of benign tumor) as normal
adrenal tissue (Fig. 5A).
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, patient 35).
The other tumors (with complete LOH) expressed the remaining paternal
allele (Fig. 5A, patient 29).
Seven of tumors with abnormalities of 11p15 region showed LOH with
normal IGF-II mRNA content (0.25–2.18). One of the three patients with
mosaicism was informative for the
ApaI-AvaII/IGF-II polymorphism and showed
monoallelic paternal expression (Fig. 5A, patient 10).
Finally, seven tumors with abnormalities of 11p15 region exhibited
strong overexpression of the IGF-II gene without LOH. Two were
informative for the ApaI-AvaII/IGF-II
polymorphism; one had a loss of imprinting with expression of the two
parental alleles (Fig. 5A, patient 47), and the other had normal
paternal monoallelic expression of the IGF-II gene (Fig. 5A, patient
76).
H19 mRNA expression in adrenocortical tumors
H19 mRNA was studied in 55 tumors and was found to be variable
according to pathological groups (Fig. 4B and Table 3); however,
abrogation of H19 expression was found in some suspect and in most
malignant tumors.
In tumors without abnormalities of the 11p15 region, H19 gene
expression (n = 23) was always detectable and varied from
0.15–11.7 times that in normal adrenal tissue (Fig. 5, B and C).
In tumors with LOH, whatever the IGF-II mRNA content [high (n =
21) or normal (n = 5)], H19 expression was low (<10% the
expression of normal adrenal tissue for 22 of them), consistent with
loss of the functional maternal H19 gene (Fig. 5, B and C).
In tumors with overexpression of the IGF-II gene and without LOH, H19
expression (n = 6) was variable (Fig. 5, B and C). It was
undetectable in two of the six tumors (including the tumor with
biallelic expression of the IGF-II gene) and was between 2.85–8.1 that
in normal adrenal tissue in the remaining tumors (including the tumor
with paternal monoallelic expression of the IGF-II gene).
Thus, H19 expression only depends on the activity of the maternal allele, and abrogation of H19 expression appears to be a final common pathway of both LOH and pathological functional imprinting.
H19 expression was not always abrogated when IGF-II was overexpressed.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We previously reported LOH (loss of maternal allele and duplication of paternal allele) of the imprinted 11p15 region and increased IGF-II gene expression in adrenocortical carcinomas (22, 23). We now report on the frequency and distribution of 11p15 LOH and IGF-II gene overexpression in this large series of cases to assess their prognostic value. We also investigated whether pathological functional imprinting was an event before LOH during adrenocortical tumorigenesis and assessed the expression of two key genes of the 11p15 region, the H19 and the IGF-II genes.
Clonal analysis had previously suggested that adrenocortical tumorigenesis may be a multistep process with sequential progression from the normal to the adenomatous and then to the malignant cell (47, 48). The most obvious finding of this study is that 11p15 LOH and high IGF-II expression are events associated with the transition from the benign to the malignant state. Indeed, LOH and/or IGF-II gene overexpression were found in 27 of the 29 malignant tumors (93.1%) and in only 3 of the 35 benign tumors (8.6%). The high frequency (83.3%) of these abnormalities in tumors classified as suspect suggests that these tumors could have been brought into a malignant phenotype. In tumors weighing about 50–200 g, which are often difficult to diagnose, the incidence of 11p15 abnormalities was high. These data suggest that tumors with such abnormalities should be regarded as malignant tumors. A prospective study of the outcome of these patients will allow us to strictly assert the prognostic value of these markers.
The second important finding concerns the pathogenetic approach. In tumors without LOH and without overexpression of the IGF-II gene (mainly benign tumors), no pathological functional imprinting was found. These data agree with previous studies; loss of imprinting of the IGF-II gene was described in other adulthood tumors (including uterine, lung, and testicular tumors), but exclusively in malignant ones (35, 36, 37).
We demonstrated that tumors with a mosaic pattern for LOH and overexpression of IGF-II gene exhibited pathological functional imprinting in the tumor cells not undergoing allelic loss at 11p15. In these tumors two different molecular mechanisms have been identified that both contribute to IGF-II overexpression: pathological imprinting and loss of the maternal allele. In a sequential scenario occurring in the same tumor cell, pathological imprinting must be the first event. Yet because we found only a few tumors with pathological imprinting and without LOH, these two events must be temporally very close. Maintenance of parental imprinting is linked to methylation status (26, 27), and changes in DNA methylation have been associated with chromatin alterations that could lead to genetic instability in cancer cells (49). Thus, pathological imprinting of the 11p15 region might predispose to allelic loss.
Previous studies on the Wilms’ tumor model showed that only 30% of tumors had 11p15 allelic loss and that 70% of the remaining tumors exhibited pathological imprinting of the 11p15 region, which is presumably an alternative mechanism to LOH to induce IGF-II overexpression (14, 15). It has been shown that deletion of the maternal H19 gene promoter allows expression of the normally restrained maternal IGF-II gene and results in a growth advantage (28). The abrogation of the H19 gene expression in Wilms’ tumor (by deletion or pathological imprinting of the maternal allele) could explain the overexpression of the IGF-II gene in Wilms’ tumors (26, 27). Loss of H19 expression was also described in some hormonally active adrenocortical carcinomas (30). Retained H19 expression in tumors without abnormality of the 11p15 region and loss of H19 expression in tumors with IGF-II gene overexpression and LOH are consistent with the control of IGF-II expression by H19 or with a local circuit linking IGF-II and H19 via enhancer competition. However, two observations concerning other tumors suggest that factors other than H19 control IGF-II expression: 1) 20% of the tumors showing LOH and abrogation of H19 expression had normal IGF-II expression; and 2) tumors without LOH or pathological imprinting, but with IGF-II gene overexpression, had normal to high H19 expression.
H19 and IGF-II genes use the same cis-acting regulatory elements (50), and the competition between the two genes is based upon differential DNA methylation between the maternal and the paternal chromosomes (51). The absence of overexpression of the IGF-II gene in 20% of the tumors undergoing LOH could be due to a demethylation of the remaining paternal allele in tumors. However, there was no clear difference in allele-specific methylation of exon 9 between tumors overexpressing and tumors not overexpressing the IGF-II gene (data not shown). This suggests that a factor(s) other than methylation participates in the control of IGF-II expression.
Mitogenic activities of IGF-II have been clearly established in various models of overgrowth disorders, including the Beckwith-Wiedemann syndrome, as well as nonsyndromic somatic overgrowth, exhibiting abnormal methylation of the H19 gene and relaxation of IGF-II imprinting in various tissues (52). A central role for IGF-II in tumorigenesis is also supported by a mouse model in which focal activation of IGF-II in the pancreas appeared to be responsible for the development of pancreatic carcinoma (32, 33). Moreover, in the Wilms’ tumor model, IGF-II has been recently shown to play a crucial role in tumor growth through the type 1 IGF receptor (31).
Whatever the mechanisms of IGF-II overexpression (LOH, pathological functional imprinting, or others), it appears with the transition from the benign to the malignant phenotype. Thus, IGF-II overexpression and the associated abnormalities at the 11p15 locus must now be used for diagnostic evaluation of adrenocortical tumors.
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Footnotes |
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Received February 26, 1997.
Revised May 2, 1997.
Accepted May 13, 1997.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Gi2 protein are not determinant
for human adrenocortical tumourigenesis. Eur J Endocrinol. 133:166–172.[Abstract]
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, Benign; 
, suspect; 
,
malignant tumors.
