CASE REPORT
Shift from Conn’s syndrome to Cushing’s syndrome in a recurrent adrenocortical carcinoma
L Barzon, G Masi, K Fincati, M Pacenti, V Pezzi1, G Altavilla2, F Fallo3 and G Palù
Department of Histology, Microbiology and Medical Biotechnologies, University of Padova, Via A. Gabelli 63, I-35121 Padova, Italy 1 Department of Pharmaco-Biology, University of Calabria, Arcavacata di Rende, Cosenza, Italy and Departments of 2Pathology and 3Medical and Surgical Sciences, University of Padova, Via A. Gabelli 63, I-35121 Padova, Italy
(Correspondence should be addressed to L Barzon; Email: luisa.barzon@unipd.it)
Abstract
Objective: Adrenocortical tumors may originate from the zona glomerulosa, zona fasciculata, or zona reticularis and be associated with syndromes due to overproduction of mineralocorticoids, glucocor- ticoids, or androgens respectively. We report an unusual case of recurrent adrenocortical carcinoma (ACC), which seems to contradict the paradigm of functional adrenal zonation.
Case report: A male patient presented with severe primary aldosteronism due to an ACC, which relapsed after adrenalectomy and adjuvant mitotane therapy. After removal of the tumor recurrence and eight cycles of chemotherapy with etoposide, doxorubicin and cisplatin, the patient presented again with ACC masses, but in association with overt Cushing’s syndrome and normal aldosterone levels.
Methods and results: Extensive pathologic examination showed that this shift in steroid hormone pro- duction was paralleled by an attenuation of tumor cell atypia and polymorphism, whereas gene expression profile analysis demonstrated a change in expression of adrenal steroidogenic enzymes. Moreover, cancer progression was associated with overexpression of the inhibin-& subunit, which could have contributed to the phenotypic changes.
Conclusions: This case of recurrent ACC demonstrates that adrenocortical cells can reverse their differ- entiation program during neoplastic progression and change their specific hormone synthesis, as a consequence of modifications in the expression profile of steroidogenic enzymes and cofactors. We hypothesize that this shift in steroid hormone secretion is a consequence of chromosome amplification induced by chemotherapy. These findings, besides opening new perspectives to study adrenocortical cell plasticity and potential, demonstrate how conventional clinical and pathologic evaluation can be combined with genomic analysis in order to dissect thoroughly the biology of cancer.
European Journal of Endocrinology 153 629-636
Case report
A 42-year-old man presented with severe hypertension (blood pressure, 200/120 mmHg) and hypokalemia (serum K+, 2.2 mmol/l). Endocrine evaluation showed elevated plasma and urinary aldosterone levels (upright plasma aldosterone, 1371 pmol/l; normal values, 140- 830 pmol/l) with suppressed plasma renin activity (PRA) (upright PRA, 0.1 ng/ml per h; normal values, 1.5-6 ng/ml per h), whereas cortisol, adrenal androgens and testosterone were within the normal range (Fig. 1). In particular, 24h urinary free cortisol was 135 nmol/24 h (normal values, 82-330 nmol/l); plasma cortisol at 0800h was 415 nmol/l (normal values, 138-550 nmol/l); at 1800 h, plasma cortisol was 287 nmol/l; and in the morning, 1 mg dexa- methsone suppression test was 115 nmol/l (normal
response, <138 nmol/l). Abdominal computed tom- ography (CT) scan demonstrated a 5 cm right adrenal mass, which was diagnosed as adrenocortical carcinoma (ACC) at histologic examination. After adrenalectomy, the patient received adjuvant mitotane therapy at doses up to 10 g/day, but after 9 months the patient pre- sented again with isolated severe aldosteronism associ- ated with a 3 x 5 cm tumor relapse in the right adrenal region and lymph-node and skin metastasis. The patient underwent complete removal of the tumor masses, fol- lowed by eight cycles of chemotherapy with etoposide, doxorubicin and cisplatin for residual disease. Notwith- standing initial control of the disease, tumor recurrence was identified by CT scan after about 8 months. Clinical examination demonstrated weight gain with central obesity (body-mass index change from 26 kg/m2 at diag- nosis to 31 kg/m2), whereas endocrine investigations
3000
Hypertension, aldosteronism
Surgery
Metastases
Death
3000
Upright plasma aldosterone (pmol/L)
Hypertension, aldosteronism
2500
Right adrenalectomy
Metastases
Hypercortisolism
2500
Surgery
Plasma cortisol (nmol/L)
2000
2000
8g
Mitotane(g/day)
Chemotherapy (EDP)
Chemo (IG)
1500
4g
10g
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H
H
H
H
H
H
H
H
H
H
1500
1000
1000
500
500
0
2
4
6
8
10
12
14
16
18
20
22
24
0
Time (months)
revealed elevated 24h urinary free cortisol (528 nmol/24 h), plasma cortisol (plasma cortisol at 0800 h, 615 nmol/l), plasma dehydroepiandrosterone sulfate (DHEA-S) (32.7 umol/l; normal values, 0.5-9.0 mmol/l), and androstenedione (26.4 nmol/l; normal values, 2.0-9.2 nmol/l) values; undetectable plasma adrenocorticotropic hormone (ACTH); and normal levels of plasma aldosterone and PRA. Plasma and urinary cortisol were unresponsive to the high- dose dexamethasone suppression test. The patient was operated again to remove three abdominal masses of 7, 5.5 and 5 cm in maximum diameter, and subsequently treated with second-line chemotherapy with irinotecan and gemcitabine. Eventually, the patient died from per- sistent hypercortisolism and metastatic disease at 24 months after diagnosis (Fig. 1).
Results and discussion
ACC is a rare and very aggressive cancer with poor prognosis. About half of cases are hormonally active and associated with clinical features of hypercortisolism (Cushing’s syndrome), virilization, feminilization, or, rarely, primary aldosteronism (Conn’s syndrome). Mixed syndromes due to overproduction of different
steroid hormones and steroid precursors are also fre- quently observed.
This case of recurrent ACC attracted our attention because of the atypical clinical presentation, charac- terized by a shift from primary aldosteronism to Cushing’s syndrome during tumor progression. This shift in adrenal steroid synthesis, which has been very rarely reported in the literature (1-3), seems to contradict the paradigm of functional adrenal zonation, according to which the three zones of the adult adrenal, that is, zona glomerulosa, zona fasci- culata and zona reticularis, have specialized steroido- genetic activity, being committed to produce mineralocorticoids, glucocorticoids and androgens respectively.
In order to investigate the mechanism at the basis of this endocrine shift, we performed a thorough patholo- gic, genetic and gene expression profile analysis of the primary lesion and its recurrences. The patient gave written, informed consent for the scientific evaluation of the tumor samples.
Pathologic examination revealed quite variable find- ings, since cells of the primary tumor and the first recurrence showed great polymorphism and atypia, frequent and atypical mitoses, and no evident organoid growth pattern (Fig. 2A). In contrast, metastases of the second relapse showed monomorphism of the tumor
Figure 2 Pathologic examination of ACC specimens (A-C): A) hematoxylin and eosin (HE) staining of abdominal lymph-node metasta- sis from the primary ACC, showing polymorphic cells with wide eosinophil dense cytoplasm, atypical central nucleus of variable size and with chromatin, and no evident organoid growth pattern. Mitoses were very frequent and often atypical (mitotic index > 20 x 10 high-power field); necrotic areas and vascular tumor cell invasion were also frequent. B) HE staining of a skin metastasis from the second ACC recurrence, showing monomorphism of the tumor cell population with a nodular growth pattern simulating an organoid structure. The neoplastic cells had large eosinophilic cytoplasm, but this was more regular than in the primary ACC and first recurrence, and nuclei were less variable in size and chromatin distribution. Mitosis was found, but necrosis was absent. Analysis of @-inhibin expression by the use of anti-a-inhibin antibody (Serotec Ltd, Oxford, UK; 1:50) demonstrated positive staining in these second
”
Cholesterol
STAR
POR
CYB5
CYP11A
CYP17
SULT2A1
Pregnenolone
17OHPreg
DHEA
DHEA-S
HSD3B2
Progesterone
17OHProg
Androstenedione
CYP21
HSD17B3
Deoxycorticosterone
Deoxycortisolo
Testosterone
CYP11B1
CYP19
CYP11B2
Corticosterone
Cortisol
Estradiol
18OH Corticosterone
A
Aldosterone
D
Cholesterol
STAR
POR
CYB5
CYP11A
CYP17
SULT2A1
Pregnenolone
17OHPreg
DHEA
DHEA-S
HSD3B2
Progesterone
17OHProg
Androstenedione
CYP21
HSD17B3
Deoxycorticosterone
Deoxycortisol
Testosterone
CYP11B1
CYP19
CYP11B2
Corticosterone
Cortisol
Estradiol
18OH Corticosterone
B
Aldosterone
E
Cholesterol
STAR
POR
CYB5
CYP11A
CYP17
SULT2A1
Pregnenolone
17OHPreg
DHEA
DHEA-S
HSD3B2
Progesterone
17OHProg
Androstenedione
CYP21
HSD17B3
Deoxycorticosterone
Deoxycortisol
Testosterone
CYP11B1
CYP19
CYP11B2
Corticosterone
Cortisol
Estradiol
18OH Corticosterone
C
Aldosterone
F
| Description | Gene | Normal adrenalª | Ratio ACC1/normalb | Ratio ACC2/normalb | Ratio ACC2/ACC1b |
|---|---|---|---|---|---|
| Cytochrome P450, subfamily I, polypeptide 2 | CYP1A2 | 8.59 | 1.92 | 1.99 | 1.49 |
| P450 (cytochrome) oxidoreductase | POR | 5.90 | 2.16 | 2.39 | 1.11 |
| Cytochrome P450, subfamily XVII | CYP17 | 5.44 | 0.42 | 4.86 | 6.67 |
| Steroidogenic acute regulatory protein | STAR | 5.40 | 2.16 | 2.53 | 1.50 |
| 24-dehydrocholesterol reductase | DHCR24 | 5.02 | 0.94 | 1.35 | 1.91 |
| Nuclear receptor subfamily 4, A1 | NR4A1 | 4.98 | 1.95 | 2.28 | 1.16 |
| Cytochrome P450, subfamily XXIA, polypeptide | CYP21A2 | 4.66 | 2.40 | 2.70 | 1.31 |
| Cytochrome P450, subfamily IIB, polypeptide 6 | CYP2B6 | 3.91 | 1.27 | 2.31 | 3.14 |
| Cytochrome P450, subfamily IIS, polypeptide 1 | CYP2S1 | 3.53 | 1.42 | 2.79 | 3.93 |
| Hydroxysteroid (17-beta) dehydrogenase 1 | HSD17B1 | 3.30 | 2.93 | 2.49 | 1.66 |
| Cytochrome P450, subfamily XIB, polypeptide 1 | CYP11B1 | 2.50 | 2.13 | 1.11 | 0.81 |
| Cytochrome P450, subfamily IIA, polypeptide 7 | CYP2A7 | 2.45 | 1.67 | 3.09 | 2.98 |
| Hydroxyacyl-coenzyme A dehydrogenase, type II | HADH2 | 2.20 | 1.56 | 1.93 | 1.78 |
| Hydroxysteroid (3-beta) dehydrogenase 2 | HSD3B2 | 2.17 | 2.22 | 2.09 | 1.29 |
| Cytochrome P450, subfamily XIA (cholesterol sec) | CYP11A | 2.17 | 1.28 | 1.60 | 1.76 |
| Hydroxysteroid dehydrogenase, 3 beta 1 | HSD3B1 | 2.12 | 4.51 | 5.71 | 2.53 |
| 7-Dehydrocholesterol reductase | DHCR7 | 2.12 | 1.98 | 3.73 | 3.14 |
| Steroid sulfotransferase 2A1, DHEA-preferring | SULT2A1 | 2.01 | 0.42 | 2.43 | 4.47 |
| Hydroxysteroid (17-beta) dehydrogenase 7 | HSD17B7 | 1.97 | 1.16 | 3.08 | 2.40 |
| Aldo-keto reductase, 7A2 | AKR7A2 | 1.95 | 1.42 | 1.29 | 1.28 |
| Steroid sulfotransferase 1C2 | SULT1C2 | 1.74 | 2.58 | 2.68 | 1.22 |
| Steroid sulfatase (microsomal), isozyme S | STS | 1.60 | 0.74 | 0.89 | 0.88 |
| Ferrodoxin reductase | FDXR | 1.58 | 3.19 | 2.85 | 1.21 |
| Cytochrome P450, subfamily IIC9 | CYP2C9 | 1.56 | 1.40 | 0.86 | 0.69 |
| Steroidogenic factor-1 (SF-1) | NR5A1 | 1.51 | 1.38 | 1.53 | 1.15 |
| Nuclear receptor subfamily 4, A2 | NR4A2 | 1.48 | 0.37 | 0.22 | 0.61 |
| Cytochrome P450, subfamily XIB, polypeptide 2 | CYP11B2 | 1.43 | 5.10 | 1.19 | 0.40 |
| Aldo-keto reductase, 1B1 | AKR1B1 | 1.36 | 1.26 | 1.09 | 2.47 |
| Cytochrome b5 | CYB5 | 1.17 | 0.49 | 0.79 | 2.67 |
| Hydroxysteroid (17-beta) dehydrogenase 4 | HSD17B4 | 1.12 | 1.26 | 1.23 | 1.26 |
| Aldo-keto reductase, 1A1 | AKR1A1 | 1.09 | 0.89 | 0.59 | 0.65 |
| Steroid sulfotransferase 1C1 | SULT1C1 | 0.98 | 0.86 | 1.21 | 0.71 |
| Steroid reductase, alpha polypeptide 1 | SRD5A1 | 0.98 | 0.84 | 0.81 | 0.45 |
| Aldo-keto reductase, 1B10 | AKR1B10 | 0.96 | 0.22 | 0.39 | 0.17 |
| Aldo-keto reductase, 1D1 | AKR1D1 | 0.89 | 0.62 | 0.35 | 0.25 |
| Steroid sulfotransferase, 2B1 | SULT2B1 | 0.88 | 0.80 | 0.54 | 0.34 |
| Liver receptor homolog 1 (LRH-1) | NR5A2 | 0.83 | 0.90 | 0.60 | 0.24 |
| Cytochrome P450, subfamily XIX | CYP19 | 0.81 | 0.19 | 0.39 | 1.31 |
| Aldo-keto reductase, 1C1 | AKR1C1 | 0.69 | 1.01 | 0.36 | 0.84 |
| Hydroxysteroid (17-beta) dehydrogenase 2 | HSD17B2 | 0.60 | 0.72 | 0.48 | 0.19 |
| Steroid sulfotransferase, 1B1 | SULT1B1 | 0.59 | 0.55 | 0.66 | 1.21 |
| Hydroxysteroid (11-beta) dehydrogenase 2 | HSD11B2 | 0.55 | 0.31 | 0.73 | 1.88 |
Ratio ACC2/ACC1 b
2.03
1.54
1.29
2.12
Ratio ACC2/normal b
1.03
1.17
1.70
1.79
Ratio ACC1/normal b
1.66
1.37
0.80
0.62
Normal adrenal ª
0.55
0.49
0.43
0.42
Gene
SULT1A2
SULT1A3
HSD11B1
HSD17B3
Table 1 Continued Description
Steroid sulfotransferase, 1A2 Steroid sulfotransferase, 1A3
Hydroxysteroid (11-beta) dehydrogenase 1
Hydroxysteroid (17-beta) dehydrogenase 3 Steroid sulfotransferase, 1A1
ACC2; second ACC recurrence.
1.26 0.31 0.68 0.90 aSignal intensity values in normal adrenocortical tissues; bratios >2 (i.e., overexpressed genes) are in boldface, ratios <0.5 (i.e., underexpressed genes) are in boldface and italic; ACC1: primary ACC; SULT1A1
cell population with a nodular growth pattern simulat- ing an organoid structure. The neoplastic cells had large eosinophilic cytoplasm, but this was more regular than in the primary ACC and first recurrence, and nuclei were less variable in size and chromatin distri- bution (Fig. 2B).
Sequence analysis of candidate genes (i.e., TP53, PTEN, GNAS1, GNAI2, CDKN1C, MEN1, PRKAR1A, INHA and APC) typically involved in adrenal tumori- genesis failed to demonstrate pathologic mutations either in the primary tumor or in recurrences, whereas measurement of mRNA levels of ACC marker genes (i.e., IGF2, H19, CDKN1C, EGFR and TOP2A) by quan- titative real-time RT-PCR demonstrated very high IGF2 and TOP2A mRNA levels and underexpression of H19 and CDKN1C in both primary primary tumor and metastases, as typically observed in ACC (4).
DNA microarray analysis and quantitative real-time RT-PCR demonstrated that the expression pattern of steroidogenic enzymes was concordant with endocrine activity of the ACC masses. In fact, mRNA levels of CYP11B2 (aldosterone synthase) were extremely high in the aldosterone-producing tumors but very low in the second relapse, which, in contrast, had high mRNA levels of genes encoding enzymes involved in the production of cortisol and adrenal androgens, such as CYP17, CYP21 and SULT2A1 (Table 1 and Fig. 2D-F) (5). Of interest, microarray analysis (per- formed with microarray glass slides containing 70 mer oligonucleotide sequences of 21 329 human genes, produced by CRIBI Core Facility, University of Padova, Italy) also showed that the most overexpressed genes in the second cortisol-secreting ACC recurrence, as compared with the aldosterone-producing primary ACC and first relapse, included a large number of genes mapping to the 19q13.3-4 chromosomal region. Among these genes, there were a large cluster of cytochrome P450 genes involved in the metabolism of steroids and xenobiotics (6) (e.g., CYP2B6, CYP2S1 CYP2A7) and the INHA gene, encoding the inhibin &- subunit (Table 2). Overexpression of cytochrome P450 genes leading to increased inactivation of anti- cancer drugs has been linked to chemotherapy resist- ance (7). Chromosomal gains and amplifications in 19q13 are often found in ACC (8), and, in our case, they could indeed have occurred during chemotherapy, causing gene overexpression. The product of the SULT2A1 gene, DHEA sulfotranspherase, also located in 19q13.3-4, normally sulfates DHEA to DHEA-S, as well as pregnenolone and 17«-hydroxypregenolone to their sulfated metabolites, removing these substrates from mineralocorticoid and glucocorticoid pathways respectively (9). SULT2A1 overexpression, in the pre- sence of high levels of CYP17 and CYP21, might have shifted aldosterone biosynthesis to both cortisol and androgen biosynthesis. These findings are in accordance with the clinical shift from Conn’s syn- drome to Cushing’s syndrome seen in our patient.
| Description | Function | Map | UniGene | Gene | Ratio |
|---|---|---|---|---|---|
| Overexpressed genes | |||||
| Ubiquitin carboxyl-terminal esterase L1 | Ubiquitin hydrolysis; neuroendocrine tissues | 4p14 | 76 118 | UCHL1 | 11.40 |
| Synuclein, gamma | Oncogene | 10q23 | 349470 | SNCG | 10.06 |
| Clusterin | Downregulated in prostate cancer | 8p21 | 75 106 | CLU | 7.79 |
| Chymotrypsinogen B1 | Serine protease | 16q23 | 74 502 | CTRB1 | 7.05 |
| Cytochrome P450, subfamily XVII | Steroid 17-alpha-hydroxylase | 10q24.3 | 1363 | CYP17 | 6.67 |
| Paternally expressed 3 | Growth-promoting functions, but also tumor suppressor | 19q13.4 | 139033 | PEG3 | 6.25 |
| K562 cell-derived leucine-zipper-like protein 1 | Transcription factor | 19q13.43 | 31 854 | LOC57106 | 5.91 |
| Adlican | VEGF receptor | Xp22.33 | 72 157 | DKFZp56411922 | 5.78 |
| Zinc finger protein 573 | Regulation of transcription | 19q13.13 | 278871 | ZNF573 | 5.59 |
| K1AA1198 protein | Zink-finger protein 490 | 19p13.2 | 175475 | KIAA1198 | 5.38 |
| Synaptophysin | Adrenocortical neoplasm marker, cholesterol binding | Xp11.23 | 75 667 | SYP | 5.19 |
| Leukocyte receptor cluster member 5 | tRNA splicing | 19q13.4 | 15 580 | LENG5 | 4.82 |
| Retinol binding protein 1, cellular | Retinol transport, antitumor activity | 3q23 | 101850 | RBP1 | 4.76 |
| Solute carrier family 4, anion exchanger, member 3 | Anion transport | 2q36 | 1176 | SLC4A3 | 4.74 |
| Protein phosphatase 1, regulatory subunit 14A | Inhibitor of smooth muscle myosin phosphatase | 19q13.1 | 348037 | PPP1R14A | 4.73 |
| HMT1 bnRNP methyltransferase-like 1 | Signal transduction | 21q22.3 | 235887 | HRMT1L1 | 4.71 |
| Solute carrier family 25 | Mitochondrial carrier with calcium-binding domains | 19q13.3 | 32 246 | SLC25A23 | 4.66 |
| Sulfotransferase 2A, DHEA-preferring, member 1 | Steroid metabolism | 19q13.3 | 81 884 | SULT2A1 | 4.47 |
| K1AA1415 protein | Guanine nucleotide exchange factor | 20q13.13 | 109315 | KIAA1415 | 4.43 |
| Inhibin, alpha | Activin inhibitor activity | 2q33-36 | 1734 | INHA | 4.41 |
| Filamin B, beta | Actin cytoskeleton organization | 3p14.3 | 81 008 | FLNB | 4.32 |
| Cargo selection protein | Similar to mannose-6-P receptor binding protein 1 | 19p13.3 | 140452 | TIP47 | 4.26 |
| Retinol dehydrogenase 13 (all-trans and 9-cis) | Oxidoreductase activity | 19q13.42 | 178617 | RDH13 | 4.19 |
| Fatty acid desaturase 1 | Fatty acid biosynthesis | 11q12.2-q13.1 | 132898 | FADS1 | 4.09 |
| PRP31 pre-mRNA processing factor 31 | Retinitis pigmentosa, snRNP formation | 19q13.42 | 183438 | PRPF31 | 4.08 |
| Ubiquitin-conjugating enzyme E2C | Cell growth and malignant transformation | 20q13.12 | 93 002 | UBE2C | 3.98 |
| Stem-loop (histone) binding protein | Histone processing | 4p16.3 | 75 257 | SLBP | 3.95 |
| Cytochrome P450, subfamily IIS, polypeptide 1 | Drug metabolism and cholesterol synthesis | 19q13.1 | 98 370 | CYP2S1 | 3.93 |
| Neuronal pentraxin I | Central nervous system development | 17q25.1-q25.2 | 84 154 | NPTX1 | 3.92 |
| Ectodermal-neural cortex (with BTB-like domain) | Actin-binding protein | 5q12-q13.3 | 104925 | ENC1 | 3.78 |
| Niemann-pick disease, type C1 | Intracellular transport of cholesterol | 18q11 | 76 918 | NCP1 | 3.72 |
| Thioredoxin-like 4A | Electron transport | 18q23 | 5074 | TXNL4A | 3.72 |
| Actinin, alpha 4 | Actin-binding protein; tumorigenicity | 19q13 | 182485 | ACTN4 | 3.70 |
| Reticulon 4 | Neuroendocrine secretion | 2p16.3 | 65 450 | RTN4 | 3.70 |
| Zinc-finger protein 83 (HPF1) | Transcription factor | 19q13.3 | 305953 | ZNF83 | 3.68 |
| Protein tyrosine phosphatase, receptor type, H | Tumor suppressor | 19q13.4 | 179770 | PTPRH | 3.65 |
| Host cell factor C1 regulator 1 (XPO1 dependent) | HCF-1 beta-propeller interacting protein | 16p13.3 | 279581 | HCFC1R1 | 3.61 |
| Anti-müllerian hormone | Gonadal development | 19p13.3 | 112432 | AMH | 3.60 |
| Thioredoxin reductase 1 | Protection against oxidative stress | 18q23 | 13 046 | TXNRD1 | 3.48 |
| Pituitary tumor-transforming 1 interacting protein | Facilitates the nuclear translocation of PTTG1 | 21q22.3 | 111126 | PTTG11P | 3.46 |
| Thy-1 cell surface antigen | Tumor suppressor gene | 11q22.3-q23 | 125359 | THY1 | 3.45 |
| Porcupine | Processing of Wnt proteins | Xp11.23 | 5326 | MG61 | 3.45 |
| KRAB zinc-finger protein KR18 | Regulation of transcription | 19q13.41 | 206882 | KR18 | 3.43 |
| Tropomyosin 2 (beta) | Structural constituent of muscle | 9p13.2-p13.1 | 300772 | TPM2 | 3.40 |
| Similar to zinc-finger protein 268 | 19q13.42 | 209430 | LOC91664 | 3.34 | |
| Thromboxane A2 receptor | Thromboxane A2 receptor activity | 19p13.3 | 89 887 | TBXA2R | 3.34 |
| Serine carboxypeptidase 1 | Serine carboxypeptidase activity | 17q23.2 | 106747 | SCPEP1 | 3.31 |
| Growth hormone receptor | Growth factor | 5p13-p12 | 125180 | GHR | 3.27 |
| Description | Function | Map | UniGene | Gene | Ratio |
|---|---|---|---|---|---|
| Liver-specific bHLH-Zip transcription factor | Receptor activity | 19q13.12 | 95 697 | LISCH7 | 3.26 |
| Brain abundant, membrane attached signal protein 1 | Membrane bound protein | 5p15.1-p14 | 79 516 | BASP1 | 3.26 |
| CCR4-NOT transcription complex, subunit 3 | Transcription regulator activity | 19q13.4 | 343571 | CNOT3 | 3.24 |
| Dynein, cytoplasmic, light polypeptide | Inhibition of NOS activity | 12q24.23 | 5120 | PIN | 3.23 |
| Plexin A1 | Semaphorin receptor activity | 3q21.3 | 334666 | PLXNA1 | 3.23 |
| Oxysterol binding protein-like 10 | Intracellular lipid receptor | 3p22.3 | 285123 | OSBPL10 | 3.22 |
| WD repeat domain 18 | 19p13.3 | 325321 | WDR18 | 3.22 | |
| Leukocyte receptor cluster member 8 | Receptor | 19q13.42 | 348571 | LENG8 | 3.21 |
| Clone MGC:9381 IMAGE:3865583 | 19q13.3 | 76 277 | 3.19 | ||
| Ovary-specific acidic protein | 4q31.1 | 154140 | OSAP | 3.18 | |
| Stearoyl-CoA desaturase | Fatty acid biosynthesis | 10q23-q24 | 119597 | SCD | 3.16 |
| Cytochrome P450, subfamily IIB, polypeptide 6 | Drug metabolism and cholesterol synthesis | 19q13.2 | 1360 | CYP2B6 | 3.14 |
| 7-dehydrocholesterol reductase | Endogenous cholesterol synthesis | 11q13 | 11 806 | DHCR7 | 3.14 |
| 3-hydroxy-3-methylglutaryl-coenzyme A reductase | Rate-limiting enzyme for cholesterol synthesis | 5q13.3-q14 | 11 899 | HMGCR | 3.10 |
| CNDP dipeptidase 2 (metallopeptidase M20 family) | Metallopeptidase activity | 18q22.3 | 273230 | CNDP2 | 3.09 |
| Pro-oncosis receptor inducing membrane injury gene | Oncosis-like cell death | 11q22.1 | 172089 | PORIMIN | 3.08 |
| Aquaporin 2 (collecting duct) | Water channel | 12q12 | 37 025 | AQP2 | 3.07 |
| Glutathione S-transferase A4 | Cellular defense against toxic compounds | 6p12.1 | 169907 | GSTA4 | 3.07 |
| Breast cancer anti-estogen resistance 1 | Signal transduction | 16q22-q23 | 273219 | BCAR1 | 3.06 |
| Nucleobindin 2 | Calcium-binding EF-hand protein | 11p15.1-p14 | 3164 | NUCB2 | 3.05 |
| Cytochrome P450, subfamily IIA, polypeptide 7 | Drug metabolism and cholesterol synthesis | 19q13.2 | 250615 | CYP2A7 | 3.05 |
| Mitogen-activated protein kinase 4 | MAP kinase activity | 18q12-q21 | 269222 | MAPK4 | 3.04 |
| Underexpressed genes | |||||
| Fatty acid binding protein 4, adipocyte | Fatty acid uptake, transport, and metabolism | 8q21 | 83 213 | FABP4 | 0.05 |
| Cell adhesion molecule with homology to LICAM | Neural cell adhesion molecule | 3p26.1 | 210863 | CHL1 | 0.08 |
| Urotensin 2 | Vasoconstrictor | 1p36 | 162200 | UTS2 | 0.10 |
| 37 kDA leucine-rich repeat protein | 7q22.1 | 155545 | P37NB | 0.11 | |
| Plasticity related gene 3 | Lipid phosphate phosphatase activity | 9q31.1 | 106825 | PRG-3 | 0.14 |
| Hypothetical protein MGC10981 | 4p16.1 | 115912 | MGC10981 | 0.15 | |
| Estrogen-related receptor gamma | Orphan nuclear receptor | 1q41 | 151017 | ESRRG | 0.16 |
| Chemokine (C-X3-C motif) ligand 1 | Chemokine activity | 16q13 | 80 420 | CX3CL1 | 0.19 |
| Chromosome 20 open reading frame 103 | 20p12 | 22 920 | C20orf103 | 0.20 | |
| Solute carrier family 25 member 15 | L-ornithine transporter activity | 13q14 | 78 457 | SLC25A15 | 0.23 |
| Growth differentiation factor 10 | Cell growth and differentiation | 10q11.22 | 2171 | GDF10 | 0.25 |
| Fatty-acid-coenzyme a ligase, long-chain 5 | Long-chain-fatty-acid-CoA ligase activity | 10q25 | 11 638 | FACL5 | 0.26 |
| Putative nuclear protein | Acidic repeat containing | Xq13.1 | 135167 | NAAR1 | 0.29 |
| Cathepsin Z | Tumorigenesis | 20q13 | 252549 | CTSZ | 0.29 |
| Interferon, gamma-inducible protein 30 | Lysosomal thiol reductase | 19p13.1 | 14 623 | IFI30 | 0.30 |
| Cytochrome P450, subfamily XIB, polypeptide 2 | Aldosterone synthesis | 8q21-q22 | 184927 | CYP11B2 | 0.30 |
| Secretin | Intestinal hormone | 11p15.5 | 302005 | SCT | 0.31 |
| Maternally expressed 3 | Tumor suppressor | 14q32 | 112844 | MEG3 | 0.32 |
| Neurotrimin | Cell adhesion, neuronal cell regonition | 11q25 | 288433 | HNT | 0.32 |
| Glutathione S-transferase M3 (brain) | Detoxification of electrophilic compounds | 1p13.3 | 2006 | GSTM3 | 0.33 |
From aldosteronism to hypercortisolism 635
Overexpression of the inhibin «-subunit in the corti- sol-producing ACC recurrence (Fig. 2C) could have also contributed to the shift from mineralocorticoid to glu- corticoid formation. The inhibin «-subunit is highly expressed in the fetal zone of the developing adrenal cortex and in the zona reticularis of adult adrenal cortex and tumors derived thereof. In this regard, the inhibin «-subunit has been found to stimulate cortisol and androgen secretion by antagonizing activin signal- ing through a dominant-negative effect (10).
In conclusion, this case of recurrent ACC, character- ized by the sequential presentation of two endocrine syndromes, Conn’s and Cushing’s syndromes, demon- strates that adrenocortical cells can reverse their differ- entiation program during neoplastic progression and change their specialized hormone production, as a con- sequence of modifications in the expression profile of steroidogenic enzymes and cofactors. We hypothesize that this shift in steroid hormone secretion is a conse- quence of chromosome amplification induced by chemotherapy, even though we cannot exclude other molecular mechanisms, such as point mutations in steroidogenic enzymes or transcription factors, chro- mosomal translocations, and clonal progression of cells with different functional properties. Shift in endo- crine activity has been also recently observed in a case of small-cell lung cancer treated by chemotherapy (11). Our findings, besides opening new perspectives to study adrenocortical cell plasticity and potential, demonstrate how conventional clinical and pathologic evaluation can be combined with genomic analysis to dissect thoroughly the biology of cancer.
Acknowledgements
This study was supported by grant no. RSF 168/04 from the Veneto Region and by funds from IOV (Istituto Oncologico Veneto) to G. Palù.
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Received 16 May 2005
Accepted 26 July 2005