Translocation t(4;11)(q35;p13) in an Adrenocortical Carcinoma
Janusz Limon, Paola Dal Cin, John Gaeta, and Avery A. Sandberg
ABSTRACT: Chromosome studies were performed on an adrenocortical carcinoma extending into the kidney. The following karyotype was present in all metaphases: 46,XX,t(4;11)(q35;p13). Two metaphases with an additional del(1)(q23) were found. The results are briefly discussed in relation to specific karyotypic changes in cancer, in general, and to those of adrenocortical tumors, in particular.
INTRODUCTION
Tumors of the adrenal cortex consist of adenomas and carcinomas. Some of these tumors are endocrinologically active and malignant [1]. Though adrenocortical tu- mors are relatively rare, cytogenetic studies of such tumors, particularly with band- ing techniques, are even rarer. Cytogenetic banding analysis of a primary nonfunc- tional adrenocortical carcinoma revealed clonal hypotriploid metaphases with complicated chromosomal rearrangements [2].
In the present communication we describe a G-banded study of a primary func- tional adrenocortical carcinoma in which the sole karyotypic change was a trans- location between chromosomes #4 and #11.
CASE REPORT
This is the case of a 25-year-old white female (K.D.) who was referred to Roswell Park Memorial Institute (RPMI) with the diagnosis of a left renal cell carcinoma with metastatic spread to the liver. The patient underwent a left radical nephrec- tomy on October 1, 1985. The primary tumor formed a large mass approximately 8 ×10×10 cm in size occupying the upper pole of the kidney. The pathologic di- agnosis was carcinoma of the left adrenal cortex with invasion of the adrenal and renal veins and metastases to renal hilar and paraaortic lymph nodes (Fig. 1). The greatly reduced size of the adrenal gland suggested that this was a functional tumor leading to secondary atrophy of the gland. Three weeks later a right hepatic lobec- tomy was performed for multiple nodular metastases with wedge resection of a nodule in the left lobe of the liver. The patient then received adriamycin therapy until February 1986. She was readmitted to RPMI in March 1986 and had a meta-
From the Roswell Park Memorial Institute, Buffalo, NY.
Address requests for reprints to Dr. Avery A. Sandberg, Department of Genetics and En- docrinology, Roswell Park Memorial Institute, 666 Elm Street, Buffalo, NY 14263. Received March 2, 1987; accepted April 7, 1987.
bolic work-up, which included urine and plasma cortisol and steroid levels (Table 1). Ultrasound showed a mass medial to the upper pole of the right kidney, possibly representing an adrenal mass. Multiple metastases were demonstrated in both lobes of the liver. The patient’s menstrual history was not remarkable except for some irregular bleeding starting in March 1986 and for which no definite cause could be found. Her WBC count remained within normal limits throughout her illness, as did the serum sodium and potassium levels. When last seen in the clinic in April 1985, the patient had developed further metastases to lung and liver, the spleen was enlarged, her blood pressure was 148/98 mm Hg and intravenous pyelography revealed the right kidney to have been displayed laterally by a mass. The patient died in May 1986.
MATERIALS AND METHODS
A piece of tumor obtained at surgery on October 1, 1985 was finely minced and transferred into culture flasks containing growth medium consisting of McCoy’s 5A medium with 17% fetal calf serum, L-glutamine and antibiotics, supplemented with collagenase (200 U/ml), and incubated for 16 hours [3]. Primary cultures were har- vested after 6 days and colcemid was added to a final concentration of 0.01 µg/ml for 2-4 hours before harvest. The cells were then exposed in situ to a hypotonic solution for 30 minutes and fixed in methanol/acetic acid (3:1), air dried on slides, and G-banded using Wright’s stain according to the method of Yunis [4].
| Date | Urinary steroids Plasma cortisol | ||||||
|---|---|---|---|---|---|---|---|
| 17-Ketosteroids (5-15 mg)" | 17-Ketogenicsteroids (3-15 mg)" | Corticosteroids (2-8 mg)" | Free cortisol (35-120 µg)' | Aldosterone (3-20 µg)" | (normal range: 7-25 AM | µg% AM; 3-15 µg% PM) PM | |
| 10/8/85 | 8 | 19 | |||||
| 10/9/85 | 46.0 | 1.0 | |||||
| 10/10/85 | 11.1 | 3.1 | |||||
| 10/23/85 | 13 | 14 | |||||
| 10/24/85 | 2.3 | ||||||
| 11/7/85 | 15 | ||||||
| 3/22/86 | 21.5 | 89.0 | 173.0 | ||||
| 3/24/86 | 12.4 | 44.0 | 160.0 | ||||
| 3/26/86 | 14.6 | 26 | |||||
| 3/27/86 | 18 | 25 | |||||
| 3/28/86 | 25 | ||||||
“Normal ranges per 24 hours are shown in parenthesis.
RESULTS
Detailed banding analysis was performed on 20 metaphases. The modal chromo- some number was 46. Eighteen metaphases displayed the following karyotype: 46,XX,t(4;11)(q35;p13) (Fig. 2). In addition, two metaphases with del(10)(q23) and a small acentric fragment, which probably represented the deleted part of chromo- some #10 (10q23 - 10qter), were found.
DISCUSSION
Cytogenetic studies on adrenocortical tumors are very rare, undoubtedly due to the relative rarity of these tumors and the limited opportunities for cytogeneticists to examine such tumors. It appears that the only previous adrenocortical tumor to have been examined with a banding technique originated in our laboratory [2]. The present report deals with the second analysis of such tumors.
The previous cytogenetic analysis of a primary nonfunctional adrenocortical car- cinoma revealed clonal abnormalities involving chromosomes #3, #4, #5, #9, #12, #14, #15, #18, and #20 [2]. These chromosomes were involved in the for- mation of six markers: 4p+, der(12)t(3;12)(p14;p13), 14q+, der(15)t(15;20) (p11;q11), der(18)t[5;18)(p13;p11), psu dic(18)t(18;3)(p11;p12), and psu dic (20)t(20;9)(q11;p11), which were present in all hypotriploid metaphases. In the present study none of the above mentioned chromosomes was involved in karyo- typic aberrations. All analyzed metaphases had only the t(4;11)(q35;p13); in ad- dition, two metaphases displayed a del(10)(q23). It is not surprising that these two adrenocortical tumors, one hormonally active and the other nonactive, were found to have entirely different karyotypes.
In view of the chromosome changes, particularly the presence of t(4;11)(q35;p13), in every metaphase examined and the failure to obtain the chro- mosome constitution of the patient’s normal cells (e.g., blood lymphocytes), it can be argued that she might have been a carrier of such a constitutional translocation. However, we believe that the following aspects speak for the chromosomally abnor- mal metaphases as being derived from cancer cells: a) Chromosome analysis was performed on a short-term (6 days) primary tissue culture, whereas cytogenetically normal cells tend to start dividing after this time [3]; b) no constitutional translo- cation involving chromosomes #4 and #11 at q35 and p13, respectively, has been described to date [5], nor has this karyotypic change been seen in tumor cells [6]; and c) the morphologic appearance of the chromosomes (e.g., fuzziness) was com- patible with that usually seen in cancer chromosomes, in contrast to the sharp banding pattern associated with normal cells. Thus, we think that the unique kar- yotypic change of t(4;11) is reflective of the cancerous nature of the cells examined and is unlikely to represent a constitutional anomaly. The presence of a minor clone with the additional change of 10q - possibly indicates karyotypic evolution in the tumor.
In the present study the translocation of part of the short arm of chromosome #11 (11pter- 11p13) to chromosome #4 at 4q35 is very interesting. Band 11p13 has been described to be involved in structural rearrangements, mainly deletions, in solid tumors and leukemias [6], e.g., in a leiomyosarcoma of the prostate 11pter-11p13 was translocated to chromosome #19 [7] and a t(11;14)(p13;q11) was found in a case of T-ALL [8]. The breakpoint at 11p13 represents a common fragile site [8-10], as well as the location of the gene for Wilms’ tumor and the enzymes catalase and LDHA [11, 12], among others. Whether these genes are in- volved or affected by the karyotypic events described, i.e., t(4;11)(q35;p13), will have to be determined on other adrenocortical tumors of similar background and cytogenetic findings. In addition, the short arm of this chromosome (p15.1- 15.5)
A
11
B
DÌ
4 der 4 Il deril
is a site of the protooncogene H-ras I [13]. As a result of the t(4;11), this oncogene was probably moved to 4q35, though the consequences of this move are unknown.
On the basis of the cytogenetic analyses of only two adrenocortical carcinomas discussed one cannot be certain as to the nature of the specific chromosome abnor- mality characterizing this type of tumor. Obviously, the pathologic interpretation of two tumors of different nature with totally different karyotypes requires comparable studies of more adrenocortical carcinomas.
Supported in part by Grant CA-14555 from the National Cancer Institute.
The authors thank Dr. R. Wolf for providing samples for this study, Kathleen Carr for technical assistance, and Anne Marie Dulinawka for clerical aspects.
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