Multiple genetic aberrations including evidence of chromosome 11q13 rearrangement detected in pituitary adenomas by comparative genomic hybridization

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Object. This study was conducted to determine whether comparative genomic hybridization (CGH) is a more sensitive method for detecting genetic aberrations than other tests currently in use.

Methods. The authors used CGH to examine 40 primary and 13 recurrent adenomas obtained from 52 patients for loss and gain of genetic material. Copy number aberrations (CNAs) were detected in 25 (48%) of the 52 patients studied. The chromosomes affected were, in order of decreasing frequency, 11, 7, X, 1, 8, 13, 5, 14, 2, 6, 9, 10, 12, 3, 18, 21, 4, 16, 15, 19, 22, and Y. Endocrinologically active adenomas were more likely to contain (p = 0.009) and had a greater number (p = 0.003) of CNAs. Of 26 adenomas with CNAs, 18 showed multiple aberrations involving entire chromosomes or chromosome arms. The most frequent CNA involving a chromosome subregion, which was present in four (8%) of 53 adenomas, was the loss of all chromosome 11 material except for a preserved common segment containing 11q13. Immunoperoxidase staining did not detect cyclin D1 expression in those four cases, making cyclin D1 an unlikely target of this rearrangement.

Conclusions. These findings indicate that genetic abnormalities are present in pituitary adenomas at a higher rate than previously reported, are associated with endocrinological activity, and often involve several chromosomes. Rearrangement at 11q13 may inactivate a tumor suppressor gene or activate an oncogene that is important in the initiation or progression of sporadic pituitary adenomas.

Article Information

Address reprint requests to: Burt Feuerstein, M.D., Ph.D., c/o Division of Publications and Grants, Department of Neurological Surgery, University of California San Francisco, P. O. Box 8099, Emeryville, California 94662.

© AANS, except where prohibited by US copyright law.

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Figures

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    a: Three-color fluorescence microscopic image of a control CGH experiment. Normal male metaphase chromosomes were hybridized with green-labeled normal male and red-labeled normal female total genomic DNA. Most chromosomes appear yellow due to equal hybridization of the labeled male and female samples. The X chromosome appears red because the green-labeled male genome contains one less copy of this chromosome than the red-labeled female genome. b: A CGH image of sample SF2001, a primary endocrinologically inactive pituitary adenoma resected in a 67-year-old man. Chromosome 11 appears red except for a yellow band on the proximal long arm, implying that the tumor genome has lost all of at least one copy of chromosome 11 except for the 11q13 region. This was the sole CNA in this tumor.

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    a: Chart showing a CGH ratio profile of the control experiment shown in Fig. 1a. Numerals to the left side of each plot identify the chromosome and “n” designates the number of chromosomes analyzed. The continuous thick and thin lines represent the green/red ratio mean and standard deviation (s.d.), respectively. The smaller vertical lines on the horizontal axis show the fractional length from the p terminus, and the larger vertical line denotes the location of the centromere. The dashed line represents a ratio of 1.0, and the dotted lines above and below represent 1.5 and 0.5, respectively. As expected, the green/red ratio for each chromosome is 1.0 except for X, which has a ratio of 0.5. (There are repetitive sequence artifacts at the centromeres of chromosomes 1 and 16). b: Chart showing CGH ratio profiles for the hybridization of sample SF2001, shown in Fig. 1b. The ratio is below 1.0 for all of chromosome 11 except for the proximal long arm (11q12–11q13). This is the sole CNA for this adenoma; the remaining chromosomes demonstrate normal ratios of 1.0. (The low ratio seen near the centromere of chromosome 9 is a repetitive sequence artifact, which is often found in control hybridization.) c: Chart showing CGH ratio profiles for the hybridization of sample SF2378, shown in Fig. 1c. The tumor has multiple abnormalities mostly involving entire chromosomes. Note that the amount of deviation of the ratio from 1.0 varies among chromosomes that were gained and those that were lost.

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    Ideograms showing a summary of CNAs in 18 primary and eight recurrent adenomas. The locations of CNAs in this group of pituitary adenomas are indicated next to the International System for Human Gene Nomenclature ideogram of G-banding patterns for each chromosome. Genetic losses are shown on the left and gains are shown on the right side of each chromosome. Each line represents a CNA from a single tumor.

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    Charts showing ratio profiles of four tumors with evidence of rearrangement at 11q13 in the following samples: SF1922 (a); SF1997 (b); SF2001 (c); and SF2475 (d). The smallest common region of preservation is at 11q13.

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