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Increased Polysomies of Chromosomes 7 and 17During (CANCER RESKARCH 53. :H74-2H83. June 15. 1993] Increased Polysomies of Chromosomes 7 and 17 during Head and Neck Multistage Tumorigenesis1 Narin Voravud, Dong M. Shin, Jae Y. Ro, Jin S. Lee, Waun Ki Hong,2 and Walter N. Hittelman3 Departments tif Medical Oncology ¡N.V., D. M. S.. J. S. L. W. K. H.. W, N. H.I ami Pathology IJ. Y. K./. The University of Texas M. D. Anderson Cancer Center. Houston. Texas 77030 ABSTRACT driven by an accumulation of genetic alterations, resulting in dysreg- ulation of proliferation and differentiation and in cell loss (8). Thus, Head and neck cancer development has been proposed to represent a potential biomarkers might include indicators of the degree of gener multistage process characterized by deregulation of proliferation and alized and specific genetic change as well as the degree of cellular differentiation and driven by an accumulation of genetic alterations in an anatomic Field repeatedly exposed to carcinogens. To visualize the accu dysregulation in the tissue at risk for tumor development (9). mulation of genetic alterations during head and neck tumorigeneses and to Head and neck cancer provides a unique model system for the study determine the extent of the genetically altered Held, we probed 25 squa- of tumorigenesis and the development of biomarkers for several rea mous cell carcinomas of the head and neck and their adjacent premalig- sons. First, head and neck cancer has been proposed to represent a nant lesions for numerical chromosome aberrations by nonisotopic. in situ field cancerization process since the whole aerodigestive tract epithe hybridization using chromosome-specific centromeric DNA probes for lium is repeatedly exposed to carcinogenic insult (e.g., tobacco, al chromosomes 7 and 17. Normal control oral epithelium from individuals cohol), placing the entire epithelium at risk for tumor development free of cancer showed no chromosome polysomy (i.e., cells with >3 chro (10. 11). The clinical correlate to the field hypothesis is a high fre mosome copies), whereas histologically normal epithelium adjacent to the quency of multiple primary neoplasms in the aerodigestive tract and tumors showed squamous cells with polysomies for chromosomes 7 and 17. an increased risk of synchronous and metachronous second primary Moreover, the frequency of cells with polysomy increased as the tissues passed from histologically normal epithelium to hyperplasia to dysplasia tumors (12, 13). Second, head and neck cancer is thought to represent to cancer. The finding of genotypic abnormalities in histologically normal a multistep tumorigenesis process whereby a series of events must and precancerous regions adjacent to the tumor supports the concept of occur prior to tumor development (14). This is evidenced by the field cancerization. The finding of progressive genetic changes as the presence of premalignant lesions adjacent to the tumor (15). While tumor develops supports the concept of multistep carcinogenesis in the these clinical and histológica! findings support the notions of field head and neck region. Such genotypic parameters could serve as biomar- cancerization and multistep tumorigenesis in the head and neck re kers in the assessment of the risk of progression to malignancy and as gion, cellular biomarkers for these processes are still lacking. intermediate end points in chemoprevention trials. One potential marker for the tumorigenesis process is the degree of genetic change in the tissue at risk. While a variety of cytogenetic INTRODUCTION changes have been described for head and neck tumors (16-18), a Upper uerodigestive tract cancer is a significant public health prob comprehensive list of specific genetic changes has been limited by lem throughout the world ( 1-3). Despite two decades of advances in impediments common to solid tumor cytogenetic studies, i.e.. the low surgery, radiotherapy, and chemotherapy, the long-term survival of frequency of mitotic figures from direct preparations, suboptimal affected individuals has only marginally improved (4). One approach chromosome preparations, and significant complexity of cytogenetic to overcoming this problem is to prevent the onset of the disease by changes (19). Identification of karyotypic changes in premalignant reducing exposure to suspected carcinogens, altering nutritional sta lesions is technically even more difficult with conventional cytoge tus, and treating high-risk individuals with chemopreventive agents. netic procedures and has seldom been reported (20-22). Moreover, the For example, recent clinical trials have indicated that 13 c/.s-retinoic spatial cellular distribution of genetic changes in premalignant and acid can reverse or inhibit oral premalignant lesions (5) and prevent malignant lesions cannot be defined by conventional cytogenetic tech second primary tumors in patients with head and neck cancer (6). niques because single cell preparations are required. The rational design of novel chemopreventive strategies requires an Recently, ISH techniques have been developed and allow the de tection of chromosomal abnormalities directly in interphase cells (23- understanding of the fundamental events of tumor development. Chemoprevention trials would also benefit greatly by the elucidation 27). This method has now been applied to many types of solid tumors using tumor cell lines or dissociated tumor material (28-31 ). More of markers with which to identify individuals at highest risk and to recently, ISH has been adapted for use on formalin-fixed, paraffin- monitor the efficacy of the chemopreventive agents in reversing or embedded tissue sections using nonisotopic. chromosome-specific inhibiting tumorigenesis (7). Recent studies in several human tumor DNA probes and enzyme-mediated (e.g., peroxidase) immunohis- systems have suggested that tumorigenesis is a multistep process. tochemical procedures (32-36). This technique now allows direct visualization of chromosome changes in normal, premalignant, and Received 12/30/92; accepted 4/12/93. The costs of publication of this article were defrayed in part by the payment of page tumor tissues without loss of tissue architecture. charges. This article must therefore be hereby marked advertisement in accordance with In this article we report the use of ISH to better understand field 18 U.S.C. Section 1734 solely lo indicate this faci. 1Supported in pan by NIH Grants CA52501. CA48364. and CA45746 and the Ripple cancerization and the multistep tumorigenesis process in human head Foundation. This work also utili/ed the facilities of the Flow Cytometry Core Facility and neck cancers. Formalin-fixed, paraffin-embedded tissue sections supported by NIH-National Cancer Institute Core Grant CAI6672 to Dr. Frederick Becker. of head and neck squamous cell carcinomas that also contained ad N. V. was the recipient of a University Cancer Foundation Clinical Fellowship. D. M. S. is a recipient of the Clinical Oncology Career Development Award (ACS 91-271 ) from the jacent normal and premalignant epithelium were subjected to ISH to American Cancer Society. visualize genetic alterations that accompany the transition from his 2 W. K. H. holds the Charles A. LeMaistre Chair in Thoracic Medical Oncology. ' To whom requests for reprints should be addressed, at Department of Medical tologically normal epithelium through premalignant lesions to malig Oncology. Box 19, The University of Texas M. D. Anderson Cancer Center. 1515 Hoi- nant lesions. To determine whether the detected genetic changes were combe Boulevard. Houston. TX 77030. Walter N. Hittelman holds the Sophie Caroline associated with alterations in DNA content, adjacent tissue sections Steves Professorship in Cancer Research. 4 The abbreviations used are: DI. DNA index; ISH. in sifit hybridization; PBS. phos- were also analyzed for DNA content using Feulgen staining and phale-buffered saline; SSC. standard sodium citrate. quantitation by image analysis. It was of particular importance for us 2874 Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1993 American Association for Cancer Research. GENETIC CHANCES DURING HEAD AND NECK TUMORIGF.NESIS to determine, first, how far back into the normal-to-premalignant H2O: in 50 ml of PBS at room temperature for 2-3 min to allow signal de transition numerical chromosome changes could be detected and sec velopment. The slides were then successively washed in PBS for 5 min. ond, whether the transition from premalignant to malignant lesions rinsed in deionized running water for 10 min, air dried, and counterstained with Giemsa stain (0.02%) for 10-20 s. The sections were then mounted in was accompanied by an accumulation of genetic changes. The present study demonstrates that genetic alterations can be detected in histo- Eukitt (Calibrated Instruments. Inc.. Hawthorne. NY) and examined under a light microscope. Details of this technique have been described elsewhere logically normal epithelium and premalignant lesions adjacent to head (35. 36). and neck carcinomas and that an increase in the fraction of cells Analysis of Chromosome Copy Number. Areas for analysis were selected exhibiting numerical abnormalities accompanies the multistep tumor- by the pathologist by comparing the hybridized slides to a corresponding igenesis process. hematoxylin-eosin-stained adjacent section. Since the centromeric region of a chromosome occupies only a small region of the interphase nucleus, the hybridized signals appear as small dark spots. At least 200 nuclei were scored MATERIALS AND METHODS
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