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Chromosomes 8, 12, and 17 Copy Number in Astler-Coller Stage C Colon Cancer in Relation to Proliferative Activity and DNA Ploidy1

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Chromosomes 8, 12, and 17 Copy Number in Astler-Coller Stage C Colon Cancer in Relation to Proliferative Activity and DNA Ploidy1 [CANCER RESEARCH 5.1.681-686, February 1. 1993] Chromosomes 8, 12, and 17 Copy Number in Astler-Coller Stage C Colon Cancer in Relation to Proliferative Activity and DNA Ploidy1 Melissa G. Steiner,2 Seth P. Harlow, Edoardo Colombo,3 and Kenneth D. Bauer4 Department of Pathology and the Cancer Center, Northwestern university, McGaw Medical Center, Chicago. Illinois 60611 ABSTRACT to glass slides; evaluation of the number of signals in each nucleus reflects the number of copies of that chromosome in that nucleus. Fluorescence in situ hybridization using centromere-specific DNA Most ISH studies have been applied to hematological cancers (22-24); probes to chromosomes 8,12, and 17 was applied to 23 archival paraffin- however, a few have addressed the chromosomal anomalies in bladder embedded stage C colonie cancer specimens. Chromosome copy number tumors (4, 25-27) and in primary breast tumors (28-30). Furthermore, was related to flow cytometric determinations of S-phase fraction and techniques of ISH can be applied to archival paraffin-embedded spec DNA ploidy. Three to eight copies of chromosomes 8, 12, and 17 were observed at mean frequencies of 28.7%, 37.8%, and 20.9%, respectively. imens (26, 30). The mean frequency of multiple copies of chromosome 12 was signifi Combining FCM and ISH on the same specimen is generally fea cantly greater than that for chromosome 17 (/' < 0.0025). The mean sible, because only thousands of cells are necessary to analyze the frequency of single copies of chromosome 17 was significantly greater than sample in a statistically évaluablemanner using either method. FCM that for chromosomes 8 and 12 (/' < 0.0025 and /' < 0.0005, respectively). is a rapid and objective screening method for DNA content in malig Regarding the fourth quartile of cases, defined on the basis of the fre nancies and has been shown to provide prognostic information based quency of multiple chromosome copies, the proportion demonstrating on DNA ploidy (31-34) and proliferative activity (31, 34). Tumor moderate to high proliferative activity greatly exceeded the proportion proliferative activity, based on cell cycle phase distribution analysis, displaying low proliferative activity. The same cases (most chromosomally aberrant) also generally demonstrated DNA aneuploidy. The results indi has been shown to correlate with tumor aggressiveness in colon cancer cate a substantial degree of karyotypic instability in advanced colon can (35) and in other tumors (36, 37). Although FCM can provide useful cer, particularly in cases with high proliferative activity and DNA aneu information regarding DNA content, cytogenetics provides more spe ploidy. cific information regarding DNA abnormalities and better sensitivity for the determination of small variations in DNA content (4, 30). The INTRODUCTION few studies combining FCM and ISH have so far been limited to bladder (4, 25, 27) and breast cancer (28, 29). The combination of Although solid tumors comprise more than 90% of human cancers FCM and ISH has started to address the relationship between DNA (1,2), more than 80% of current cytogenetic data on human neoplasia ploidy and karyotypic abnormality; however, there is a paucity of are based on hematopoietic neoplasms ( 1). What is known about solid studies (29, 30) combining these techniques to investigate the rela tumors has often been obtained from highly advanced tumors which tionship between chromosomal anomalies and proliferative activity. are at a cytogenetically late stage; however, chromosomal anomalies In the present study, rhodamine-labeled DNA probes, recognizing have also been noted in diagnostic biopsies and in adenomas or the highly repetitive region of the centromeres of chromosomes 8, 12, precancerous lesions (1, 3). Considering the relatively high incidence and 17, were applied to 23 archival paraffin-embedded colonie can of colorectal cancers, both benign and malignant, the number of cases cer specimens. The tumors analyzed were of a homogeneous stage studied cytogenetically is surprisingly small. (Astler-Coller Dukes stage C), in an attempt to define the frequency of Recurrent abnormalities that have been identified in colorectal can abnormalities in cancers of comparatively similar age. Chromosome cer include several chromosomes (1-11). The best documented chro copy number data were related to tumor proliferative activity (S-phase mosomal aberrations in spontaneous colonie tumors are deletions of fraction) and DNA ploidy to address possible interrelationships be 17p and 18q, which have been shown to be late stage events (7-9, 12). tween these biological features. Chromosomal anomalies may reflect oncogenic changes ( 13-21 ). Fur thermore, aberrations in chromosome copy number reflect karyotypic instability and may relate to tumor aggressiveness and progression MATERIALS AND METHODS (4,9, 17,21). Interphase cytogenetics, the specific application of ISH5 techniques Pathologic Material. Pathologic specimens for this study were obtained from patients who underwent surgery at Northwestern Memorial Hospital from to interphase cells or nuclei, allows for the investigation of numerical 1978 to 1985. Archival paraffin blocks were analyzed from 23 patients who abnormalities in target chromosomes without requiring the culture of had resections for primary untreated adenocarcinoma of the colon that, on neoplastic cells or preparation of metaphase spreads. Fluorescence pathological staging, were all classified as Astler-Coller stage C (38). Corre labeled DNA probes can be applied to interphase cells (FISH) affixed sponding slides from all specimens were reviewed by a pathologist, and careful diagrams of the location of tumor cells were made so that areas containing the highest yield of neoplastic cells without debris or nonneoplastic cells could be Received 7/27/92; accepted 11/19/92. dissected free when sectioning the blocks. Paraffin-embedded tissues used in The costs of publication of this article were defrayed in part by the payment of page this investigation had been fixed in 10% neutral buffered formalin and pro charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. cessed by standard histological embedding techniques. 1Supported in part by Grant PDT-285 awarded by the American Cancer Society Preparation of Nuclear Suspensions. Paraffin blocks were sectioned into (National Office). 50-nm sections, and areas of representative tumor cells were hand dissected to 2 Present address: Genentech, Inc., 460 Point San Bruno Blvd., South San Francisco, obtain an optimal sample. The tissue was then deparaffinized and dissociated CA 94080. 3 Present address: Department of Pathology, Valduce Hospital, 22100 Como, Italy. according to the literature (36, 39). Briefly, the tumor slices were washed for 4 Present address: Genentech, Inc., 460 Point San Bruno Blvd., South San Francisco, IO min each in successive solutions of xylene, xylene, 100% ethanol, 100% CA 94080. To whom requests for reprints should be addressed. ethanol, 90% ethanol, 70% ethanol, and 50% ethanol and then placed in 5 The abbreviations used are: ISH, in situ hybridization; FCM, flow cytometry; FISH, fluorescence in situ hybridization; HBSS, Hanks' balanced salt solution; HEPES, 4-(2- distilled water. After at least 24 h, the tissue was washed in distilled water, hydroxyethyl)-l-piperazineelhanesulfonic acid; DAPI, 4',6'-diamidino-2-phenylindole finely minced with dissecting scissors, suspended in 0.5% pepsin solution dihydrochloride; LQ, first quartile; HQ, fourth quartile. (Sigma, St. Louis, MO) (in 0.9% NaCl and adjusted to pH 1.5 with HC1) and 681 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1993 American Association for Cancer Research. CHROMOSOME ABERRATIONS RELATE TO S-PHASE AND DNA PLOIDY incubated at 37°C.The suspension was vigorously mixed with a Vortex mixer histograms had a background of cellular debris contributing to the DNA at 5-min intervals for 30 min or until the solution became turbid. The digested histogram. This was subtracted using a "sliced nuclei" curve fitted to the material was then filtered through 37-um monofilament mesh (Tetko, background to the left of the G0G, peak and to the right of the G2M peak (41). Briarcliff, NY). HBSS-HEPES was added to the filtrate, which was then Tumor proliferative activity was expressed in terms of the calculated percent centrifuged at 4°Cand 1000 rpm for 10 min; the pellet was resuspended in age of cells in S-phase. The S-phase data were divided into three levels based HBSS-HEPES and the nuclei were counted. on a statistical definition: Preparation of Slides for ISH. The resulting nuclear suspensions were Mean % S-phase ±0.5 SD = moderate proliferative activity. fixed in methanohacetic acid (3:1) for 20 min: at this point the suspensions could be stored at -20°C or centrifuged at 4°Cand 1000 rpm for 10 min and An S-phase fraction below this range (i.e., <13.7%) was defined as low then washed 2-3 times in the fixative before finally being resuspended at 1-2 x IO6 nuclei/ml. The fixed nuclei were dropped onto poly-Mysine (Sigma)- proliferative activity, whereas S-phase values greater than this range (i.e., >21%) were defined as high proliferative activity. -coated slides, already wet with fixative and warmed over a humid bath. Two Normal colonie epithelium from the same block as the tumor was used as a to three rounds of dropping and brief drying were carried out to achieve control to determine which DNA ploidy peak represented the diploid G0G, sufficient nuclei per slide. The slides were stored at least 12 h in slide boxes in sealed plastic bags at -20°C, but they may be stored for several weeks in this population. An aneuploid population was considered to be present only when two or more distinct G0G, populations were present. The DNA index was manner. calculated by dividing the mean fluorescence channel of the aneuploid G0G, Prehybridization Steps. Using a diamond-tipped scribe, the areas for hy peak by the mean channel number of the diploid G()G] peak.
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