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(CANCER RESEARCH 50, 3816-3825, July 1, 1990] Special Lecture Molecular Cytogenetics: Rosetta Stone for Understanding Cancer—Twenty-ninth G. H. A. Clowes Memorial Award Lecture1 Janet D. Rowley University of Chicago, Chicago, Illinois 60637 This article provides me with an occasion to review our of the viral oncogenes (5). In a sense, each group of investigators progress in a central area of cancer research, namely the genetic gave the other scientific validity. The fact that oncogenes were changes that occur within the cancer cell that are critically directly involved in chromosome translocations demonstrated involved in the transformation of a normal to a malignant cell. that both translocations and oncogenes were critically involved I think it is especially appropriate that three named awards in human cancer. The correlation of the chromosome location (Clowes, Rosenthal, and Rhoads) presented at the 1989 annual of human protooncogenes as well as other cancer related genes meeting of the American Association for Cancer Research went with recurring chromosome rearrangements is shown in Fig. 1. to investigators who have made contributions to our under Cytogeneticists thus progressed from being mere "stamp collec standing of the genetic changes in cancer cells. Clearly, to tors" to being major contributors in cancer research, an im concentrate on genes to the exclusion of cell biology would be provement in status that I welcome. too narrow and short-sighted an approach. Nonetheless, I am The genetic changes that occur in different types of malignant convinced that until we have isolated the genes that are centrally cells are quite varied and clearly several different changes occur involved in at least some of the malignant processes in different in the same cell as it is altered from a normal to a fully cell types, we will be unable to answer the fundamental ques malignant cell. Cytogenetic analysis has been the key to defining tions about malignant transformation. More importantly, we at least two major categories of rearrangements, namely recur will be unable to answer the questions with precision. I will ring translocations and consistent deletions. One of the first limit my consideration to those changes that have been detected translocations, identified in 1972, was the 9;22 translocation in by analyzing the karyotypic pattern of human cancer cells using chronic myeloid leukemia about which I will say more later (6). chromosome banding, and in particular to those found in leu There are now at least 70 recurring translocations that have kemia. been detected in human malignant cells. But the identification We are living in a golden age of the biomedicai sciences. of consistent chromosome deletions has been equally important Increasingly sophisticated instruments and creative scientific because it has provided the absolutely essential information strategies allow remarkably precise understanding of some as regarding the chromosome location of the genes that are in pects of cancer biology. It is clear that during the course of the volved in cancer. I submit that the retinoblastoma gene would last three decades, the scientific community's assessment of the not have been cloned, or at least not yet, if cytogeneticists had role of chromosome changes in the complex process of malig not identified deletions of the long arm of chromosome 13, and nant transformation has changed from considering them to be specifically of band 13ql4, in patients with constitutional chro merely trivial epiphenomena to recognizing their fundamental mosome abnormalities who had a high incidence of retinoblas involvement for at least some tumors. This change in attitude toma (7). This is not to detract from the careful and exciting has occurred for at least two reasons. First, the demonstration work of many scientists in actually cloning the gene, but at of specific recurring chromosome rearrangements, including least they knew where to look (8). This triumph has now been translocations and deletions, that were often uniquely associ joined by the recent cloning of the DCC (deleted in colorectal ated with a particular type of leukemia, lymphoma, or sarcoma carcinomas) gene on chromosome 18; the fact that a gene provided clear evidence that these rearrangements were criti important in the transformation of colorectal cells was located cally involved in malignant transformation (1-3). About 70 on chromosome 18 was the result of cytogenetic analysis of recurring translocations as well as many nonrandom deletions colon cancer cells that revealed that loss of chromosome 18 and other structural abnormalities are listed in the chapter on was a recurring abnormality (9, 10). structural chromosome changes in neoplasia included in Hu It has been a source of great disappointment to me that we man Gene Mapping 10 (4). The evidence for the presence of have progressed so slowly in cloning most of the genes located recurring chromosome abnormalities in a wide variety of human at the breakpoints in the recurring translocations or inversions neoplasms was the result of 30 years of painstaking chromo in human leukemia. This emphasizes the fact that knowing the some analysis by my cytogenetic colleagues around the world. location of the breakpoint is very helpful in selecting the genes The honor attached to this Clowes award should be shared with to use as probes for these rearrangements. However, a chro all of them. mosome band contains at least 5 million base pairs, and the A second, and I believe an even more powerful, force acting likelihood that the DNA probe that you "pull off the shelf is within the general scientific community to reassess the role of at the breakpoint and can detect a rearrangement on Southern karyotypic alterations was the identification of the genes in blot analysis is vanishingly small. The lymphoid leukemias and volved in some of the chromosome rearrangements and the lymphomas are the major exceptions to this slow progress, discovery that some of these genes were the human counterparts because the immunoglobulin genes in B-cell tumors and the T- cell receptor genes in T-cell tumors have provided the essential Received 3/23/90. 1The research described has been supported by Department of Energy Contract DNA probes to clone several dozen translocations (11-13). DE-FG02-86ER60408 and USPHS Grant CA 42557. Presented at the Eightieth Annual Meeting of the American Association for Cancer Research, May 26, Fortunately, the rapid progress being made in mapping the 1989, in San Francisco, CA. human genome, coupled with major advances in working effec- 3816 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1990 American Association for Cancer Research. FOR C 1C* MYLN JUN THRB[ERBA2] #SCL/TAL1\ TGFA MLVI2 NRASf REL | Gl-R RAP1AÕ »IGK POGFR CSF2(GM)#IL3IL4ILSGFLFGFA K/Tv X PF4N IL1 A/B IL8 FGF5 SKI ICO MGS/1 »PRLL EGF FGFB EGRI TFR IL2 ADRB2RVCSF1CSF1RÕFMS1ADRA1RPOGFRB TRK \ TGFB2 i M3(EVI1) HRAS1 0TAL1/TTG 4" tPDGFA IGF2 RALA INS IL6 «TCRG * KRAS2 EGFR[ERBß1] SPII ROSI MYB ••4 MASI #TCRB IGF1 ESR FNG IGF2R #CAN 1 o 1 1 1 2 TP53 «TCRA/D CSF3(G) #RB1 THRA1ÕERBA1] ERABBÃŽ INT4 TGFB3 NGFR FOS GH1/2 4 FES AKT1 *TCL1# 4 ELK2 IGF1R #IGH 1 3 1 4 1 5 1 6 1 7 1 8 Left Side Italic: protooncogene or tumor suppressor gene Plain: growth factor or receptor or cancer related gene <E> n cloned translocation breakpoint t ambiguous location HCK( SRC *BCR ETS2 Right Side PDGFBISIS] RRAS e | region of chromosome duplication i region of chromosome deletion 2 2 1 9 2 O 21 4 recurring breakpoints DBL ^" cloned breakpoints Italic viral integration sites or breakpoint lacking a transcript Fig. 1. Map of the chromosome location of protooncogenes or of genes that appear to be important in malignant transformation and the breakpoints observed in recurring chromosome abnormalities in human leukemia, lymphoma, and solid tumors. Known protooncogenes are indicated in bold italics and other cancer related genes are listed in standard type. The protooncogenes and their locations are placed to the left of the appropriate chromosome band or region (indicated by a bracket). The breakpoints in recurring translocations, inversions, etc., are indicated with an arrowhead to the right of the affected chromosome band. The solid vertical lines on the right indicate regions frequently present in triplicate; the dashed lines indicate recurring deletions. Recurring viral integration sites and cloned translocation breakpoints with no identified transcripts are indicated to the right of the appropriate band. Genes or recurring breakpoints that have been cloned are identified by #. The locations of the cancer specific breakpoints are based on the Report of the Committee on Structural Chromosome Changes in Neoplasia, Human Gene Mapping 10 (4). [Author's note: Any map of this sort involves selection as to the genes that should or should not be included: I have been relatively conservative. Also for recurring breakpoints and deletions, I have included only those listed as Status I or II in HGM10. This figure was prepared by Michelle S. Rebelsky.) 3817 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1990 American Association for Cancer Research. MOLECULAR CYTOGENETICS lively with large pieces of DNA, should lead to the successful chromosome, No. 21 or 22, was involved and was the Ph' really cloning of most of the recurring translocations in the acute the result of a chromosome deletion as had been assumed in leukemias and sarcomas in the next 5 years. the 1960s? With the use of the banding, the Ph' chromosome From the beginning of the cytogenetic analysis of human was shown to involve chromosome 22, and in 1972 I could malignant disease it has been clear that virtually all solid show that it occurred as the result of a translocation rather tumors, including the non-Hodgkin's lymphomas, have an ab than a deletion.

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