Chromosomes and Neoplasia

Transcription

1 ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 13, No. 5 Copyright 1983, Institute for Clinical Science, Inc. Chromosomes and Neoplasia WARREN G. SANGER, Ph.D. University of Nebraska Medical Center Center for Human Genetics Omaha, NE ABSTRACT Specific chromosome changes are consistently observed in num erous types of neoplasms. These chromosome changes are generally seen only in malignant cells and are not present in somatic cells. Associations of an increased incidence of cancer following exposure to certain chromosome breakage agents, in chromosome instability syndromes, and in patients with gene or constitutional chromosomal imbalances, suggest that chromosomal changes play a role in the etiologies of malignancies. The purpose of this paper is to review briefly chromosomal aberrations in cancer in relation to etiology. Awareness of the probable m ultiple causes of human cancer and the im portance of multidisciplinary collaboration in the investigation of these diseases are essential for a b etter understanding of this complex group of diseases. Introduction Interest in the field of hum an cancer cytogenetics increased in 1960 when the association of the Philadelphia chromosome w ith chronic m yelogenous leu kem ia was first d escrib ed.19 This discovery evoked and supported the idea that some tum ors w ere derived from a single abnormal cell and w ere clonal in origin. Approximately 12 years ago, the in tro d u ctio n of various chrom osom e banding techniques paved th e way for much more detailed cytogenetic analysis of malignant cells. These techniques not only enabled the exact identification of each chromosome but also allowed for the detection of relatively small structural abnorm alities of individual chrom o somes. It is now possible for cytogenetic laboratories to detect deletions, partial triso m ies, tran slo catio n s, and o th e r structural chromosome abnormalities. B overi s h y p o th e sis,3 p u b lish ed in 1914, states first that malignant cells have an abnorm al chrom osom al constitution and, second, that any event leading to an abnormal chromosome constitution will result in a malignant tumor. Nearly 70 years after Boveri s hypothesis was published, the role of chromosome changes in oncogenesis is still m et with controversy. Since the advent of banding procedures, the information relevant to chromosome changes in neoplasms has b e come voluminous and most investigators agree that chromosomal changes in the developm ent of neoplasia are important. Specifically relevant to the hematologic malignancies is the fact that cytogenetic observations often assist in a specific di /83/ $00.90 Institute for Clinical Science, Inc.

2 agnosis and can aid the clinician in providing prognostic inform ation in some situations.2a 16,24 25 This paper will not attem pt to docum en t specific chrom osom al changes which have been reported with certain neoplasms; instead, an attem pt will be m ade to p resen t an overview of chromosomes as related to the neoplastic process (table I). Agents and D iseases which Predispose to Cancer A g e n t s W h i c h C a u s e C h r o m o s o m e B r e a k a g e ( C l a s t o g e n s ) C ertain chem icals, viruses, and ionizing radiation have been shown to initiate chromosome damage and some of these have been implicated as being carcinogens; these topics have been extensively review ed.4,5,10,21 It is the opinion of this author that m ost carcinogens or their m etabolites probably cause chromosomal breakage (viz clastogenic). C h r o m o s o m e I n s t a r il it y D is e a s e s T hree autosom al recessive diseases, Fancon i s anemia, Bloom syndrome, and TABLE I Selected Agents and Conditions Which Pose an Increased Risk of Neoplasm Chromosome Breakage Agents Radiation - ionizing Viruses - only certain types Chemicals - only certain types Chromosome Instability Diseases Fanconi anemia Bloom syndrome Ataxia telangiectasia Constitutional Chromosomal Anomalies Down syndrome Klinefelter syndrome Turner syndrome XY females Trisomy 8 mosaicism Chromosome 13 deletion [del(13)(ql4)] Chromosome 11 deletion [del(11)(ql3)] CHROMOSOMES AND NEOPLASIA 3 67 Breast carcinoma and leukemia Gonadoblastoma Retinoblastoma Aniridia and Wilms tumor ataxia telangiectasia, are characterized by increased spontaneous chrom o some breakage in cultured lymphocytes and fibroblasts. All three of these diseases involve a defect in deoxyribonucleic acid (DNA) repair and an increased incidence of malignancy, primarily of the lymphatic system; however, these neoplasms also occasionally involve the myeloid system. Siblings w ith F an co n i s anemia who both developed acute myelogenous leukem ia associated w ith monosomy for chromosome No. 7 in malignant cells w ere recently studied by us. Also of interest and of possible relevance is the fact that these three chromosome instability syndrom es involve an im m une deficiency during the course of the disease. C o n s t it u t io n a l C h r o m o s o m a l A n o m a l ie s An increased association of leukem ia in ch ild re n w ith D ow n syndrom e is w ell established. C hildren with Down syndrom e have a 1/95 risk of developing leukem ia13 com pared to 1/3,000 in other white children.1 There is also an established increased incidence of breast carc in o m a in K lin e fe lte r (47,XXY) p a tien ts.11 A probable increased incidence of leukem ia in K linefelter6 and Turner (45,X) patients16 has also been reported as has an increased incidence of gonadoblastom a in XY fem ales.18 T here is a suggested predisposition to malignancy in general for patients who have trisomy 8 mosaicism.22 An interstitial deletion of chromosome 13 has been associated with re tin o b lasto m a28 as has a d eletio n of chrom osom e 11 with aniridia and W ilms tum or.23 Tum or Cell Cytogenetics W hen hum an malignant cells are analyzed by early m etaphase (figure 1) or prom etaphase procedures and w hen one can be reasonably confident that tumor

3 368 SANGER ip : \ I i n n <X t c o li j ( 19 20» «ft F igure It !!' 4 ^. Vl t* -li li 0 i. 7* XY It 21 I# Karyotype of an Eary Metaphase preparation of approximately the 550 band stage. cells are being examined, neoplastic cells usually have chromosome abnormalities. Utilizing these high resolution cytoge netic procedures, new abnormalities are being detected,27 and it has been sug gested that m ost neoplastic cells may have a chromosome abnormality.29 In the exceptions to this, the question remains as to whether or not abnormalities are present but not detectable by current techniques. Knudson s two hit theory of carcino genesis1415 proposes the presence of two m utational events in order for tumorigenesis to occur. If the first hit were rep resen ted by an inherited gene or chrom osom e disorder, a second h it would be much m ore likely to cause cancer in this situation than in a person not having a first h it at the tim e of conception. Likewise, increased chro mosomal breakage in the chromosome instability syndromes and breakage in duced by exposure to clastogenic agents would increase the chance for two critical mutational events. This would result in a higher incidence of cancer, which is ob served in these syndromes and in clas togenic exposures. C urrent and Future Emphasis Existing data suggest that chrom o some abnormalities are involved in pre disposition, causation, or are perhaps sometimes secondary to the neoplastic

4 process. B etter classification of tum or subtypes might be achieved through correlation of histological findings with specific chromosome abnormalities. O f a more provocative nature is the fact th at the location of chrom osom al b reakpoin ts in certain p seu d o d ip lo id human cancers have been associated with various im m unoglobulin loci. Rowley26 recently described localizations of im munoglobulin loci on chromosomes 2, 14 and 22 which are chromosomes involved in translocations in Burkitt lymphoma and B cell acute lymphocytic leukemia. These discoveries em phasize the im portance of attem pting to correlate cytogenetic findings w ith virology, im m unology, biochemistry, and pathological characteristics of individual tumors. It is of utm ost im portance that various disciplines attem pt to correlate data relevant to specific neoplasms so that a b etter u nderstanding of malignancies and cancer may develop. Also, since progression of malignancies is often associated with additional changes in the chromosomal pattern, sequential cytogenetic studies on a specific tum or may be helpful in monitoring the disease. R eferences 1. B a e h n e r, R.: Hematological malignancies: and lymphoma. Smith s Blood Diseases of Infancy and Childhood. Miller, D., Pearson, H., Baehner, R., and McMillan, C., eds. St. Louis, C.V. Mosby Co., 1978, pp B e r g e r, R.: The chromosomes in hematology. Cancer Genet. Cytogenet. 4:69-88, B o v e r i, T.: Zur Frage der Entstehung maligner Tumorgen. Jena, Gustav Fischer, 1914, S C o h e n, M. M. and S h a w, M. W.: Specific effects of viruses and antimetabolites on mammalian chromosomes. The Chromosome: Structural and Fundamental Agents. Dawe, C. S., ed. Baltimore, Waverly Press, 1965, pp F r a u m e n i, J., Jr.: Persons at High Risk of Cancer: An Approach to Cancer Etiology and Control. New York, Academic Press, Inc., G a r a e d t s, J., M o l, A., B r i e t, E., H a r t g r in k - G r o e n e w e l d, C., and d e n O H o l a n d e r, G. : Klinefelter syndrome: Predisposition to acute nonlymphocytic leukemia? Lancet 1:774, C H R O M O S O M E S A N D N EO PL A SIA G e r m a n, J.: Blooms syndrome: The phenotype of human genetic disorders predisposing to chromosome instability and cancer. Chromosomes and Cancer. German, J., ed. New York, Wiley, , pp G e r m a n, J. : Genes which increase chromosomal instability in somatic cells and predispose to cancer. Progress Med. Genet. 8 : , G o l o m b, H. M. and R o w l e y, J. D.: Significance of cytogenetic abnormalities in acute leukemias. Hum. Pathol. 12: , H a r n d e n, D. G.: Viruses, chromosomes and tumours: The interaction between viruses and chrom osomes. Chrom osom es and Cancer, German, J, ed. New York, Wiley, , pp H a r n d e n, D., M a c l e a m, N., and L a n g l a n d s, A.: Carcinoma of the breast and Klinefelters syndrome. J. Med. Genet. 8 : , H e c h t, F. and M c C a w, B.: Chromosome instability syndromes. Genetics of Human Cancer. Mulvihill, J., Miller, R., Fraumeni, J., Jr., eds. New York, Raven Press, J a c k s o n, E., T u r n e r, J., K l a u b e r, M., and N o r r i s, F.: Down s syndrome: Variation of leukemia occurrence in institutionalized population. J. Chron. Dis. 2 7 : , K n u d s o n, A., S t r o n g L., and A n d e r s o n, D.: Hereditary cancer in man. Prog. Med. Genet. 9 : , K n u d s o n, A. and S t r o n g, L.: Mutation and cancer: A model for Wilms tumor of the kidney. J. Natl. Cancer Instit. 4 8 : , L a r s o n, R., G o l o m b, H., and R o w l e y, J.: Chromosome changes in hematologic malignancies. Cancer J. Clinicians 31: , M i t e l m a n, F. and L e v a n, G.: Clustering of aberration to specific chromosomes in human neoplasms III. Incidence and geographic distribution of chromosome aberration in cases. Hereditas, 8 9 : , M u l v i h i l l, J., W a d e, W., and M i l l e r, R.: Go- nadoblastoma in dysgenic gonads with a Y-chromosome. Lancet 1:8 6 3, N o w e l l, P. C. and H u n g e r f o r d, D. A.: A minute chromosome in chronic granulocytic leukemia. Science : , O x f o r d, J., H a r n d e n, D., P a r r i n g t o n, J., and D e l h a n t y, J.: Specific chromosome aberration in ataxia telangiectasia. J. Med. Genet. 12: , P u r t i l o, D.: Malignant lymphoproliferative disease induced by Epstein Barr virus in immunodeficient patients, including X-linked cytogenetic and familial syndromes. Cancer Genet. Cytogenet. 4 : , R i c c a r d i, V. and F o r g a s o n, J.: Chromosome 8 abnormalities as components of neoplastic and hematologic disorders. Clin. Genet. 7 4 : , R i c c a r d i, V., S u j a n s k y, E., S m i t h, A., and F r a n c k e, V.: Chromosomal imbalance in the aniridia-wilms tumor association, lip interstitial deletions. Pediatrics 6 7 : ,

5 3 7 0 SA N G E R 24. R o w l e y, J. : Chromosome abnormalities in human leukemia. Annu. Rev. Genet. 14:17-39, Rowley, J. D.: PhJ-positive leukemia including chronic myelogenous leukemia. Clin. Haemat. 9:55-86, R o w l e y, J. : Identification of the constant chromosome regions involved in human hematologic malignant disease. Science 216: , Y u n i s, J., B l o o m f i e l d, C., and E n s r u d, K. : All patients with acute nonlymphocytic leukemia may have a chromosomal defect. New Eng. J. Med. 305: , Y u n i s, J. and R a m s a y, N.: Retinoblastoma and sub-band deletion of chromosome 13. Amer. J. Dis. Child. 732: , Y u n i s, J. : Specific fine chromosomal defects in cancer: An overview. Hum. Pathol. 72: , 1981.