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Chromosomes in neoplasia: An appeal for unpublished data
Chromosomes in Neoplasia: An Appeal for Unpublished Data Felix Mitelman and G6ran Levan
ABSTRACT: In relation to a recent survey of chromosome aberrations in 856 human neoplasms the following points are presented: 1) the chromosome aberrations of significance to the biology of neoplasms are nonrandom; 2) aberrations of a particular chromosome tend to be of similar kind; 3) aberrations cluster to a limited number of specific chromosomes; 41 geographic differences have been observed in chromosome aberrations; 5) the karyotypic pattern of a neoplasm may be influenced by previous exposure to potential carcinogenic agents; 61 the role of chromosome aberrations in neoplasia-a hypothesis; 7) a plea is made far unpublished data to be included in our next survey of chromosome aberrations. INTRODUCTION Few areas of mammalian cytogenetics have gained more from the chromosome banding techniques than cancer cytogenetics. Being able to identify, by means of Q-, G-, and R-bandings, individual chromosomes and chromosome regions has stimulated the collection of immense amounts of data about cancer-associated chromosomal aberrations, and the systematic evaluation of these data has disclosed a number of correlations between chromosome change and neoplastic disease. The data on chromosomes in human neoplasia are widely scattered in the literature and there is an urgent need for a periodic collection and survey of all the relevant material. We have done so on three occasions [1-3]. Our data have been collected from three main sources: 1) published cases obtained by three separate computer-based literature scans; 2) unpublished cases kindly communicated by numerous colleagues (see acknowledgments in Mitelman and Levan [3]) in answer to our appeal for such data 2 years ago [4]; and 3} unpublished cases from our laboratory. By the end of 1977, the total number of neoplasms for which the chromosomes had been studied by banding techniques, in direct preparations or after short-term in vitro culture, could be estimated to be well above 2500. The majority of these were chronic myeloid leukemia (CML) with the Philadelphia (Ph i} chromosome, t(9;22), as the sole abnormality. Our survey of 1978, from which these CML cases were excluded, comprised 856 cases with aberrations. For technical reasons-hematologic malignancies are more receptive to chromosome analysis than solid t u m o r s - t h e distribution of the 856 cases studied was heavily skewed in favor of hematologic diseases. The myeloproliferative disorders comprised more than 65% of the 856 cases, and From the Department of Clinical Genetics, University Hospital, Lund, and the Institute of Genetics, University of Gothenburg, Sweden.
Address reprint requests to: Dr. F. Mitelman, Department of Clinical Genetics, University Hospital, S-221 85 Lund, Sweden. Received December 27, 1978; accepted March 8, 1979. © Elsevier North Holland, Inc., 1979 Cancer Genetics and Cytogenetics 1, 29-32 (1979)
0165-4608/79/01002904502.25
30
F. Mitelman and G. Levan one particular leukemia t y p e - a c u t e myeloid l e u k e m i a - constituted more than 25%. Also, a certain bias cannot be excluded since many cases might not have come from unselected series. In spite of these obvious deficiencies in the material, a number of conclusions were possible concerning the incidence and significance of chromosomal aberrations in neoplasia (see below). Once again, we appeal to cancer cytogeneticists to keep us posted regarding their new data that they might be included in the next edition of our survey of chromosomes in human neoplasms.
NONRANDOMNESS OF CHROMOSOME ABERRATIONS
All tumor types, of which a fair number have been investigated, show conclusively that the chromosomal aberrations are nonrandom. In each of them only a few chromosome types are preferentially involved (Table 1). TYPES OF ABERRATION
There is a clear tendency that aberrations of particular chromosomes are similar in type; either loss, gain, or change in structure at specific loci. It may eventually be possible to subdivide a certain disorder into distinct chromosomal subgroups, not only according to the particular chromosomes affected but also according to the type of aberration. AFFECTED AND NONAFFECTED CHROMOSOMES
It is obvious from Table I that the aberrations of all tumor types clustered about 12 of the 24 chromosome types, i.e., Nos. 1,3,5,7,8,9,13,14,17,20,21, and 22. No less than eight of these types were involved in three or more disorders. This, in our opinion, means that the chromosomes most often affected carry genetic material of importance to normal development and/or proliferation of cells (see below). ARE THERE GEOGRAPHIC DIFFERENCES?
The 856 cases in our recent survey were subdivided into the geographic regions from which they had been described or from which the patients came. This revealed certain hints that differences in chromosome pattern may exist among geographic regions. For instance, this was found in acute leukemia, chronic myeloid leukemia, polycythemia vera and various other myeloproliferative disorders, malignant lymphomas, and meningiomas. In view of the fact that in experimental tumors different oncogenic agents have been shown to induce different patterns of chromosome aberration in histopathologically identical tumors [5,6], the geographic heterogeneity of chromosomal aberration in human neoplasms may, conversely, be taken to indicate heterogeneity in the distribution of etiologic agents. EFFECTS OF EXPOSURE TO MUTAGENS/CARCINOGENS
Recently another indication of agent-dependence of chromosome aberrations-specifically in human n e o p l a s m s - was obtained, when patients with acute nonlymphocytic leukemia were surveyed concerning exposure to possible mutagenic/carcinogenic agents [7]. The patients were divided into two groups: 1) those occupationally exposed to chemical solvents, pesticides, and petrol products, and 2) those with no history of such exposure. In group 1, 83% of the patients exhibited chromosome aberrations in the leukemic cells, whereas in group 2 only 24% had aberrations.
Chromosomes in Neoplasia Table 1
31
Human chromosomes preferentially engaged in 15 tumor types Tumor type
Myeloprolifarative disorders Acute myeloid leukemia Chronic myeloid leukemia Polycythemia vera Various myeloproliferative disorders Lymphoproliferative disorders Malignant lymphomas (nen-Burkitt) Burkitt's lymphoma Acute lymphocytic leukemia Chronic lymphocytic leukemia Monoclonal gammopathies Solid tumors Meningiomas Benign epithelial tumors Carcinomas Malignant melanoma Neurogenic tumors Sarcomas
Preferential engagement of chromosome No. 5, 7, 8, 21 8, 9, 17, 22 1, 8, 9, 20 1, 5, 7, 8 1, 3, 9, 14 7, 8, 14 1, 21, 22 1, 14, 17 1, 3, 14 8, 22 8, 14 1, 3, 5, 7, 8 1, 9 1, 22 13, 14
Furthermore, a detailed analysis of the karyotypic changes revealed striking differences between the two groups. These results are well in line with the correlation between etiology and karyotypic pattern referred to in the preceding paragraph. SIGNIFICANCE OF CHROMOSOMAL ABERRATION IN CANCER DEVELOPMENT Our survey of 856 cases of human neoplasms, together with our observations in experimental tumors, have led us to certain theories about the role of chromosome aberrations in neoplastic development. We believe that the observable chromosomal changes are of two essentially different kinds: 1) primary (active) and 2) secondary (passive). The former take place in specific loci that must be manipulated to effect the malignant transformation. Instances of such primary changes may be the Ph I in CML and the 14q+ marker in Burkitt's lymphoma. The primary type of change may often be submicroscopic. The secondary (passive) changes are less specific and their origin is often due to accidental chromosome disturbances. Most such changes are eliminated, only those with positive selection value survive to play a role in the karyotypic evolution of the malignant stem line. The secondary changes act to enhance the effect of the primary change. This can be contrived either by increasing the number of chromosome loci, in which the primary change has occurred, or by eliminating the normal, unchanged homologue. Gains and losses of entire chromosomes, which are quite common occurrences during cancer development, belong to this category. Many of the structural changes may also belong there, their results often being "hidden" monosomy or polysomy. Normally, any chromosomal change is deleterious to the cell in which it occurs. The very fact that the stem lines of many tumors exhibit gross chromosomal deviations, such as trisomy for a specific chromosome, is significant in our opinion. How would it be possible-except by additional genetic changes at the submicroscopic l e v e l - t h a t a trisomic cell could acquire competitive superiority over surrounding cells with the normal chromosomal complement? We think
32
F. Mitelman and G. Levan that the a s s u m p t i o n of two essentially different types of chromosomal changes is in good agreement with the data n o w available both from h u m a n and experimental malignancies. The present hypothesis was outlined in Levan and Mitelman [8] and was discussed more fully in Mitelman and Levan [3].
APPEAL FOR UNPUBLISHED DATA During the first few years after the chromosome b a n d i n g techniques had been put to c o m m o n use, almost all findings i n m a l i g n a n t cells were exciting and profited from their news value. It was easy to find editors happy to accept even single cases for p u b l i c a t i o n i n their journals. Today editors are reluctant even to consider p u b l i s h i n g papers on chromosomes of any of the well-studied neoplasms, such as myeloproliferative disorders. Still these data are i n d i s p e n s a b l e for m a n y purposes, as comperative studies, analysis of geographic differences, studies on etiologic factors in connection with occupational exposure, etc. In our opinion, it is extremely important that as m a n y as possible of these cases are registered and made available for these and other purposes. We would, therefore, like to take this opportunity to repeat our appeal from 1976: We shall whole-heartedly welcome any i n f o r m a t i o n - p u b l i s h e d or u n p u b l i s h e d - c o n c e r n i n g n e w cases of h u m a n neoplasia analyzed by chromosome banding, a n d if possible s u p p l e m e n t e d with data on occupation and/or u n u s u a l exposure to potentially mutagenic/carcinogenic agents. A n y information supplied will be included, with due reference, i n the next edition of our survey. Financial support for the present work from the Swedish Cancer Society and from the John and Augusta Persson Foundation for Medical Research is gratefully acknowledged.
REFERENCES 1. Levan G, Mitelman F (1975): Clustering of aberrations to specific chromosomes in human neoplasms. Hereditas 79, 156 - 160. 2. Mitelman F, Levan G (1976): Clustering of aberrations to specific chromosomes in human neoplasms. If. A survey of 287 neoplasms. Hereditas 82, 167 - 174. 3. Mitelman F, Levan G (1978): Clustering of aberrations to specific chromosomes in human neoplasms. III. Incidence and geographic distribution of chromosome aberrations in 856 cases. Hereditas 89, 207 - 232. 4. Mitelman F, Levan G (1976): Do only a few chromosomes carry genes of prime importance for malignant transformation? Lancet 2,264. 5. Levan A, Levan G, Mitelman F (1977): Chromosomes and cancer. Hereditas 86, 15 - 30. 6. Mitelman F, Mark J, Levan G, Levan A (1972): Tumor etiology and chromosome pattern. Science 176, 1340-1341. 7. Mitelman F, Brandt L, Nilsson PG (1978): Relation among occupational exposure to potential mutagenic/carcinogenic agents, clinical findings, and bone marrow chromosome in acute nonlymphocytic leukemia. Blood 52, 1229-1237. 8. Levan G, Mitelman F (1977): Chromosomes and the etiology of cancer. In: Chromosomes Today, vol. 6, A de la Chapelle and M Sorsa, ed. Elsevier/North-Holland, Amsterdam, pp. 363-371.
ABSTRACT: In relation to a recent survey of chromosome aberrations in 856 human neoplasms the following points are presented: 1) the chromosome aberrations of significance to the biology of neoplasms are nonrandom; 2) aberrations of a particular chromosome tend to be of similar kind; 3) aberrations cluster to a limited number of specific chromosomes; 41 geographic differences have been observed in chromosome aberrations; 5) the karyotypic pattern of a neoplasm may be influenced by previous exposure to potential carcinogenic agents; 61 the role of chromosome aberrations in neoplasia-a hypothesis; 7) a plea is made far unpublished data to be included in our next survey of chromosome aberrations. INTRODUCTION Few areas of mammalian cytogenetics have gained more from the chromosome banding techniques than cancer cytogenetics. Being able to identify, by means of Q-, G-, and R-bandings, individual chromosomes and chromosome regions has stimulated the collection of immense amounts of data about cancer-associated chromosomal aberrations, and the systematic evaluation of these data has disclosed a number of correlations between chromosome change and neoplastic disease. The data on chromosomes in human neoplasia are widely scattered in the literature and there is an urgent need for a periodic collection and survey of all the relevant material. We have done so on three occasions [1-3]. Our data have been collected from three main sources: 1) published cases obtained by three separate computer-based literature scans; 2) unpublished cases kindly communicated by numerous colleagues (see acknowledgments in Mitelman and Levan [3]) in answer to our appeal for such data 2 years ago [4]; and 3} unpublished cases from our laboratory. By the end of 1977, the total number of neoplasms for which the chromosomes had been studied by banding techniques, in direct preparations or after short-term in vitro culture, could be estimated to be well above 2500. The majority of these were chronic myeloid leukemia (CML) with the Philadelphia (Ph i} chromosome, t(9;22), as the sole abnormality. Our survey of 1978, from which these CML cases were excluded, comprised 856 cases with aberrations. For technical reasons-hematologic malignancies are more receptive to chromosome analysis than solid t u m o r s - t h e distribution of the 856 cases studied was heavily skewed in favor of hematologic diseases. The myeloproliferative disorders comprised more than 65% of the 856 cases, and From the Department of Clinical Genetics, University Hospital, Lund, and the Institute of Genetics, University of Gothenburg, Sweden.
Address reprint requests to: Dr. F. Mitelman, Department of Clinical Genetics, University Hospital, S-221 85 Lund, Sweden. Received December 27, 1978; accepted March 8, 1979. © Elsevier North Holland, Inc., 1979 Cancer Genetics and Cytogenetics 1, 29-32 (1979)
0165-4608/79/01002904502.25
30
F. Mitelman and G. Levan one particular leukemia t y p e - a c u t e myeloid l e u k e m i a - constituted more than 25%. Also, a certain bias cannot be excluded since many cases might not have come from unselected series. In spite of these obvious deficiencies in the material, a number of conclusions were possible concerning the incidence and significance of chromosomal aberrations in neoplasia (see below). Once again, we appeal to cancer cytogeneticists to keep us posted regarding their new data that they might be included in the next edition of our survey of chromosomes in human neoplasms.
NONRANDOMNESS OF CHROMOSOME ABERRATIONS
All tumor types, of which a fair number have been investigated, show conclusively that the chromosomal aberrations are nonrandom. In each of them only a few chromosome types are preferentially involved (Table 1). TYPES OF ABERRATION
There is a clear tendency that aberrations of particular chromosomes are similar in type; either loss, gain, or change in structure at specific loci. It may eventually be possible to subdivide a certain disorder into distinct chromosomal subgroups, not only according to the particular chromosomes affected but also according to the type of aberration. AFFECTED AND NONAFFECTED CHROMOSOMES
It is obvious from Table I that the aberrations of all tumor types clustered about 12 of the 24 chromosome types, i.e., Nos. 1,3,5,7,8,9,13,14,17,20,21, and 22. No less than eight of these types were involved in three or more disorders. This, in our opinion, means that the chromosomes most often affected carry genetic material of importance to normal development and/or proliferation of cells (see below). ARE THERE GEOGRAPHIC DIFFERENCES?
The 856 cases in our recent survey were subdivided into the geographic regions from which they had been described or from which the patients came. This revealed certain hints that differences in chromosome pattern may exist among geographic regions. For instance, this was found in acute leukemia, chronic myeloid leukemia, polycythemia vera and various other myeloproliferative disorders, malignant lymphomas, and meningiomas. In view of the fact that in experimental tumors different oncogenic agents have been shown to induce different patterns of chromosome aberration in histopathologically identical tumors [5,6], the geographic heterogeneity of chromosomal aberration in human neoplasms may, conversely, be taken to indicate heterogeneity in the distribution of etiologic agents. EFFECTS OF EXPOSURE TO MUTAGENS/CARCINOGENS
Recently another indication of agent-dependence of chromosome aberrations-specifically in human n e o p l a s m s - was obtained, when patients with acute nonlymphocytic leukemia were surveyed concerning exposure to possible mutagenic/carcinogenic agents [7]. The patients were divided into two groups: 1) those occupationally exposed to chemical solvents, pesticides, and petrol products, and 2) those with no history of such exposure. In group 1, 83% of the patients exhibited chromosome aberrations in the leukemic cells, whereas in group 2 only 24% had aberrations.
Chromosomes in Neoplasia Table 1
31
Human chromosomes preferentially engaged in 15 tumor types Tumor type
Myeloprolifarative disorders Acute myeloid leukemia Chronic myeloid leukemia Polycythemia vera Various myeloproliferative disorders Lymphoproliferative disorders Malignant lymphomas (nen-Burkitt) Burkitt's lymphoma Acute lymphocytic leukemia Chronic lymphocytic leukemia Monoclonal gammopathies Solid tumors Meningiomas Benign epithelial tumors Carcinomas Malignant melanoma Neurogenic tumors Sarcomas
Preferential engagement of chromosome No. 5, 7, 8, 21 8, 9, 17, 22 1, 8, 9, 20 1, 5, 7, 8 1, 3, 9, 14 7, 8, 14 1, 21, 22 1, 14, 17 1, 3, 14 8, 22 8, 14 1, 3, 5, 7, 8 1, 9 1, 22 13, 14
Furthermore, a detailed analysis of the karyotypic changes revealed striking differences between the two groups. These results are well in line with the correlation between etiology and karyotypic pattern referred to in the preceding paragraph. SIGNIFICANCE OF CHROMOSOMAL ABERRATION IN CANCER DEVELOPMENT Our survey of 856 cases of human neoplasms, together with our observations in experimental tumors, have led us to certain theories about the role of chromosome aberrations in neoplastic development. We believe that the observable chromosomal changes are of two essentially different kinds: 1) primary (active) and 2) secondary (passive). The former take place in specific loci that must be manipulated to effect the malignant transformation. Instances of such primary changes may be the Ph I in CML and the 14q+ marker in Burkitt's lymphoma. The primary type of change may often be submicroscopic. The secondary (passive) changes are less specific and their origin is often due to accidental chromosome disturbances. Most such changes are eliminated, only those with positive selection value survive to play a role in the karyotypic evolution of the malignant stem line. The secondary changes act to enhance the effect of the primary change. This can be contrived either by increasing the number of chromosome loci, in which the primary change has occurred, or by eliminating the normal, unchanged homologue. Gains and losses of entire chromosomes, which are quite common occurrences during cancer development, belong to this category. Many of the structural changes may also belong there, their results often being "hidden" monosomy or polysomy. Normally, any chromosomal change is deleterious to the cell in which it occurs. The very fact that the stem lines of many tumors exhibit gross chromosomal deviations, such as trisomy for a specific chromosome, is significant in our opinion. How would it be possible-except by additional genetic changes at the submicroscopic l e v e l - t h a t a trisomic cell could acquire competitive superiority over surrounding cells with the normal chromosomal complement? We think
32
F. Mitelman and G. Levan that the a s s u m p t i o n of two essentially different types of chromosomal changes is in good agreement with the data n o w available both from h u m a n and experimental malignancies. The present hypothesis was outlined in Levan and Mitelman [8] and was discussed more fully in Mitelman and Levan [3].
APPEAL FOR UNPUBLISHED DATA During the first few years after the chromosome b a n d i n g techniques had been put to c o m m o n use, almost all findings i n m a l i g n a n t cells were exciting and profited from their news value. It was easy to find editors happy to accept even single cases for p u b l i c a t i o n i n their journals. Today editors are reluctant even to consider p u b l i s h i n g papers on chromosomes of any of the well-studied neoplasms, such as myeloproliferative disorders. Still these data are i n d i s p e n s a b l e for m a n y purposes, as comperative studies, analysis of geographic differences, studies on etiologic factors in connection with occupational exposure, etc. In our opinion, it is extremely important that as m a n y as possible of these cases are registered and made available for these and other purposes. We would, therefore, like to take this opportunity to repeat our appeal from 1976: We shall whole-heartedly welcome any i n f o r m a t i o n - p u b l i s h e d or u n p u b l i s h e d - c o n c e r n i n g n e w cases of h u m a n neoplasia analyzed by chromosome banding, a n d if possible s u p p l e m e n t e d with data on occupation and/or u n u s u a l exposure to potentially mutagenic/carcinogenic agents. A n y information supplied will be included, with due reference, i n the next edition of our survey. Financial support for the present work from the Swedish Cancer Society and from the John and Augusta Persson Foundation for Medical Research is gratefully acknowledged.
REFERENCES 1. Levan G, Mitelman F (1975): Clustering of aberrations to specific chromosomes in human neoplasms. Hereditas 79, 156 - 160. 2. Mitelman F, Levan G (1976): Clustering of aberrations to specific chromosomes in human neoplasms. If. A survey of 287 neoplasms. Hereditas 82, 167 - 174. 3. Mitelman F, Levan G (1978): Clustering of aberrations to specific chromosomes in human neoplasms. III. Incidence and geographic distribution of chromosome aberrations in 856 cases. Hereditas 89, 207 - 232. 4. Mitelman F, Levan G (1976): Do only a few chromosomes carry genes of prime importance for malignant transformation? Lancet 2,264. 5. Levan A, Levan G, Mitelman F (1977): Chromosomes and cancer. Hereditas 86, 15 - 30. 6. Mitelman F, Mark J, Levan G, Levan A (1972): Tumor etiology and chromosome pattern. Science 176, 1340-1341. 7. Mitelman F, Brandt L, Nilsson PG (1978): Relation among occupational exposure to potential mutagenic/carcinogenic agents, clinical findings, and bone marrow chromosome in acute nonlymphocytic leukemia. Blood 52, 1229-1237. 8. Levan G, Mitelman F (1977): Chromosomes and the etiology of cancer. In: Chromosomes Today, vol. 6, A de la Chapelle and M Sorsa, ed. Elsevier/North-Holland, Amsterdam, pp. 363-371.