41
9
Section ofComparative Medicine
Professor D G Harmden (Department of Cancer Studies, Medical School, University of Birmingham, Birmingham, B15 2TJ)
long sequence of events involving interaction between the aberrant cells and the host must ensue before clinical evidence of malignant disease is manifest. The rate of proliferation of the cell will depend not only on the cell's inherent capacity for cell division, but also on its responsiveness to host control mechanisms and on such factors as hbrmone balance of the host, while the antigenic structure of the cell will interact with the capacity of the host to respond immunologically. An accumulation of evidence makes it clear that, in this process of progression towards full malignancy, the variability which is one of the most important characteristics of the tumour cell plays an important role in the process of cell selection; and that this process often results in the predominance of cells with a characteristic abnormal karyotype (de Grouchy & Turleau 1974).
Chromosome Abnormalities and Predisposition Towards Cancer Chromosome abnormalities have been recognized in tumour cells for a very long time (Boveri 1914) and it is still true to say that the majority of cancers in both man and animals show chromosome abnormalities. The significance of these changes has been and remains a matter of considerable contention. There are four possibilities: (1) the chromosome changes may themselves represent a visible manifestation of the primary change in neoplasia; (2) they may be a consequence of malignant change rather than the cause, but may, nevertheless, be an important feature of the tumour cell because they confer on the cells a variability upon which tumour progression may depend; (3) the chromosome changes in tumour cells may reflect the instability of the progenitor cells in which the tumour arose and therefore may be an indication of a predisposing factor in the development of malignancy; (4) the chromosome changes may be epiphenomena which accompany malignant transformation but which are of little consequence in either tumour i1iitiation or progression. Before concentrating upon predisposition, the other three possibilities must be considered.
Primary change: Most workers now agree that change in the genetic material of the cell is probably the fundamental change in neoplasia. This change may arise in a number of different ways, e.g. by direct damage to the DNA, by errors of repair of DNA, by insertion of new DNA or by alteration in the regulation of the genetic material without structural damage. Such change may not, of course, result in demonstrable chromosome damage. The fact that some tumour cells, e.g. some human acute leukemias, have apparently normal chromosomes is therefore not inconsistent with the idea that genetic change is the primary event; but it does strongly suggest that visible chromosome abnormalities are not a prerequisite of malignant change. Some authors (e.g. Wakonig-Vaartaja 1962) have argued that chromosomal evidence of clonal evolution supports the idea that chromosome change is the initiating event. While this may be true in some cases it is certainly not universally true. Progression: It is now quite clear that after the initiating stimulus has been applied and the initial intracellular changes have taken place, a
Epiphenomena: The idea that chromosome changes are of no consequence in cancer has had many supporters and for a time it seemed that they might be right. The evidence now overwhelmingly supports the idea that chromosome changes are important, both in progression and as a predisposing factor. Predisposition By predisposition 1 mean that the chromosome abnormality is present before the initiation of the neoplastic process and in some way makes it more likely either that initiation will take place or, having taken place, will be more likely to progress to malignancy. Constitutional chromosome abnormalities: In only three groups of patients with constitutional abnormalities is there good evidence that they have an increased incidence of malignant disease. In trisomy 21 (Down's syndrome)- there is an increased frequency of leukeemia (Holland et al. 1962). Evidence that other malignancies are also increased in Down's syndrome is weak. In the XXY male (Klinefelter's syndrome) there is an increased incidence of breast carcinoma (Harnden et al. 1971) while in females with an XY sex chromosome constitution or who are mosaics with one XY cell line, there is an increased frequency of gonadoblastoma (Mulvihill et al. 1975). The mechanisms by which the increased susceptibility is brought about is not known. There are some suggestions that cells from these groups of patients are more susceptible to transformation by SV40 virus (e.g. Potter & Potter 1975). However, the low level of this increased susceptibility and the variability of this test leaves room for doubt that this is necessarily a demonstration of the underlying mechanism of susceptibility. Increased sensitivity of Down's
42
Proc. roy. Soc. Med. Volume 69 January 1976
10
syndrome lymphocytes to the chromosomedamaging effects of X-rays again suggests that the susceptibility may be at the level of cellular change (Evans & Adams 1973). On the other hand, it may be that the constitutional chromosome abnormality confers on the patient other abnormal features which make malignancy more probable, e.g. in Down's syndrome there is some evidence of immunological insufficiency which could mean that surveillance directed against potential cancer cells is inadequate. Two groups (XXY males and XY females) have a grossly abnormal hormonal balance and this might be an important factor in determining susceptibility. While these specific associations are striking, it does seem clear that the association between cancer and constitutional chromosome abnormality is not a general one, since O'Riordan et al. (1972) found the frequency of such abnormalities in cancer patients did not differ from that found in the general population. Chromosome breakage syndromes: There are three syndromes where spontaneous breakage of chromosomes occurs in both lymphoid and fibroblastic cells. In Fanconi's anemia (Schroeder et al. 1964), the breakage occurs apparently at random. In Bloom's syndrome there is a predilection for chromatid exchanges between identical loci on homologous chromosomes (German 1974) and also a large increase in sister chromatid exchanges (Chaganti et al. 1974). In ataxia telangiectasia (AT) chromosome rearrangements occur as the result of breakage throughout the karyotype but there is a specificity for breakage at the locus 14q13 (Harnden 1974a). Each of these syndromes is associated with an increased incidence of malignant disease. In Fanconi's anemia the increase appears to be in leukaemia and lymphoma only, while in the others there is a preponderance of leukemia and lymphoma but other neoplasms are also increased in frequency. Patients with Bloom's syndrome and ataxia telangiectasia dften have an impaired immune competence and, as in Down's syndrome, poor surveillance may be important in the development of malignancy. However, this is not true in Fanconi's anemia and there is reason to believe that in all of these syndromes the chromosome changes are of major significance. In 'AT for example there is a remarkable development of clones of cytogenetically marked lymphoid cells (Hecht et al. 1973). All the clones reported so far have a rearrangement involving at least one chromosome 14, normally at the locus 14q13, suggesting that this locus is concerned with lymphoproliferation. The parallel with the Philadelphia chromosome in chronic myeloid leukaemia is striking (especially the fact that a preferential but not exclusive translocation is
involved) and it might not be unreasonable to suggest that in both cases a chromosomal rearrangement precedes the malignant process in AT leading to lymphoproliferation and in patients with the Ph' leading to myeloproliferation (McCaw et al. 1975). The malignancy could, on this model, arise within a pre-existing clone which already had a proliferative advantage. One would then predict that in AT the malignancies should have the clonal karyotype, and indeed this has already been reported in one case (McCaw et al. 1975). One would also predict that individuals will exist who have the Philadelphia chromosome in a high proportion of their myeloid cells but who have not got chronic myeloid leukaemia. One such woman, the mother of a case of CML, has been described by Hirschhorn Q4968). This will be hard to prove because of the 4iborious nature of the work required. The concept of clones of cells arising within individuals may not, however, be one that must be confined to subjects with inherited disorders. Lymphocyte clones with abnormal chromosomes have been reported in subjects exposed to ionizing radiation while clones of chromosomally abnormal fibroblasts have been found in cells cultured not only from patients with the chromosome breakage syndromes, but also from normal individuals. The frequency with which clones arise may, however, be higher in patients with a susceptibility to cancer. Burnet (1974) has suggested that intrinsic mutagenesis (i.e. development of aberrant clones) with age may be of fundamental importance both in the process of ageing and in the development of neoplasia. While there is no evidence yet that our finding of clones in cultured cells necessarily indicates that such clones are present in vivo, they would provide some evidence in favour of Burnet's hypothesis. Induced chromosome abnormatlities: There is a remarkable correlation between mutagenesis and carcinogenesis (Ames et al. 1973). While not all mutagens are proven carcinogens, it does seem true that most carcinogens are mutagens. Similarly, there is a close correlation between chromosome damage and carcinogenesis and this is true not only of spontaneous damage but also of induced damage. Radiation-induced chromosome damage is dose related (Evans 1974), as is cancer induction, though no one has yet succeeded in giving a convincing demonstration that radiation-induced chromosome abnormalities are related to the chromosome changes seen in radiation-induced cancers. Since the cancer cells probably arise by a process of selection from within the irradiated population, such a demonstration may be difficult to provide. Viruses, too, can cause chromosome damage. Even viruses such as measles and yellow fever which are not known to cause cancer (and seem
11
highly unlikely to do so) cause chromosome breakage, but they rarely, if ever, cause chromosome rearrangements (Harnden 1974b). While one must hesitate to make sweeping generalizations, it does seem that in those virus cell interactions which frequently lead on to cellular transformation and malignancy, chromosome rearrangement as opposed to chromosome breakage is common. Lastly, many chemical substances cause chromosome damage when applied to cultured cells at nontoxic doses, but the relationship of such damage to malignant transformation is not easy to assess. Chemically induced cellular transformation in vitro does occur (e.g. Rhim & Huebner 1973) but it is not as easy to effect as viral transformation. It seems, therefore, that chemical damage to chromosomes does not necessarily lead on to malignancy. Recent studies of ours with nitrophenylenediamines have made consideration of this point most important (Searle et al. 1975). In this case chromosome damage was demonstrated in cultured human lymphocytes at levels just below the toxic level. The compound concerned (2nitro-para-phenylenediamine) is a constituent widely used in semi-permanent hair dyes and a very large number of people are using these dyes and applying high concentrations directly to the skin of the scalp. It is essential therefore to try to determine whether this is evidence that these substances constitute a potential human hazard. Similarly, in workers exposed to vinyl chloride there is evidence that chromosome aberrations may be demonstrated in lymphocytes cultured from peripheral blood (Funes-Cravioto et al. 1975). Is this an indication that such patients are at risk of getting cancer? Probably the best way to find an answer is by analogy with ionizing radiation. At low levels of radiation an appreciable amount of chromosome damage may be demonstrated in cultured lymphocytes even though the cancer risk must be very low assuming a linear dose response relationship for cancer induction. At high doses where the chromosome damage is considerable the incidence of cancer, though elevated, represents only a tiny fraction of those in whom damaged chromosomes are found. It seems reasonable, therefore, to suggest that a chromosome damaging agency whether chemical, physical or biological should be regarded as a potential carcinogen, but the induction of chromosome damage does not necessarily mean that malignancy will ensue. It does, however, make it more likely, and, if the damage is dose related as with radiation, the amount of damage will be some measure of risk.
Acknowledgment: I wish to express my thanks to the Cancer Research Campaign for their continuing support.
Section of Comparative Medicine
43
REFERENCES Ames B N, Durston W E, Yamasaki E & Lee F D (1973) Proceedings ofthe National Academy ofSciences ofthe USA 70, 2281 Boveri T (1914) Zur Frage der Entstellung maligner Tumoren. G Fischer, Jena Burnet M (1974) Intrinsic Mutagenesis. A Genetic Approach to Ageing. Medical & Technical Publishing, Lancaster Chaganti R S K, Schonberg S & German J (1974) Proceedings of the National Academy ofSciences of the USA 71, 4508-4512 de Grouchy J & Turleau C (1974) In: Chromosomes and Cancer. Ed. J German. Wiley, New York; p 287 Evans H J (1974) In: Chromosomes and Cancer. Ed. J German. Wiley, New York; p 191 Evans H J & Adams A (1973) In: Advances in Radiation Research. Ed. J F Duplan & A Chapiro. Gordon & Breach, New York; Funes-Cravioto F, Lambert B, Lindsten J, Ehrenberg L, Natarajan A T & Osterman-Golkar S (1975) Lancet i, 459 German J (1974) In: Chromosomes and Cancer. Ed. J German. Wiley, New York; p 601 Harnden D G (1974a) In: Chromosomes and Cancer. Ed. J German. Wiley, New York; p 619 (1974b) In: Chromosomes and Cancer. Ed. J German. Wiley, New York; p 151 Harnden D G, MacLean N & Langlands A 0 (1971) Journal ofMedical Genetics 8, 460 Hecht F, McCaw B K & Koler R D (1973) New England Journal of Medicine 289, 286-291 Hirschhorn K (1968) In: Perspectives in Leukwmia. Ed. W Dameshek & R M Dutcher. Grune & Stratton, New York; pp 113-122 Holland W W, Doll R & Carter C D (1962) British Journal of Cancer 16, 177 McCaw B K, Hecht F, Harnden D G & Teplitz R (1975) Proceedings ofthe National Academy of Sciences of the USA 72, 2071-2075 Mulvihill J J, Wade W M & Miller R W (1975) Lancet i, 863 O'Riordan M L, Langlands A 0 & Harnden D G (1972) European Journal ofCancer 8, 373-379 Potter A M & Potter C W (1975) British Journal of Cancer 31, 348 Rhim J S & Huebner R J (1973) Cancer Research 33, 695-700 Schroeder T M, Anschutz F & Knopp A (1964) Humangenetik 1, 194-196 Searle C E, Harnden D G, Venitt S & Gyde H (1975) Nature (London) 225, 506-507 Wakonig-Vaartaja R (1962) British Journal of Cancer 16, 616-618
Dr P K Pani
(Houghton Poultry Research Station, Houghton, Huntingdon, PE] 7 2DA) Genetics of Resistance of Fowl to Infection by RNA Tumour Viruses
Lymphoid leukosis is a lymphoproliferative disease of fowl caused by RNA tumour viruses. No definitive therapy or efficient preventive measure has yet been developed to control the disease. Attempts have been made to breed chickens resistant to leukosis in the past but with very little success. During the past fifteen years, however, progress has been made in understanding the genetic basis of resistance to infection by avian tumour viruses. The finding that host genes regulate cellular infection has stimulated the interest of population geneticists in the possibility that these genes could be fixed in chicken lines in order to breed leukosis-resistant stock. Recently, the finding that normal chick
9
Section ofComparative Medicine
Professor D G Harmden (Department of Cancer Studies, Medical School, University of Birmingham, Birmingham, B15 2TJ)
long sequence of events involving interaction between the aberrant cells and the host must ensue before clinical evidence of malignant disease is manifest. The rate of proliferation of the cell will depend not only on the cell's inherent capacity for cell division, but also on its responsiveness to host control mechanisms and on such factors as hbrmone balance of the host, while the antigenic structure of the cell will interact with the capacity of the host to respond immunologically. An accumulation of evidence makes it clear that, in this process of progression towards full malignancy, the variability which is one of the most important characteristics of the tumour cell plays an important role in the process of cell selection; and that this process often results in the predominance of cells with a characteristic abnormal karyotype (de Grouchy & Turleau 1974).
Chromosome Abnormalities and Predisposition Towards Cancer Chromosome abnormalities have been recognized in tumour cells for a very long time (Boveri 1914) and it is still true to say that the majority of cancers in both man and animals show chromosome abnormalities. The significance of these changes has been and remains a matter of considerable contention. There are four possibilities: (1) the chromosome changes may themselves represent a visible manifestation of the primary change in neoplasia; (2) they may be a consequence of malignant change rather than the cause, but may, nevertheless, be an important feature of the tumour cell because they confer on the cells a variability upon which tumour progression may depend; (3) the chromosome changes in tumour cells may reflect the instability of the progenitor cells in which the tumour arose and therefore may be an indication of a predisposing factor in the development of malignancy; (4) the chromosome changes may be epiphenomena which accompany malignant transformation but which are of little consequence in either tumour i1iitiation or progression. Before concentrating upon predisposition, the other three possibilities must be considered.
Primary change: Most workers now agree that change in the genetic material of the cell is probably the fundamental change in neoplasia. This change may arise in a number of different ways, e.g. by direct damage to the DNA, by errors of repair of DNA, by insertion of new DNA or by alteration in the regulation of the genetic material without structural damage. Such change may not, of course, result in demonstrable chromosome damage. The fact that some tumour cells, e.g. some human acute leukemias, have apparently normal chromosomes is therefore not inconsistent with the idea that genetic change is the primary event; but it does strongly suggest that visible chromosome abnormalities are not a prerequisite of malignant change. Some authors (e.g. Wakonig-Vaartaja 1962) have argued that chromosomal evidence of clonal evolution supports the idea that chromosome change is the initiating event. While this may be true in some cases it is certainly not universally true. Progression: It is now quite clear that after the initiating stimulus has been applied and the initial intracellular changes have taken place, a
Epiphenomena: The idea that chromosome changes are of no consequence in cancer has had many supporters and for a time it seemed that they might be right. The evidence now overwhelmingly supports the idea that chromosome changes are important, both in progression and as a predisposing factor. Predisposition By predisposition 1 mean that the chromosome abnormality is present before the initiation of the neoplastic process and in some way makes it more likely either that initiation will take place or, having taken place, will be more likely to progress to malignancy. Constitutional chromosome abnormalities: In only three groups of patients with constitutional abnormalities is there good evidence that they have an increased incidence of malignant disease. In trisomy 21 (Down's syndrome)- there is an increased frequency of leukeemia (Holland et al. 1962). Evidence that other malignancies are also increased in Down's syndrome is weak. In the XXY male (Klinefelter's syndrome) there is an increased incidence of breast carcinoma (Harnden et al. 1971) while in females with an XY sex chromosome constitution or who are mosaics with one XY cell line, there is an increased frequency of gonadoblastoma (Mulvihill et al. 1975). The mechanisms by which the increased susceptibility is brought about is not known. There are some suggestions that cells from these groups of patients are more susceptible to transformation by SV40 virus (e.g. Potter & Potter 1975). However, the low level of this increased susceptibility and the variability of this test leaves room for doubt that this is necessarily a demonstration of the underlying mechanism of susceptibility. Increased sensitivity of Down's
42
Proc. roy. Soc. Med. Volume 69 January 1976
10
syndrome lymphocytes to the chromosomedamaging effects of X-rays again suggests that the susceptibility may be at the level of cellular change (Evans & Adams 1973). On the other hand, it may be that the constitutional chromosome abnormality confers on the patient other abnormal features which make malignancy more probable, e.g. in Down's syndrome there is some evidence of immunological insufficiency which could mean that surveillance directed against potential cancer cells is inadequate. Two groups (XXY males and XY females) have a grossly abnormal hormonal balance and this might be an important factor in determining susceptibility. While these specific associations are striking, it does seem clear that the association between cancer and constitutional chromosome abnormality is not a general one, since O'Riordan et al. (1972) found the frequency of such abnormalities in cancer patients did not differ from that found in the general population. Chromosome breakage syndromes: There are three syndromes where spontaneous breakage of chromosomes occurs in both lymphoid and fibroblastic cells. In Fanconi's anemia (Schroeder et al. 1964), the breakage occurs apparently at random. In Bloom's syndrome there is a predilection for chromatid exchanges between identical loci on homologous chromosomes (German 1974) and also a large increase in sister chromatid exchanges (Chaganti et al. 1974). In ataxia telangiectasia (AT) chromosome rearrangements occur as the result of breakage throughout the karyotype but there is a specificity for breakage at the locus 14q13 (Harnden 1974a). Each of these syndromes is associated with an increased incidence of malignant disease. In Fanconi's anemia the increase appears to be in leukaemia and lymphoma only, while in the others there is a preponderance of leukemia and lymphoma but other neoplasms are also increased in frequency. Patients with Bloom's syndrome and ataxia telangiectasia dften have an impaired immune competence and, as in Down's syndrome, poor surveillance may be important in the development of malignancy. However, this is not true in Fanconi's anemia and there is reason to believe that in all of these syndromes the chromosome changes are of major significance. In 'AT for example there is a remarkable development of clones of cytogenetically marked lymphoid cells (Hecht et al. 1973). All the clones reported so far have a rearrangement involving at least one chromosome 14, normally at the locus 14q13, suggesting that this locus is concerned with lymphoproliferation. The parallel with the Philadelphia chromosome in chronic myeloid leukaemia is striking (especially the fact that a preferential but not exclusive translocation is
involved) and it might not be unreasonable to suggest that in both cases a chromosomal rearrangement precedes the malignant process in AT leading to lymphoproliferation and in patients with the Ph' leading to myeloproliferation (McCaw et al. 1975). The malignancy could, on this model, arise within a pre-existing clone which already had a proliferative advantage. One would then predict that in AT the malignancies should have the clonal karyotype, and indeed this has already been reported in one case (McCaw et al. 1975). One would also predict that individuals will exist who have the Philadelphia chromosome in a high proportion of their myeloid cells but who have not got chronic myeloid leukaemia. One such woman, the mother of a case of CML, has been described by Hirschhorn Q4968). This will be hard to prove because of the 4iborious nature of the work required. The concept of clones of cells arising within individuals may not, however, be one that must be confined to subjects with inherited disorders. Lymphocyte clones with abnormal chromosomes have been reported in subjects exposed to ionizing radiation while clones of chromosomally abnormal fibroblasts have been found in cells cultured not only from patients with the chromosome breakage syndromes, but also from normal individuals. The frequency with which clones arise may, however, be higher in patients with a susceptibility to cancer. Burnet (1974) has suggested that intrinsic mutagenesis (i.e. development of aberrant clones) with age may be of fundamental importance both in the process of ageing and in the development of neoplasia. While there is no evidence yet that our finding of clones in cultured cells necessarily indicates that such clones are present in vivo, they would provide some evidence in favour of Burnet's hypothesis. Induced chromosome abnormatlities: There is a remarkable correlation between mutagenesis and carcinogenesis (Ames et al. 1973). While not all mutagens are proven carcinogens, it does seem true that most carcinogens are mutagens. Similarly, there is a close correlation between chromosome damage and carcinogenesis and this is true not only of spontaneous damage but also of induced damage. Radiation-induced chromosome damage is dose related (Evans 1974), as is cancer induction, though no one has yet succeeded in giving a convincing demonstration that radiation-induced chromosome abnormalities are related to the chromosome changes seen in radiation-induced cancers. Since the cancer cells probably arise by a process of selection from within the irradiated population, such a demonstration may be difficult to provide. Viruses, too, can cause chromosome damage. Even viruses such as measles and yellow fever which are not known to cause cancer (and seem
11
highly unlikely to do so) cause chromosome breakage, but they rarely, if ever, cause chromosome rearrangements (Harnden 1974b). While one must hesitate to make sweeping generalizations, it does seem that in those virus cell interactions which frequently lead on to cellular transformation and malignancy, chromosome rearrangement as opposed to chromosome breakage is common. Lastly, many chemical substances cause chromosome damage when applied to cultured cells at nontoxic doses, but the relationship of such damage to malignant transformation is not easy to assess. Chemically induced cellular transformation in vitro does occur (e.g. Rhim & Huebner 1973) but it is not as easy to effect as viral transformation. It seems, therefore, that chemical damage to chromosomes does not necessarily lead on to malignancy. Recent studies of ours with nitrophenylenediamines have made consideration of this point most important (Searle et al. 1975). In this case chromosome damage was demonstrated in cultured human lymphocytes at levels just below the toxic level. The compound concerned (2nitro-para-phenylenediamine) is a constituent widely used in semi-permanent hair dyes and a very large number of people are using these dyes and applying high concentrations directly to the skin of the scalp. It is essential therefore to try to determine whether this is evidence that these substances constitute a potential human hazard. Similarly, in workers exposed to vinyl chloride there is evidence that chromosome aberrations may be demonstrated in lymphocytes cultured from peripheral blood (Funes-Cravioto et al. 1975). Is this an indication that such patients are at risk of getting cancer? Probably the best way to find an answer is by analogy with ionizing radiation. At low levels of radiation an appreciable amount of chromosome damage may be demonstrated in cultured lymphocytes even though the cancer risk must be very low assuming a linear dose response relationship for cancer induction. At high doses where the chromosome damage is considerable the incidence of cancer, though elevated, represents only a tiny fraction of those in whom damaged chromosomes are found. It seems reasonable, therefore, to suggest that a chromosome damaging agency whether chemical, physical or biological should be regarded as a potential carcinogen, but the induction of chromosome damage does not necessarily mean that malignancy will ensue. It does, however, make it more likely, and, if the damage is dose related as with radiation, the amount of damage will be some measure of risk.
Acknowledgment: I wish to express my thanks to the Cancer Research Campaign for their continuing support.
Section of Comparative Medicine
43
REFERENCES Ames B N, Durston W E, Yamasaki E & Lee F D (1973) Proceedings ofthe National Academy ofSciences ofthe USA 70, 2281 Boveri T (1914) Zur Frage der Entstellung maligner Tumoren. G Fischer, Jena Burnet M (1974) Intrinsic Mutagenesis. A Genetic Approach to Ageing. Medical & Technical Publishing, Lancaster Chaganti R S K, Schonberg S & German J (1974) Proceedings of the National Academy ofSciences of the USA 71, 4508-4512 de Grouchy J & Turleau C (1974) In: Chromosomes and Cancer. Ed. J German. Wiley, New York; p 287 Evans H J (1974) In: Chromosomes and Cancer. Ed. J German. Wiley, New York; p 191 Evans H J & Adams A (1973) In: Advances in Radiation Research. Ed. J F Duplan & A Chapiro. Gordon & Breach, New York; Funes-Cravioto F, Lambert B, Lindsten J, Ehrenberg L, Natarajan A T & Osterman-Golkar S (1975) Lancet i, 459 German J (1974) In: Chromosomes and Cancer. Ed. J German. Wiley, New York; p 601 Harnden D G (1974a) In: Chromosomes and Cancer. Ed. J German. Wiley, New York; p 619 (1974b) In: Chromosomes and Cancer. Ed. J German. Wiley, New York; p 151 Harnden D G, MacLean N & Langlands A 0 (1971) Journal ofMedical Genetics 8, 460 Hecht F, McCaw B K & Koler R D (1973) New England Journal of Medicine 289, 286-291 Hirschhorn K (1968) In: Perspectives in Leukwmia. Ed. W Dameshek & R M Dutcher. Grune & Stratton, New York; pp 113-122 Holland W W, Doll R & Carter C D (1962) British Journal of Cancer 16, 177 McCaw B K, Hecht F, Harnden D G & Teplitz R (1975) Proceedings ofthe National Academy of Sciences of the USA 72, 2071-2075 Mulvihill J J, Wade W M & Miller R W (1975) Lancet i, 863 O'Riordan M L, Langlands A 0 & Harnden D G (1972) European Journal ofCancer 8, 373-379 Potter A M & Potter C W (1975) British Journal of Cancer 31, 348 Rhim J S & Huebner R J (1973) Cancer Research 33, 695-700 Schroeder T M, Anschutz F & Knopp A (1964) Humangenetik 1, 194-196 Searle C E, Harnden D G, Venitt S & Gyde H (1975) Nature (London) 225, 506-507 Wakonig-Vaartaja R (1962) British Journal of Cancer 16, 616-618
Dr P K Pani
(Houghton Poultry Research Station, Houghton, Huntingdon, PE] 7 2DA) Genetics of Resistance of Fowl to Infection by RNA Tumour Viruses
Lymphoid leukosis is a lymphoproliferative disease of fowl caused by RNA tumour viruses. No definitive therapy or efficient preventive measure has yet been developed to control the disease. Attempts have been made to breed chickens resistant to leukosis in the past but with very little success. During the past fifteen years, however, progress has been made in understanding the genetic basis of resistance to infection by avian tumour viruses. The finding that host genes regulate cellular infection has stimulated the interest of population geneticists in the possibility that these genes could be fixed in chicken lines in order to breed leukosis-resistant stock. Recently, the finding that normal chick
