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Cancer genetics: from Boveri and Mendel to microarrays
Author: Allan Balmain
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"PERSPECTIVES imbalance that is too severe and so death ensues. This work convinced Boveri that the individual chromosomes carry different information, a thesis summarized in his chromosomal theory of heredity in 1902?1904 (REFS 3?5). The association between the abnormal growth of sea-urchin eggs that carry the ?wrong? chromosomal complement and the unrestricted growth of tumours did not escape Boveri?s notice and, in his study of sea-urchin chromosomes 3 , he suggested that tumours might arise as a consequence of abnormal segregation of chromosomes to daughter cells. This hypothesis was developed and extended in 1914, in his cel- ebrated Zur Frage der Entstehung Maligner Tumoren (?The Origin of Malignant Tumours?) 6 . He postulated that tumour growth is based on ??a particular, incorrect chromosome combination which is the cause of the abnormal growth characteris- tics passed on to daughter cells??. In addi- tion to the experimental observations and their insightful interpretations, Boveri made several predictions that, in retrospect, are chillingly accurate. Many concepts that are now commonly accepted were fore- shadowed by Boveri, including cell-cycle checkpoints, oncogenes and tumour-sup- pressor genes, tumour predisposition, and the relationship between genetic instability and cancer (BOX 1). It is a sobering thought that the experimental proof of many of these predictions became the cornerstone of cancer research over the next 85 years (see TIMELINE). Proto-oncogenes and cancer Boveri postulated the existence of ?growth- stimulatory chromosomes? and, further- more, that the unlimited growth of malig- nant tumour cells is attributable to a permanent increase in the number of these growth-promoting chromosomes. The con- cept of the gene had, of course, not been developed at that time, but if we substitute the word ?gene? for ?chromosome?, this vision clearly predicted the Nobel-prize-winning discovery of cellular proto-oncogenes by Harold Varmus and Mike Bishop in the 1970s ? that genes that are present in all ?normal? cells can become deregulated, amplified or overexpressed and contribute to malignancy 7,8 . This ground-breaking discov- ery was made through the study of RNA tumour viruses, some of which had captured cellular genes that, when expressed at high level or in mutant form in normal cells, made these cells adopt the characteristics of rapid, uncontrolled growth that are typical of many tumours. The discovery of these genes The human genome has now been sequenced, a century after the re- discovery of Mendel?s Laws, and the publication of Theodor Boveri?s chromosomal theory of heredity. Tracing the historical landmarks of cancer genetics from these early days to the present time not only gives us an appreciation of how far we have come, but also emphasizes the challenges that we face if we are to unravel the genetic basis of hereditary and sporadic cancers in the next century. Theodor Boveri is one of the towering figures of twentieth-century genetics (FIG. 1), as he was the first to provide a mechanistic basis for the transmission of traits that were pro- posed by Mendel 1 . Boveri died in 1915, but, unlike Mendel, did not have to wait 50 years to receive recognition from his peers. Two of the significant contemporary figures in developmental biology ? E. B. Wilson and Hans Spemann ? dedicated their text books to him, and Wilson wrote a piece specifically on Boveri that included the statement: ?Boveri stood without a rival among the biol- ogists of his generation; and his writings will long endure as classical models ?? 2 . Boveri?s work on the fertilization of sea- urchin eggs by two sperm instead of one showed that distribution of unequal num- bers of chromosomes to the daughter cells gives rise to specific characteristics that depend on the random combinations of chromosomes that they inherit (FIG. 2). Some daughter cells survive but develop abnormally, whereas others have a genetic NATURE REVIEWS | CANCER VOLUME 1 | OCTOBER 2001 | 77 Cancer genetics: from Boveri and Mendel to microarrays Allan Balmain TIMELINE Figure 1 | A portrait of Theodor Boveri. (Reproduced from Baltzer, F. Theodor Boveri. Wissenschaftliche Verlagsgesellschaft. Stuttgart, Germany (1962). Courtesy of Peter Wolbert, The University of W�rzburg.) � 2001 Macmillan Magazines Ltd 78 | OCTOBER 2001 | VOLUME 1 www.nature.com/reviews/cancer PERSPECTIVES external growth-factor stimulation by becoming phosphorylated at specific sites, which, in turn, removes the inhibitory influence and allows passage through the checkpoint 22?23 . The concept of inherited predisposition and homozygous inactiva- tion of a tumour-suppressor gene was also noted by Boveri. He predicted that cancer predisposition could be attributed to the inheritance of chromosomes (genes) that have ?weaker resistance against the action of factors that stimulate cell division? 6 . Furthermore, for a tumour to develop, ?the homologous elements of both chromo- somes have to be similarly weakened? 6 , leading to a chromosomal explanation of the increased incidence of cancer in the progeny of consanguineous marriages. In 1971, Knudson carried out an epi- demiological study of retinoblastoma development in children. The results echoed some of Boveri?s predictions, but allowed the formulation of a mathematical model that was subject to experimental testing. He postulated that ?two hits? are required for the complete inactivation of a the field of cancer genetics, as they showed that a specific change in DNA could, when transferred in the form of whole genome DNA into an otherwise fairly normal cell, confer at least some of the properties of malignancy on that cell 14 . Further studies on human tumours identified the causative change as a point mutation in a single gene ? one of the members of the RAS proto- oncogene family (HRAS) 15?17 . Mechanistic studies in animal models showed that this same gene is consistently activated in specif- ic animal models of cancer 18 , and that they are caused by exposure to particular car- cinogens 19?20 . These studies provided the first direct link between mutagen exposure and changes in target genes that are involved in causing malignancy. Tumour-suppressor genes If the 1970s and early 1980s were the era of RNA tumour viruses and oncogenes, the subsequent decade was dominated by tumour-suppressor genes. These were also predicted by Boveri, who foresaw that ?inhibitory chromosomes? (teilungshem- mende Chromosomen) would be physically removed by malignant tumours. He postu- lated that inhibitory chromosomes formed part of a mechanism that keeps normal cells in check, until a specific extracellular stimulus relieves the inhibition and allows cell division to proceed. The prototype tumour-suppressor gene, known as the retinoblastoma or RB gene 21 , fulfilled these criteria as it inhibits cell-cycle progression at the G1/S boundary and responds to and the clarification of their roles in the nor- mal processes of growth control, differentia- tion and development has had a significant impact on our understanding of cellular function, in addition to providing us with an array of targets for the development of new cancer therapies. The development of cytogenetic tech- niques was crucial in developing our understanding of the chromosome aberra- tions that were visualized by Boveri under the microscope. The history of the ?Philadelphia chromosome?, a fusion of two chromosome fragments that is detected in the blood cells of patients with chronic myeloid leukaemia (CML), illustrates how therapeutic drug development can arise from an understanding of the genetic changes in cancer cells. The Philadelphia chromosome was initially discovered in 1960 (REF. 9); it took more than a decade to identify the chromosomes involved in the translocation 10 , a further decade to find the gene that was activated as a consequence of this change 11 , and almost two more decades to develop a drug that is targeted specifically at the activated gene product 12 . Many other cytogenetic studies, predominantly of leukaemias (reviewed in REF. 13), identified a series of specific chromosomal changes that are associated with malignancy, some of which might yield to the same therapeutic strategy as that found for the product of the Philadelphia chromosome translocation. A revolutionary series of experiments involving DNA transfection provided the first real demonstration of a causal role for genetic alterations in cell transformation. These studies had an electrifying effect on ?Boveri stood without a rival among the biologists of his generation; and his writings will long endure as classical models?? aa b c d c d b d aab c ? ? cc d aa ? d ? b c d bb ab 1 12 2 3 344 Figure 2 | Multiple cell poles cause unequal segregation of chromosomes. a | Boveri showed that fertilization of sea-urchin eggs by two sperm results in multiple cell poles. Individual chromosomes then attach to different combinations of poles ? for example, one copy of chromosome c is attached to poles 1 and 2, and one copy is attached to poles 2 and 3. b | Chromosomes are segregated to the four poles at cell division, leaving some cells with too many copies of the chromosomes and some with too few ? for example, cell 2 has two copies of chromosome c and cell 4 has none. Box 1 | Boveri?s predictions ? Cell-cycle checkpoints (Hemmungseinrichtung: inhibitory mechanism) that would allow cell division only when a specific external stimulus is experienced by the cell. ? Tumour-suppressor genes (Teilungshemmende Chromosomen), the effects of which can be overcome by external signals, and which are physically lost in progressively growing tumours. ? Oncogenes (Teilungsfoerdernde Chromosomen) that become amplified (im permanenten �bergewicht) during tumour development. ? Tumour progression from benign to malignant, involving sequential changes of increased growth-stimulatory chromosomes and loss of growth-inhibitory chromosomes. ? The clonal origin of tumours. ? Genetic mosaicism. ? Cancer predisposition through inheritance of chromosomes (genes) that are less able to suppress malignancy. ? Cancer predisposition through inheritance of genes that cause aberrant mitoses. ? Inheritance of the same ?weak chromosome? from both parents leads to homozygosity for the defective chromosome and, consequently, to high-penetrance cancer syndromes ? for example, xeroderma pigmentosum. ? The role of wounding and inflammation in tumour promotion. ? Loss of cell adhesion in metastasis. ? Sensitivity of malignant cells to radiation therapy. � 2001 Macmillan Magazines Ltd PERSPECTIVES many investigators over the past two decades. In addition to aneuploidy, caused by uncontrolled segregation of chromo- somes to daughter cells, altered stability at the nucleotide level also has an important role. Loeb and colleagues proposed that it would be difficult for an aspiring tumour cell to acquire the number of mutations that are necessary for development of malignan- cy during the lifetime of the host, and that this conundrum could be solved by postu- lating the existence of ?mutator? genes 41 . These were predicted to be genes that increase the rate of mutation within tumour cells when they themselves are mutated, allowing the cells to reach the hit rate that is required to eliminate all of the controls exerted by normal checkpoints. Accordingly, the study of familial cancers has again provided answers, with the discovery of germ-line mutations in genes that affect DNA repair and lead to hereditary non-poly- posis colorectal cancer (HNPCC). Defects in genes that control genetic stability at the level of short repeat sequences, rather than at the chromosome level, were first noticed in stud- ies of non-familial or sporadic cancers 42,43 , and some of the causative genetic changes were identified in samples from individuals with HNPCC 44 . These and many other studies indi- cated that the genome is a database of infor- mation that is constantly monitored for both large- and small-scale defects. Any deficiencies in normal cells are coupled to efficient mecha- nisms for repair, or, in certain circumstances, to cell death. The TP53 tumour-suppressor tumour-suppressor gene 24 , suggesting that cancer predisposition results from inheri- tance of a specific mutation in a suppressor gene, but that the development of tumours requires subsequent somatic alterations that result in loss of the wild-type copy of the same gene. The tools that are necessary to test the Knudson hypothesis at the mole- cular level, as well as to detect the chromo- somal changes observed by Boveri, were provided by Cavenee and colleagues 25 .They devised methods for tracking the parental origin of particular alleles, and following their subsequent fate during tumorigenesis through loss of heterozygosity (LOH) resulting from somatic deletions or recom- binations. These tools were exploited in the mapping 25 and subsequent cloning of RB 21 , and also by several other groups to identify the ?high-penetrance? genes that are respon- sible for familial colon and breast can- cers 26?30 . The importance of these discover- ies lies not only in the identification of the genes, but also in the elucidation of the growth-control pathways in which they operate, which provide a plethora of previ- ously unsuspected diagnostic and thera- peutic drug targets. The TP53 tumour-suppressor gene occu- pies another special niche in the history of cancer genetics. p53 was first identified in a complex with SV40 T antigen, a protein pro- duced by a DNA tumour virus 30?31 , and was initially assumed to act exclusively as an oncogene. The first indications that the story might not be quite so simple came from studies of mouse and human leukaemia cell lines in which Trp53 and TP53, respectively, had rearrangements that led to loss of func- tion, rather than activation 33?35 . In addition, the concept that viral oncoproteins trans- form cells by binding and inactivating tumour-suppressor proteins was clearly shown for the adenoviral E1A?RB protein interaction 22 , raising the possibility that the interaction between p53 and the SV40 large T antigen could also lead to loss of p53 func- tion. Nevertheless, the prevailing view of p53 as an oncogene persisted until LOH evi- dence from human tumour analysis pin- pointed TP53 within a region that was con- sistently deleted in tumours 36,37 . Sequencing and functional studies, which identified inactivating or loss-of-function mutations in TP53, confirmed its role as a bona fide tumour-suppressor gene in agreement with the Knudson two-hit proposal 38 . This work set the stage for an explosion of research on the pathways by which this protein monitors DNA damage in humans and other organ- isms, and regulates cell growth, cell death and tumorigenesis 39 . Interestingly, TP53,like RB, exists in mutant heritable forms in the germ line, and contributes to familial can- cers when the remaining wild-type allele is lost by somatic genetic alterations 40 . Genetic instability and cancer The concept of genetic (chromosomal) instability, which was originally proposed by Boveri as a cause of abnormal growth and cancer, has been confirmed and extended by NATURE REVIEWS | CANCER VOLUME 1 | OCTOBER 2001 | 79 Boveri identified the chromo- some as the unit of heredity and proposed that chromoso- mal aberrations were the cause of cancer 3?6 . Knudson pro- posed the ?two-hit? hypothesis 24 . Discovery of the ?Philadelphia chromo- some? ? a translocation between chromosomes 9 and 22, leading to the activation of the Abelson leukaemia virus (ABL) oncogene 9 . Discovery of cellular proto- oncogenes that are related to the transforming genes of retroviruses 7 . Activated oncogenes in tumour DNA ? first demonstration of a causal genetic event associated with cancer. DNA derived directly from tumours was shown to transform ?nor- mal? cells when intro- duced into these cells as a high-molecular-weight complex 14 . Loss of hetero- zygosity analy- sis was used to map the first tumour-sup- pressor gene, RB 25 . Identification of p53 in a com- plex with viral proteins 31?32 . Cloning and iden- tification of RB ? the first tumour- suppressor gene 21 . Cloning of the gene responsible for famil- ial adenomatous polyposis (APC) 26?28 . This gene was sub- sequently shown to act as a ?gatekeep- er?. APC mutations are also seen in spo- radic colon cancers. Demonstration that TP53 was a human tumour-suppressor gene, rather than (or in addition to) an onco- gene 37 . Subsequent studies showed that TP53 was the most fre- quently mutated gene in human cancers. Identification of the telomeric sequence of Trypanosoma brucei 46 . Identification of the first familial breast cancer sus- ceptibility gene, BRCA1 29?30 . Mutations in this gene and its close rel- ative BRCA2 cause familial breast cancer, but, in con- trast to some other high- penetrance susceptibility genes, they are not com- monly mutated in sporadic cancers. The first draft of the human genome sequence is published (see online links box). Cloning of telom- erase (TERT) and demonstration that telomerase expres- sion can extend the lifespan of human cells 49?52 . Discovery of microsatellite instability in human tumours and identification of a mismatch repair gene (MSH2) as the first gene responsible for hereditary non-polyposis colon cancer (HNPCC) 42?44 . Timeline | Genetic landmarks in cancer research 1902?1914 1960 1971 1976 1979 1983 1984 1986 1989 1991 1993 1994 1997?1998 2001 � 2001 Macmillan Magazines Ltd 80 | OCTOBER 2001 | VOLUME 1 www.nature.com/reviews/cancer PERSPECTIVES early screening and targets for therapeutic development. Perhaps more importantly, however, gene networks that control the rate- limiting steps of disease progression will pro- vide us with basic insights into cancer biology that are not available by other methods. Although much information will come from large-scale sequencing of human tumour DNA samples, it is clear that this ?tumour-cen- tric? approach will not detect variants in genes that are only expressed in stromal cells, immunocompetent cells or other components of the tumour microenvironment that have important functions as non-cell-autonomous factors in cancer predisposition. So, what tools are necessary to find these genes? We already know that many genetic modifiers have been mapped ? if not actu- ally identified ? from mouse models of cancer, and that these alleles engage in genetic interactions that result in the whole effect being greater than the sum of the individual components 56 . The importance of genetic interactions was underlined in evolutionary terms by Sewall Wright, who stated that ?a gene is selected on how well its effects fit in with those of the current genetic system? 57 . Wright?s proposal was that the driving force of selection per se was not necessarily the individual gene variant or mutation, but the combinatorial effect of this variant with the particular constella- tion of other variants within the host genet- ic background. He was referring to evolu- tionary selection, but the same principle applies to selection of tumour cells, in that certain mutations are selected when the genetic background (including occurrence of other mutations) is appropriate. In the development of colon cancer, for example, TP53 mutations seem to be necessarily pre- ceded by mutations in the adenomatous polyposis coli (APC) gene 58 , presumably because TP53 mutations in normal colon cells do not provide the appropriate selec- tive advantage. Similarly, specific low-pene- trance cancer-predisposition genes might only confer susceptibility or resistance to cancer in a particular context: the genetic topography has to be appropriate to observe functional interactions. Mouse models have been adapted for the study of cancer gene interactions, whereas human-cancer-susceptibility stud- ies have focused on identifying genes with relatively strong effects that are detectable by classical linkage analysis in families or by association studies using candidate gene polymorphisms. The identification of many interacting low-penetrance alleles for human cancer susceptibility might require ~ 15?20% of the familial cases 53 , indicating that most of the genetic risk factors remain to be discovered. Sporadic cancers also have a strong genetic component, particularly for certain tumour types, such as prostate cancer 54 . Why have the genes that are responsible not been found? The reasons are related to the probability that the low- hanging fruit of cancer susceptibility has already been plucked, and that all or most of the familial cases that conform to the ?one gene?one disease? model have already been found. The methods of cancer-suscep- tibility gene detection that were so success- ful in the twentieth century might not suf- fice to find the larger number of low-penetrance genes that control suscepti- bility to sporadic forms of the disease. If these genes are hard to find, have weak effects and number in the dozens, if not hun- dreds, why should we embark on the arduous task of finding them? First, it is clear from ani- mal models of cancer that many low-pene- trance genes are extremely powerful preventive agents. For example, skin cancer that is induced by exogenous carcinogens can be almost completely suppressed by the introduc- tion of dominant resistance genes into suscep- tible mouse strains by breeding with strongly resistant species 55 . Second, identification of human polymorphisms that control sporadic disease susceptibility is one of the ?holy grails? of drug discovery, offering the opportunity for gene is one of many that are involved in cell death; consequently, mutations that cause loss of function of these genes lead to an increase in survival of tumour cells 45 . Telomeres, crisis and cancer No discussion of the views of Boveri on chromosome instability and cancer would be complete without mentioning the associ- ation of telomere crisis with events that lead to tumorigenesis. Telomeres consist of a series of small repeat sequences at the ends of chromosomes that act as caps, protecting them from degradation during cell growth and differentiation 46 . Cell division results in the gradual shortening of telomeres 47 ,even- tually resulting in crisis when the chromo- some ends become dysfunctional. This rings an alarm bell that results in cell death by a mechanism that involves activation of p53- mediated apoptosis 48 . Tumours circumvent this fate both by inactivating the cell-death pathway, and by switching on telomerase ? an enzyme that helps to maintain telomere length ? which allows them to acquire the capacity for infinite cell division 49?52 . These observations, made only within the very recent past, show the uncanny foresight of Boveri in his analysis of the genetic basis of chromosome stability. Although the concept of telomeres did not exist in 1914, the ?weakness? that Boveri discusses in the fol- lowing passage could be interpreted as the progressive change in telomere length that only becomes manifest after many cell divi- sions. This telomere shortening leads to cri- sis, chromosome end-to-end fusions and genetic instability 48 : ?For unknown reasons, a ?weakness? may occur in specific chromo- somes with respect to control of mitosis that at first remains latent and thus is transmit- ted to a large number of daughter cells ? With the beginning of senescence, perhaps this latent weakness becomes manifest in the failure of mitotic control in such a way that when cell division occurs, there is a possibility of generating daughter cells with recurrent genetic abnormalities.? Susceptibility to sporadic cancer It is clear from the above discussion that familial cases of cancer have been more important in the development of our understanding of the genetic basis of the disease than is their numerical impact on the human cancer burden ? familial can- cers account for only ~ 5% of human can- cers, the remainder being ?sporadic? cases. The long sought-after BRCA1 and BRCA2 genes that confer strong susceptibility to breast and ovarian cancer account for only ?For unknown reasons, a ?weakness? may occur in specific chromosomes with respect to control of mitosis that at first remains latent and thus is transmitted to a large number of daughter cells ? With the beginning of senescence, perhaps this latent weakness becomes manifest in the failure of mitotic control in such a way that when cell division occurs, there is a possibility of generating daughter cells with recurrent genetic abnormalities.? � 2001 Macmillan Magazines Ltd PERSPECTIVES 29. Futreal, P. A. et al. BRCA1 mutations in primary breast and ovarian carcinomas. Science 266, 120?122 (1994). 30. Miki, Y. et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266, 66?71 (1994). 31 Lane, D. P. & Crawford, L. V. T antigen is bound to a host protein in SV40-transformed cells. Nature 278, 261?263 (1979). 32. Linzer, D. I. & Levine, A. J. Characterization of a 54K Dalton cellular SV40 tumor antigen present in SV40- transformed cells and uninfected embryonal carcinoma cells. Cell 17, 43?52 (1979). 33. Wolf, D. & Rotter, V. Inactivation of p53 gene expression by an insertion of Moloney murine leukemia virus-like DNA sequences. Mol. Cell. Biol. 4, 1402?1410 (1984). 34. Wolf, D. & Rotter, V. Major deletions in the gene encoding the p53 tumor antigen cause lack of p53 expression in HL-60 cells. Proc. Natl Acad. Sci. USA 82, 790?794 (1985). 35. Mowat, M., Cheng, A., Kimura, N., Bernstein, A. & Benchimol, S. Rearrangements of the cellular p53 gene in erythroleukaemic cells transformed by Friend virus. Nature 314, 633?636 (1985). 36. Fearon, E. R., Hamilton, S. R. & Vogelstein, B. Clonal analysis of human colorectal tumors. Science 238, 193?197 (1987). 37. Baker, S. J. et al. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science 244, 217?221 (1989). 38. Baker, S. J., Markowitz, S., Fearon, E. R., Willson, J. K. & Vogelstein, B. Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 249, 912?915 (1990). 39. Lane, D. P. p53 guardian of the genome. Nature 358, 15?16 (1992). 40. Malkin, D. et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas and other neoplasms. Science 250, 1233?1238 (1990). 41. Loeb, L. A., Springgate, C. F. & Battula, N. Errors in DNA replication as a basis of malignant change. Cancer Res. 34, 2311?2321 (1974). 42. Ionov, Y., Peinado, M. A., Malkhosyan, S., Shibata, D. & Perucho, M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic neoplasia. Nature 363, 558?561 (1993). 43. Thibodeau, S. N., Bren, G. & Schaid, D. Microsatellite instability in cancer of the proximal colon. Science 260, 816?819 (1993). 44. Parsons, R. et al. Hypermutability and mismatch repair deficiency in RER+ tumor cells. Cell 75, 1227?1236 (1993). 45. Evan, G. I. & Vousden, K. H. Proliferation, cell cycle and apoptosis in cancer. Nature 411, 342?348 (2001). 46. Blackburn, E. H. & Challoner, P. B. Identification of a telomeric DNA sequence in Trypanosoma brucei. Cell 36, 447?457 (1984). 47. Hastie, N. D. et al. Telomere reduction in human colorectal carcinoma and with ageing. Nature 346, 866?869 (1990). 48. Chin, L. et al. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97, 527?538 (1999). 49. Nakamura, T. M. et al. Telomerase catalytic subunit homologs from fission yeast and human. Science 277, 955?959 (1997). 50. Meyerson, M. et al. hEST2 the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell 90, 785?795 (1997). 51. Bodnar, A. G. et al. Extension of life-span by introduction of telomerase into normal human cells. Science 279, 349?352 (1998). 52. Vaziri, H. & Benchimol, S. Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span. Curr. Biol. 8, 279?282 (1998). 53. Ponder, B. Cancer genetics. Nature 17, 336?341 (2001). 54. Lichtenstein, P. et al. Environmental and heritable factors in the causation of cancer ? analyses of cohorts of twins from Sweden, Denmark, and Finland. N. Engl. J. Med. 343, 78?85 (2000). 55. Balmain, A. & Nagase, H. Cancer resistance genes in mice: models for the study of tumour modifiers. Trends Genet. 14, 139?144 (1998). 56. Fijneman, R. J., de Vries, S. S., Jansen, R. C. & Demant, P. Complex interactions of new quantitative trait loci, Sluc1, Sluc2, Sluc3, and Sluc4, that influence the susceptibility insights derived from combinations of mouse models to identify the candidate interacting loci. By analogy with high-pen- etrance familial cancer genes, such as RB and TP53, it might be expected that the low-penetrance alleles will influence the genetic pathways adopted by tumours, leav- ing ?signature patterns? that could ultimate- ly help to identify the crucial polymor- phisms. Advances in high-throughput technologies will lead to a complete charac- terization of all possible somatic genetic alterations at the sequence level in human cancers. This information, together with the identification of the germ-line variants that contribute to cancer susceptibility, will hopefully explain the relationship between inherited predisposition genes and those that acquire mutations during tumour growth and progression. One prediction from mouse genetics is that allele-specific changes in tumours will be an important factor in determining individual cancer risk, but a large-scale study of this question in humans has not yet been attempted. The characterization of the complex network of interactions that influence can- cer development will be facilitated by the emergence of novel microarray-based tech- nologies, such as BAC (bacterial artificial chromosome) microarrays for the high - resolution detection of genetic changes in tumours 59 , or cDNA-based, oligonucleotide- based or high-throughput proteomics approaches to detecting changes in gene expression 60,61 . Many laboratories are build- ing computer models of gene networks and, indeed, of whole cell-signalling path- ways, in an attempt to simulate the com- plexities of living systems 62 (also see online links box). One of the most powerful weapons in the fight against cancer is now within our grasp ? the complete sequences of the human and mouse genomes. Our newly acquired ability to call up the array of genes and their sequences has already trans- formed our approaches to cancer genetics, enabling existing technologies and facilitat- ing the development of spectacular concep- tual and practical advances. All of these tools provide a formidable armoury of weapons that will help us to emerge from the twenty-first century with the problems posed by this devastating disease under control. It is unfortunate that we no longer have Boveri to turn to for accurate predictions of where we are headed. Allan Balmain is at the Cancer Research Institute, UCSF, San Francisco, California 94143-0875, USA. e-mail: abalmain@cc.ucsf.edu 1. Mendel, G. Versuche uber pflanzen hybriden. Verh. Naturforsch. Ver. Brunn. 4, 3?47 (1866). 2. Wilson, E. B. Erinnerungen an Theodor Boveri (ed. Roentgen, W. C.) (J. C. B. 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NATURE REVIEWS | CANCER VOLUME 1 | OCTOBER 2001 | 81 � 2001 Macmillan Magazines Ltd 82 | OCTOBER 2001 | VOLUME 1 www.nature.com/reviews/cancer PERSPECTIVES to lung cancer in the mouse. Nature Genet. 14, 465?467 (1996). 57. Wright, S. Genic and organismic selection. Evolution 34, 825?843 (1980). 58. Kinzler, K. W. & Vogelstein, B. Gatekeepers and caretakers. Nature 386, 761?763 (1997). 59. Albertson, D. G. et al. Quantitative mapping of amplicon structure by array CGH identifies CYP24 as a candidate oncogene. Nature Genet. 25, 144?146 (2001). 60. Perou, C. M. et al. Molecular portraits of human breast tumours. Nature 406, 747?752 (2000). 61. Haab, B. B., Dunham, M. J. & Brown, P. O. Protein microarrays for highly parallel detection and quantitation of specific proteins and antibodies in complex solutions. Genome Biol. 2, 1?13 (2001). 62. Gibbs, W. W. Cybernetic cells. Sci. Am. 285, 52?57 (2001). Acknowledgements Work in the author?s laboratory has been supported mainly by the Cancer Research Campaign (UK) and by the National Cancer Institute (USA). I am grateful to colleagues and the anonymous reviewers for useful comments on the manuscript. Online links DATABASES The following terms in this article are linked online to: CancerNet: http://cancernet.nci.nih.gov/index.html chronic myeloid leukaemia LocusLink: www.ncbi.nlm.nih.gov/LocusLink/ APC | BRCA1 | BRCA2 | HRAS | TP53 | Trp53 | RB OMIM: www.ncbi nlm.nih.gov/Omim/ adenomatous polyposis coli | hereditary non-polyposis colorectal cancer | xeroderma pigmentosum FURTHER INFORMATION Boveri information web sites: www.biozentrum.uni-wuerzburg.de/about/boveri.html; http://zygote.swarthmore.edu/fert6b.html Computer models of cellular signalling: www.cellularsignaling.org Human Genome Sequence: http://www.ncbi.nlm.nih.gov/ Mendel?s Genetics: http://anthro.palomar.edu/mendel/mendel_1.htm MendelWeb: www.netspace.org/MendelWeb/ Tobacco and the global lung cancer epidemic Robert N. Proctor TIMELINE Tobacco is the world?s single most avoidable cause of death. The World Health Organization has calculated that the 5.6 trillion cigarettes smoked per year at the close of the twentieth century will cause nearly 10 million fatalities per year by 2030. Lung cancer is the most common tobacco- related cause of cancer mortality, with one case being produced for every 3 million cigarettes smoked. How was the global lung cancer epidemic recognized, and what can we expect in the future? The tobacco plant is native to the Americas; archaeological evidence indicates that Mayans were smoking the leaf as early as the first cen- tury BC (FIG. 1). Columbus discovered the Arawaks using dried tobacco leaves in several curious rituals, and was offered the plant as a gift. Several of his men took up smoking, and the habit was soon exported to Europe and the rest of the world. Tobacco was used spo- radically throughout the seventeenth and eighteenth centuries, although objections were sufficiently strong in many places to have bans enacted. A Chinese imperial edict of 1612 barred growing or smoking the leaf, and the city of Berlin banned smoking in 1723 1 . Smoking was illegal in 14 American states as late as 1921, although none of these bans would survive the decade. Tobacco has been used in many different forms. Native Americans ?drank? the smoke in hand-rolled palm or maize leaves, whereas European sailors tended to prefer chewing to avoid the hazards of fire. Cigarettes were not popular until the nineteenth century; the French Revolution gave snuff an aristocratic odour and cleared a path for ?little cigars? 2 . Health effects were limited in these early years, however, as the methods most commonly used to cure the leaf made the smoke too harsh to inhale. Cigarettes were also time-con- suming to manufacture: the women and girls who hand-rolled cigarettes in the mid 1800s could usually roll only about 200 per day. Cigarette production was given an enor- mous boost in 1880 with the invention of the Bonsack cigarette-rolling machine (FIG. 2), which could churn out more than 100,000 cigarettes per day. W. Duke, Sons and Company of Durham, North Carolina, installed two such machines in 1884, allowing them to produce an unprecedented 744 mil- lion cigarettes in a single year. When com- bined with mass marketing and the invention of safety matches (in 1855), cigarettes quickly became a popular consumer item. Americans smoked only about eight cigarettes per person per year in the 1880s; by the end of the century, this figure would more than quadruple. Cigarettes were included with the rations of soldiers in the First World War, and many of the young men who entered the war as abstainers returned home as addicts. Consumption was further increased by new methods of advertising and government encouragement, following the recognition that tobacco could supply an impressive streak of tax revenues. Tobacco taxes in the United States, for example, went from about $13 million in 1910 to nearly $5 billion (10 9 ) some 60 years later. Tobacco provided 8% of Germany?s entire national tax income in the 1930s , and China today earns an even higher percentage (~ 10%). Dependence on tax rev- enues is one of the main reasons why govern- ments have been reluctant to challenge the tobacco juggernaut. One tobacco company Figure 1 | The oldest existing illustration of a smoker ? a Mayan god. (Image courtesy of Imperial Tobacco.) � 2001 Macmillan Magazines Ltd "
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