- Email: [email protected]
Molecular genetics of cancer
MOLECULAR
MEDICINE
TODAY, SEPTEMBER
Round
1996
The colorectal cancer and is linked to germline defects in at least four mismatch-repair genes. 'Mutator mutations' cause a deep genomic instability, making these people susceptible to colon cancer. A number of pharmacological polymorphisms have also been linked to cancer susceptibility, and recent advances are described. As Roland Wolf and his co-authors put it, however, 'although the technology is now available to determine the =genetic blueprint" of an individual relatively easily and quickly, the relevance and applicability of this technology to routine clinical medicine has yet to be determined.' Errol Zeiger discusses the pros and cons of using bactedal tests as indicators of carcinogenic potential. The Sa/mone//ahis rever~on assay (Ames test) has been extensively validated in a number of laboratories. The Sa/mone//a mutagenicity assays have yielded sensitivity values (proportions of carcinogens that are mutagenic) of about 50%; these values are highly dependent on the classes of chemicals under study. Despite the relatively 'low' figure, the positive predictivity of the Sa/rnonella test for rodent carcinogenicity is about 80-90% - i.e. a positive response in Sa/mone//a is predictive of cancer. The reverse, however, is not true: a negative response in Sa/mone//a is not predictive of noncarcinogenicity. Many environmental exposures are implicated in the induction of chromosomal damage. The chapter by E.M. Parry and J.M. Parry discusses how the chromosomal damage can be studied in somatic cells in vitro. They present conventional in vitro cytogenetics - studying chromosomal aberrations, sister chromatid exchanges and micronuclei. The availability of the new technique of fluorescence in situ hybddization (FISH) means that many cytogenetic questions can now be answered. FISH increases the power of in vitro cytogenetics in human health protection, as shown by David A. Eastmond and D.S. Rupa in their chapter. The use of chromosome-specific repetitive probes is facilitating the detection of aneuploidy and chromosome breakage in cells by speeding up cytogenetic analyses, allowing increased numbers of samples to be handled and the analyses to be performed on interphase cells. John A. Heddle presents a chapter on in rive assays for mutagenicity. The new techniques using transgenic mice are gaining popularity. Detection of the relevant mutations will soon be possible, together with mutation spectra. Roy Forster reviews the use of transgenic animals in genetic toxicology. Genetically engineered cells are being used for genetic toxicologytesting.According to C.L. Crespi, cell lines expressing multiple human cytochrome P450 enzymes show considerable promise as a screening systemfor human promutagen activation. Overall, the book is very readable and professionally produced. David Phillips and Stanley
Venitt have carefully edited the book and recruited leaders in their field from around the world to contribute to this worthwhile endeavour. The standard of centdbutions is high and the information is presented in a balanced and easily accessible way. For a genetic toxicologist, this book is useful, if not essential. For toxicologists in general, it is basic reading to enable them to begin unravelling the mysteries that environmental mutagens have yet to reveal to us. Harri Vainio MD Chief, Unit of Chemoprevention, International Agency for Research on Cancer, 150 Cours Albert-Thomas, 69372 Lyon Cedex 08, France. Tel: +33 72 73 84 18 Fax: +33 72 73 85 75 e.maih [email protected]
M o l e c u l a r genetics of c a n c e r
When we stop to think about it (which we rarely do), it is quite staggering to realize how much information has accumulated on molecular aspects of cancer in the ten short years since the first gene implicated in a human familial tumour (retinoblastoma) was isolated. An overview of progress is, therefore, timely and this volume sets out to present 'the most up-to-date information possible, together with insights into how this information is being used in the clinical management of patients with these tumours.' The subject matter is subdivided chiefly by tumour type, although a separate chapter is allocated to p53. Most of the expected common cancers are here, breast/ovary,colon, lung, Wilm's, the multiple endocrine neoplasias MEN1 and 2, neurofibromatosis and, of course, retinoblastoma itself.The contributorsare all well-known authorities in their fields, drawn from North American and European centres. Although there is a mixture of both single-author and multi-author chapters, they have clearly been written to a uniform bdef, and emphasize not only the major genes identified as primarily responsiblefor specific syndromes,but also the ways in which the gene products might interact with other components of the biochemical pathways that regulate cell growth and differentiation. p53is probably the most extensively studied of all the 'cancer genes', and the admirably lucid account here by Thierry Soussi draws together evidence from an enormous range of expedmental work, illustrating not only the multiple functions of the p53 protein, but also the role of different carcinogens in inducing distinctive mutations and how that information can be applied to infer causation of some cancers. There are similar illuminating discussions of the emerging relationships between structure and function of the RB (retinoblastoma), Wilm's, NF-1 (neurofibromatosis)and RET (MEN2)
up
books
proteins. Molecular interaction is indeed the pervading theme, and while there are important insights of general relevance to be drawn from individual cancers, an overview placing some of the observation in a wider context would have been a welcome addition. In its absence, there is inevitably some overlap between chapters. For example, the possible interpretations of multiple tumour suppressor gene loci on chromosome 11p are discussed both in the Wilm's tumour chapter and in a chapter on rhabdomyosarcoma, while the many roles of p53 crop up not only in its own chapter, but also in those on lung cancer, Wilm's tumour and elsewhere. This is not a serious criticism, however, since each chapter can be read on its own and, overall, repetition is well within acceptable limits. There are some unexpected omissions, notably the absence of any discuSsion on the late consequences of RB mutations in terms of adult-onset tumours, and although there is a slightly incongruous final chapter on knockout mice for the REToncogene, it makes little reference to MEN2, while the MEN2 chapter has very little to say about animal models. Although it does not set out to be a primer on molecular genetics, but rather a 'refresher' for those who already have a knowledge of at least some of its aspects, the style is nonintimidatory, and both jargon and detailed accounts of specific laboratory techniques are refreshingly absent. There is an adequate index and every chapter cardes a comprehensive reference list. The contributions are illustrated throughout by clear and simple line diagrams, supplemented by occasional photographs of gels. There are no clinical pictures but this is not intended as a medical textbook. Indeed, despite the declared intention quoted above, the emphasis is definitely on the basic science rather than its clinical applications. This is hardly surprising, given that the book is chiefly a synthesis of established work rather than speculation about the future. Nevertheless, it will certainly appeal to clinicians with an interest in the genetics of cancer. It is perfectly possible to read and enjoy this book at a single sitting, but most of the chapters will merit several return visits. In the nature of medical science, the information contained here will become out of date rather quickly but for the next few years it will fill an important niche. It is strongly recommended to anyone working in the field. C. Michael Steel PhD, DSc, FRCPath Professor in Medical Science, University of St Andrews, Bute Medical Building, St Andrews, Fife, UK KY16 9TS. Tel: +44 1334 463558 Fax: +44 1334 463600 e.mail: [email protected] 371
MEDICINE
TODAY, SEPTEMBER
Round
1996
The colorectal cancer and is linked to germline defects in at least four mismatch-repair genes. 'Mutator mutations' cause a deep genomic instability, making these people susceptible to colon cancer. A number of pharmacological polymorphisms have also been linked to cancer susceptibility, and recent advances are described. As Roland Wolf and his co-authors put it, however, 'although the technology is now available to determine the =genetic blueprint" of an individual relatively easily and quickly, the relevance and applicability of this technology to routine clinical medicine has yet to be determined.' Errol Zeiger discusses the pros and cons of using bactedal tests as indicators of carcinogenic potential. The Sa/mone//ahis rever~on assay (Ames test) has been extensively validated in a number of laboratories. The Sa/mone//a mutagenicity assays have yielded sensitivity values (proportions of carcinogens that are mutagenic) of about 50%; these values are highly dependent on the classes of chemicals under study. Despite the relatively 'low' figure, the positive predictivity of the Sa/rnonella test for rodent carcinogenicity is about 80-90% - i.e. a positive response in Sa/mone//a is predictive of cancer. The reverse, however, is not true: a negative response in Sa/mone//a is not predictive of noncarcinogenicity. Many environmental exposures are implicated in the induction of chromosomal damage. The chapter by E.M. Parry and J.M. Parry discusses how the chromosomal damage can be studied in somatic cells in vitro. They present conventional in vitro cytogenetics - studying chromosomal aberrations, sister chromatid exchanges and micronuclei. The availability of the new technique of fluorescence in situ hybddization (FISH) means that many cytogenetic questions can now be answered. FISH increases the power of in vitro cytogenetics in human health protection, as shown by David A. Eastmond and D.S. Rupa in their chapter. The use of chromosome-specific repetitive probes is facilitating the detection of aneuploidy and chromosome breakage in cells by speeding up cytogenetic analyses, allowing increased numbers of samples to be handled and the analyses to be performed on interphase cells. John A. Heddle presents a chapter on in rive assays for mutagenicity. The new techniques using transgenic mice are gaining popularity. Detection of the relevant mutations will soon be possible, together with mutation spectra. Roy Forster reviews the use of transgenic animals in genetic toxicology. Genetically engineered cells are being used for genetic toxicologytesting.According to C.L. Crespi, cell lines expressing multiple human cytochrome P450 enzymes show considerable promise as a screening systemfor human promutagen activation. Overall, the book is very readable and professionally produced. David Phillips and Stanley
Venitt have carefully edited the book and recruited leaders in their field from around the world to contribute to this worthwhile endeavour. The standard of centdbutions is high and the information is presented in a balanced and easily accessible way. For a genetic toxicologist, this book is useful, if not essential. For toxicologists in general, it is basic reading to enable them to begin unravelling the mysteries that environmental mutagens have yet to reveal to us. Harri Vainio MD Chief, Unit of Chemoprevention, International Agency for Research on Cancer, 150 Cours Albert-Thomas, 69372 Lyon Cedex 08, France. Tel: +33 72 73 84 18 Fax: +33 72 73 85 75 e.maih [email protected]
M o l e c u l a r genetics of c a n c e r
When we stop to think about it (which we rarely do), it is quite staggering to realize how much information has accumulated on molecular aspects of cancer in the ten short years since the first gene implicated in a human familial tumour (retinoblastoma) was isolated. An overview of progress is, therefore, timely and this volume sets out to present 'the most up-to-date information possible, together with insights into how this information is being used in the clinical management of patients with these tumours.' The subject matter is subdivided chiefly by tumour type, although a separate chapter is allocated to p53. Most of the expected common cancers are here, breast/ovary,colon, lung, Wilm's, the multiple endocrine neoplasias MEN1 and 2, neurofibromatosis and, of course, retinoblastoma itself.The contributorsare all well-known authorities in their fields, drawn from North American and European centres. Although there is a mixture of both single-author and multi-author chapters, they have clearly been written to a uniform bdef, and emphasize not only the major genes identified as primarily responsiblefor specific syndromes,but also the ways in which the gene products might interact with other components of the biochemical pathways that regulate cell growth and differentiation. p53is probably the most extensively studied of all the 'cancer genes', and the admirably lucid account here by Thierry Soussi draws together evidence from an enormous range of expedmental work, illustrating not only the multiple functions of the p53 protein, but also the role of different carcinogens in inducing distinctive mutations and how that information can be applied to infer causation of some cancers. There are similar illuminating discussions of the emerging relationships between structure and function of the RB (retinoblastoma), Wilm's, NF-1 (neurofibromatosis)and RET (MEN2)
up
books
proteins. Molecular interaction is indeed the pervading theme, and while there are important insights of general relevance to be drawn from individual cancers, an overview placing some of the observation in a wider context would have been a welcome addition. In its absence, there is inevitably some overlap between chapters. For example, the possible interpretations of multiple tumour suppressor gene loci on chromosome 11p are discussed both in the Wilm's tumour chapter and in a chapter on rhabdomyosarcoma, while the many roles of p53 crop up not only in its own chapter, but also in those on lung cancer, Wilm's tumour and elsewhere. This is not a serious criticism, however, since each chapter can be read on its own and, overall, repetition is well within acceptable limits. There are some unexpected omissions, notably the absence of any discuSsion on the late consequences of RB mutations in terms of adult-onset tumours, and although there is a slightly incongruous final chapter on knockout mice for the REToncogene, it makes little reference to MEN2, while the MEN2 chapter has very little to say about animal models. Although it does not set out to be a primer on molecular genetics, but rather a 'refresher' for those who already have a knowledge of at least some of its aspects, the style is nonintimidatory, and both jargon and detailed accounts of specific laboratory techniques are refreshingly absent. There is an adequate index and every chapter cardes a comprehensive reference list. The contributions are illustrated throughout by clear and simple line diagrams, supplemented by occasional photographs of gels. There are no clinical pictures but this is not intended as a medical textbook. Indeed, despite the declared intention quoted above, the emphasis is definitely on the basic science rather than its clinical applications. This is hardly surprising, given that the book is chiefly a synthesis of established work rather than speculation about the future. Nevertheless, it will certainly appeal to clinicians with an interest in the genetics of cancer. It is perfectly possible to read and enjoy this book at a single sitting, but most of the chapters will merit several return visits. In the nature of medical science, the information contained here will become out of date rather quickly but for the next few years it will fill an important niche. It is strongly recommended to anyone working in the field. C. Michael Steel PhD, DSc, FRCPath Professor in Medical Science, University of St Andrews, Bute Medical Building, St Andrews, Fife, UK KY16 9TS. Tel: +44 1334 463558 Fax: +44 1334 463600 e.mail: [email protected] 371