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A new cancer-genetics bible
DISSECTING ROOM
DISSECTING ROOM
A new cancer-genetics bible The Genetic Basis of Human Cancer Edited by B Vogelstein, K Kinzler. 1998. New York: McGraw Hill. Pp 731. $95. ISBN 0-07-067596-1.
lthough B Boveri has been rightly credited since 1914 with having divined that the basis of cancer must be in the chromosomes, oncology and genetics have developed for decades almost independently of each other. By the 1960s the basis of cancer was still sought in biochemistry and in cell biology, even while genetics had progressed from the study of pedigrees to understanding the molecular basis of gene structure and expression. It is true that family clustering of cancer was mentioned in an introductory chapter in every pathology textbook, but generally this was regarded as a curiosity rather than as a telltale observation. Bert Vogelstein and Ken Kinzler have taken on the formidable job of editing a book to show us how, over the past two decades, the dichotomy
A
between oncology and genetics has been reconciled: they have succeeded splendidly. In retrospect it seems fairly obvious that, while this integration has been made possible by a host of methodological advances, it was also hindered for a long time by a conceptual divide, whereby genetics had to do with what we inherit, whereas cancer was mostly on acquired disorder. Knudson was the first to bridge the gap formally, when he stated a hypothesis that linked an inherited mutation and a somatic mutation in the pathogenesis of cancer. However, it was only with the cloning of transforming oncogenes and of tumour suppressor genes that the link blossomed, from an attractive bud, into the general concept that it is today. Few people have contributed personally to develop this paradigm as
Vogelstein and Kinzler have, and one picks up the book with confidence in their authority. That confidence is never betrayed. One can tell immediately—from typeface and graphics—that the volume must have originated (clonal evolution?) from the classic Metabolic and Molecular Basis of Inherited Diseases (or MMBID: those of us who remember the first edition in 1960 still tend to call it “the Stanbury”). In fact, several chapters are essentially reproduced from the 1995 edition of MMBID, and several others first appeared in the 1997 CD-ROM version of the same, which was expanded specifically in the area of cancer genetics. It is impossible to do justice in a few lines to the many virtues of this text of four parts: basic concepts, control of cell growth, the inherited cancer syndromes, and cancer “site by site”. It is not clear how much editing the two editors have done in detail, but they have certainly selected the authors of individual chapters with
David Furness. Wellcome Trust Medical Photographic Library
Alan Boyde. Wellcome Trust Medical Photographic Library
Biomedical Image Awards
The 20 best images acquired during the past year by the Wellcome Trust’s Medical Photographic Library are now on show at the Trust’s Two10 Gallery in London, UK. The sixth in the series of exhibitions exploring the link between contemporary medical science and art, Biomedical Image Awards shows how modern imaging techniques provide insights into healthy and diseased organisms. The above scanning electronmicrographs of (left) a bone sample from the spine of an 89-year-old woman with osteoporosis (by Alan Boyde, University College London) and (right) the retina of a guineapig eye (by David Furness, Keele University) have been chosen as the best of the bunch. The exhibition ends on July 31,1998.
THE LANCET • Vol 351 • June 13, 1998
1821
DISSECTING ROOM
care, since many are lucid and comprehensive reviews in their own right. The sections that Vogelstein and Kinzler have written themselves are masterful. In two central pages they promulgate the nomenclature they first formally proposed in 1997 in a letter to Nature. Many of the genes that are mutated in tumours— they say—can be classified either as “caretakers”, (ie, normally responsible for keeping the genome and the chromosomes intact); or as “gatekeepers” (ie, normally responsible for keeping the control of cell proliferation intact). Whereas gatekeeper genes correspond roughly to those we have until now called tumour suppressor genes, the concept of caretaker genes as a functional set is novel: I suspect that both terms are here to stay. Most chapters are generously illustrated, including line diagrams of genes, and cartoons of how they work (we are now so spoiled that we would expect these to be in colour; and in a tome of this calibre, the photomicrographs ought to be of better quality). The unifying theme of the book—cancer is a genetic disorder—never becomes fragmented by the bewildering variety of the multi-step sequences that can give rise to cancer, because most of the chapters are riveting; eventually, each tumour will be defined by the identity of the individual steps in the sequences. At the moment, for several type of tumour, the information on genetic lesions is scanty, and this has made the task of many of the authors of the final segment of the text rather hard— although some did not help themselves by writing text without any illustration whatsoever. The abundant information on mutations in oncogenes and tumour suppressor genes is beginning to build a consistent pattern of how gain of function and loss of function are brought about at the molecular level. The individual databases are of course inevitably out of date by the time they are printed, but many
1822
can now be accessed directly on the Internet (see http://www.uwcm.ac.uk/uwcm /mg/hgmd0.htm). Whereas the third part deals mostly with inherited mutation, the fourth section deals mostly with acquired mutations. This combination had been already announced by the editors in their preface, when they introduce cancer as a special example of polygenic inheritance. Of course the interaction of, say, an inherited variant of the low-density-lipoprotein receptor and the intake of cholesterol is still deterministic in causing atherosclerosis. By contrast, the somatic events required to cause cancer in somebody who has inherited a BRCA1 mutation have a stochastic character: thus in one case penetrance depends on controllable factors in the environment whereas what makes the pathogenesis of cancer almost unique is that we do not have a concept of how to control random somatic mutations, except by avoiding exposure to agents
that may increase their numbers. To our anthropocentric mentality it seems that evolution has perfected caretaker genes for precisely that purpose. This book is well poised for becoming, with respect to the molecular basis of cancer, what MMBID has been for decades with respect to inherited disorders: it deserves to be widely popular and it is easy to forecast that the text will have new editions at frequent intervals, whether in hard copy, on compact disk, or on-line. For less than the cost of a cDNA library it will provide the molecular oncologist with an invaluable reference source; and for much less than the cost of a single dose of chemotherapy it will provide the practising oncologist with an upto-date survey of why a patient has come to need that treatment. Lucio Luzzato Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
False hopes or no hopes? False Hopes Daniel Callahan. 1998. New York: Simon & Schuster. $24. ISBN 0-684-81109-X.
eviewing False Hopes caused a perceptible ebb in my personal energy. Imagine a middle-aged man being told that inhabitants of the developed world should not aspire to a life expectancy beyond the late 70s or early 80s, and that expectations of a much longer life, which are expressed by many Americans and Europeans, may destroy any remaining solidarity between the upper and lower social classes. Imagine seeing in black and white the proposition that the past half century’s progress in use of technology and science to improve health and extend life expectancy is not sufficient reason to expect that in the next half century equal progress will be achieved. As a matter of fact, the author suggests, the notion of progress may itself be an illusion. Imagine reading that the production, use of, and therefore payment for new medical technology, even if it is useful technology, will undermine the structure of health insurance in Europe and reduce solidarity among socioeconomically defined classes because it will put excessive cost pressure on national treasuries. Perhaps Callahan should have warned
R
potential readers that the use of an antidepressant, even if it is produced by the evil empire of technology, is warranted before cracking into this volume. Indeed, perhaps the book’s title should be changed from “False Hopes” to “No Hopes.” Certainly, my 90-year-old mother would find the messages in this book disquieting. Callahan does offer a little solace. The use of public-health measures and changes in personal health habits, even if they require some coercion to implement, and the practice of evidence-based medicine, which is currently in vogue, at least in the UK, all might help, he suggests, to ameliorate the dire consequences that are predicted in this depressing book. However, whether or not one agrees with Callahan’s world view, this book must be read. Its arguments touch the core of current debates about the future relation between medicine and society. And to appreciate the book’s relevance, one must understand something about the author’s heart. False Hopes is not written by a person who hates the elderly, or who is antitechnology. It is written by a person who has a good soul, who is struggling
THE LANCET • Vol 351 • June 13, 1998
DISSECTING ROOM
A new cancer-genetics bible The Genetic Basis of Human Cancer Edited by B Vogelstein, K Kinzler. 1998. New York: McGraw Hill. Pp 731. $95. ISBN 0-07-067596-1.
lthough B Boveri has been rightly credited since 1914 with having divined that the basis of cancer must be in the chromosomes, oncology and genetics have developed for decades almost independently of each other. By the 1960s the basis of cancer was still sought in biochemistry and in cell biology, even while genetics had progressed from the study of pedigrees to understanding the molecular basis of gene structure and expression. It is true that family clustering of cancer was mentioned in an introductory chapter in every pathology textbook, but generally this was regarded as a curiosity rather than as a telltale observation. Bert Vogelstein and Ken Kinzler have taken on the formidable job of editing a book to show us how, over the past two decades, the dichotomy
A
between oncology and genetics has been reconciled: they have succeeded splendidly. In retrospect it seems fairly obvious that, while this integration has been made possible by a host of methodological advances, it was also hindered for a long time by a conceptual divide, whereby genetics had to do with what we inherit, whereas cancer was mostly on acquired disorder. Knudson was the first to bridge the gap formally, when he stated a hypothesis that linked an inherited mutation and a somatic mutation in the pathogenesis of cancer. However, it was only with the cloning of transforming oncogenes and of tumour suppressor genes that the link blossomed, from an attractive bud, into the general concept that it is today. Few people have contributed personally to develop this paradigm as
Vogelstein and Kinzler have, and one picks up the book with confidence in their authority. That confidence is never betrayed. One can tell immediately—from typeface and graphics—that the volume must have originated (clonal evolution?) from the classic Metabolic and Molecular Basis of Inherited Diseases (or MMBID: those of us who remember the first edition in 1960 still tend to call it “the Stanbury”). In fact, several chapters are essentially reproduced from the 1995 edition of MMBID, and several others first appeared in the 1997 CD-ROM version of the same, which was expanded specifically in the area of cancer genetics. It is impossible to do justice in a few lines to the many virtues of this text of four parts: basic concepts, control of cell growth, the inherited cancer syndromes, and cancer “site by site”. It is not clear how much editing the two editors have done in detail, but they have certainly selected the authors of individual chapters with
David Furness. Wellcome Trust Medical Photographic Library
Alan Boyde. Wellcome Trust Medical Photographic Library
Biomedical Image Awards
The 20 best images acquired during the past year by the Wellcome Trust’s Medical Photographic Library are now on show at the Trust’s Two10 Gallery in London, UK. The sixth in the series of exhibitions exploring the link between contemporary medical science and art, Biomedical Image Awards shows how modern imaging techniques provide insights into healthy and diseased organisms. The above scanning electronmicrographs of (left) a bone sample from the spine of an 89-year-old woman with osteoporosis (by Alan Boyde, University College London) and (right) the retina of a guineapig eye (by David Furness, Keele University) have been chosen as the best of the bunch. The exhibition ends on July 31,1998.
THE LANCET • Vol 351 • June 13, 1998
1821
DISSECTING ROOM
care, since many are lucid and comprehensive reviews in their own right. The sections that Vogelstein and Kinzler have written themselves are masterful. In two central pages they promulgate the nomenclature they first formally proposed in 1997 in a letter to Nature. Many of the genes that are mutated in tumours— they say—can be classified either as “caretakers”, (ie, normally responsible for keeping the genome and the chromosomes intact); or as “gatekeepers” (ie, normally responsible for keeping the control of cell proliferation intact). Whereas gatekeeper genes correspond roughly to those we have until now called tumour suppressor genes, the concept of caretaker genes as a functional set is novel: I suspect that both terms are here to stay. Most chapters are generously illustrated, including line diagrams of genes, and cartoons of how they work (we are now so spoiled that we would expect these to be in colour; and in a tome of this calibre, the photomicrographs ought to be of better quality). The unifying theme of the book—cancer is a genetic disorder—never becomes fragmented by the bewildering variety of the multi-step sequences that can give rise to cancer, because most of the chapters are riveting; eventually, each tumour will be defined by the identity of the individual steps in the sequences. At the moment, for several type of tumour, the information on genetic lesions is scanty, and this has made the task of many of the authors of the final segment of the text rather hard— although some did not help themselves by writing text without any illustration whatsoever. The abundant information on mutations in oncogenes and tumour suppressor genes is beginning to build a consistent pattern of how gain of function and loss of function are brought about at the molecular level. The individual databases are of course inevitably out of date by the time they are printed, but many
1822
can now be accessed directly on the Internet (see http://www.uwcm.ac.uk/uwcm /mg/hgmd0.htm). Whereas the third part deals mostly with inherited mutation, the fourth section deals mostly with acquired mutations. This combination had been already announced by the editors in their preface, when they introduce cancer as a special example of polygenic inheritance. Of course the interaction of, say, an inherited variant of the low-density-lipoprotein receptor and the intake of cholesterol is still deterministic in causing atherosclerosis. By contrast, the somatic events required to cause cancer in somebody who has inherited a BRCA1 mutation have a stochastic character: thus in one case penetrance depends on controllable factors in the environment whereas what makes the pathogenesis of cancer almost unique is that we do not have a concept of how to control random somatic mutations, except by avoiding exposure to agents
that may increase their numbers. To our anthropocentric mentality it seems that evolution has perfected caretaker genes for precisely that purpose. This book is well poised for becoming, with respect to the molecular basis of cancer, what MMBID has been for decades with respect to inherited disorders: it deserves to be widely popular and it is easy to forecast that the text will have new editions at frequent intervals, whether in hard copy, on compact disk, or on-line. For less than the cost of a cDNA library it will provide the molecular oncologist with an invaluable reference source; and for much less than the cost of a single dose of chemotherapy it will provide the practising oncologist with an upto-date survey of why a patient has come to need that treatment. Lucio Luzzato Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
False hopes or no hopes? False Hopes Daniel Callahan. 1998. New York: Simon & Schuster. $24. ISBN 0-684-81109-X.
eviewing False Hopes caused a perceptible ebb in my personal energy. Imagine a middle-aged man being told that inhabitants of the developed world should not aspire to a life expectancy beyond the late 70s or early 80s, and that expectations of a much longer life, which are expressed by many Americans and Europeans, may destroy any remaining solidarity between the upper and lower social classes. Imagine seeing in black and white the proposition that the past half century’s progress in use of technology and science to improve health and extend life expectancy is not sufficient reason to expect that in the next half century equal progress will be achieved. As a matter of fact, the author suggests, the notion of progress may itself be an illusion. Imagine reading that the production, use of, and therefore payment for new medical technology, even if it is useful technology, will undermine the structure of health insurance in Europe and reduce solidarity among socioeconomically defined classes because it will put excessive cost pressure on national treasuries. Perhaps Callahan should have warned
R
potential readers that the use of an antidepressant, even if it is produced by the evil empire of technology, is warranted before cracking into this volume. Indeed, perhaps the book’s title should be changed from “False Hopes” to “No Hopes.” Certainly, my 90-year-old mother would find the messages in this book disquieting. Callahan does offer a little solace. The use of public-health measures and changes in personal health habits, even if they require some coercion to implement, and the practice of evidence-based medicine, which is currently in vogue, at least in the UK, all might help, he suggests, to ameliorate the dire consequences that are predicted in this depressing book. However, whether or not one agrees with Callahan’s world view, this book must be read. Its arguments touch the core of current debates about the future relation between medicine and society. And to appreciate the book’s relevance, one must understand something about the author’s heart. False Hopes is not written by a person who hates the elderly, or who is antitechnology. It is written by a person who has a good soul, who is struggling
THE LANCET • Vol 351 • June 13, 1998