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The power and promise of molecular genetics in gastroenterology
June 1996
EDITORIALS 2015
The Power and Promise of Molecular Genetics in Gastroenterology See article on page 1975.
L
ike many areas of medicine, gastroenterology is ideally positioned to take advantage of modern molecular medicine. However, often those basic advances that are potentially most relevant are not reported in clinical journals. In the ever more complex and competitive environments of clinical medicine and clinical investigation, there is increasing difficulty in finding time and in maintaining the skills to sift through basic science literature. At the moment when science is at a most exciting and powerful point, this substantial impediment impairs the effective integration of basic scientific advances into clinical disciplines. In this issue of GASTROENTEROLOGY, we include a Rapid Communication that represents a basic advance of substantial interest to the gastroenterologist. In it, Whitcomb et al. report the mapping of the locus of the defective gene responsible for familial pancreatitis.1 Consistent with the ‘‘timeliness hypothesis,’’ Le Bodic et al.2 have also concurrently reported the mapping of a similar locus in a large French kindred with this disease. The mapping and cloning of new and relevant genes and the launching and application of novel strategies for gene therapy are typical of advances that are becoming common and reflect the power and excitement of molecular medicine. We are convinced that such advances have an important place in the journal and that they will ultimately have substantial impact on our clinical practice. We are delighted to be able to attract such reports and to offer them to our readership in a timely way. This also provides us with the opportunity to review the current status and future promise of molecular genetics to gastroenterology. Identification of specific molecular defects that are associated with and responsible for human disease has never been easier. With the resources provided by initiatives like the Human Genome Project, investigators can now take advantage of extraordinary technological advances and detailed databases that have substantially changed the approaches to the identification of genes associated with disease. The time necessary to clone such genes has been impressively reduced over the last several years as a function of these resources. Ten years ago, the identification of such a gene was almost entirely dependent on fundamental information about the biochemical basis of / 5e0e$$0048
05-17-96 17:39:14
gasa
a disease. Clearly, the number of diseases in which such detailed information and insights exist is extremely small, making this route for gene discovery quite limited. With the rapid expansion of a catalogue of normal genes, the candidate gene approach to disease gene identification has become more popular and productive. This method uses a simple and directed analysis of the candidate gene in a disease population when knowledge of the pathogenesis of that process implicates a particular gene or gene family. This approach will continue to be popular and ever more successful as our database of human genes continues to expand. Because both of the former methods of disease gene identification require insights into the functional and/or biochemical nature of the suspected defect, they have been most effectively applied to disorders with clear and simple patterns of Mendelian inheritance. It has therefore become important to develop additional approaches to disease gene identification that are more broadly applicable. Positional cloning is such an approach that requires no functional information about a potential defect to ensure success. While this approach is fully applicable to disorders with simple inheritance, it also has great potential in complex polygenic disease, where multiple genes are postulated to interact with each other or with environmental factors to create a gradient of genetic susceptibility to disease. In positional cloning approaches, linkage is initially explored within a particularly large kindred (such as those studied by Whitcomb et al.1 and Le Bodic et al.2) or for multiple affected families. Other positional clues, such as visible cytogenetic rearrangements or large and evident deletions, can greatly facilitate the effort. Expanded trinucleotide repeat domains is a special condition that is also quite helpful in localizing a disease locus. The statistical analysis of linkage has become routine for disorders that follow simple inheritance patterns, but linkage is typically much less clear for complex multifactorial diseases. To help identify these loci, a number of specialized statistical methodologies, such as affected sibpair, affected pedigree member, regressive models, and linkage-disequilibrium–based approaches have been developed.3 As the density of available gene maps and markers increases, so will the facility and success of positional cloning. As this occurs, using the positional and candidate gene approaches as complementary methods should provide tremendous power to search for any significant inherited component of any disease process. WBS-Gastro
2016 EDITORIALS
GASTROENTEROLOGY Vol. 110, No. 6
The first successful application of positional cloning resulted in the identification of the X-linked gene for chronic granulomatous disease in 1986.4 By 1995, there were 42 successful applications of this approach,5 and other examples are accumulating at a rapid rate. A noted example of positional cloning in a complex and likely polygenic disorder that is of particular interest to the gastroenterologist is the recent report by Hugot et al.6 These investigators reported that a locus on chromosome 16 was linked to the development of Crohn’s disease. The list of specific gene defects that have been identified and are relevant to the gastroenterologist is rapidly expanding. This list already includes the genes responsible for cystic fibrosis,7 familial polyposis coli,8 Wilson’s disease,9 Hirschsprung’s disease,10 and several tumorsuppressor genes involved in hereditary nonpolyposis colon cancer and pancreatic cancer syndromes.11,12 What does disease gene identification make possible? Perhaps the most direct and simple application relates to improved diagnostic capabilities, with resultant new approaches to genetic counseling and preventive medicine. Already, such efforts are active for some of the gastrointestinal disease genes listed above.13,14 Disease gene identification also has the potential to confirm or redirect explorations toward the elucidation of the molecular pathogenesis of these disorders. Molecular themes responsible for the development and progression of malignancy are being proposed and refined at an extraordinary pace as a function of some of these observations.11 Finally, and perhaps most importantly, such observations should facilitate the eventual development of strategies to repair or circumvent the deleterious impact of the identified gene defects. These strategies may involve conventional drug therapies made relevant by greater insights into pathogenesis or could even take the form of gene therapy. Here, too, there has already been substantial progress in applying gene therapy to some of these disorders.15 While it is too early to understand the impact of the ultimate identification of the hereditary pancreatitis gene (or genes), this will have the potential to add new insights into the pathogenesis and treatment of this elusive and serious disorder. It is of interest that two distinct kindreds both map to the same chromosomal locus,1,2 supporting the possibility that the same gene is defective in both. If the defect is in a pancreatic protease gene or in a gene for a protein that regulates protease activity, a genetic basis for intrapancreatic protease activation could be implicated. This would add complementary evidence to support previous physiological and cell biological studies showing intracellular activation of zymogens in experimental pancreatitis.16 This might also support at least one potential therapeutic approach to use cell-per/ 5e0e$$0048
05-17-96 17:39:14
gasa
meant protease inhibitors in some subset of these patients. Even if the process responsible for the rare hereditary form of this disease is not responsible for or active in the majority of cases of pancreatitis, the information coming from these efforts could be valuable to help engineer a new transgenic animal model of this disease to further explore its pathogenesis and therapy. The availability and power of disease gene cloning methodologies should make all of us ever more vigilant to recognize opportunities for their application. We will all be that much wiser and more effective as a result. LAURENCE J. MILLER
Center for Basic Research in Digestive Diseases Mayo Clinic and Foundation Rochester, Minnesota
References 1. Whitcomb DC, Preston RA, Aston CE, Sossenheimer MJ, Barua PS, Zhang Y, Wong-Chong A, While GJ, Wood PG, Gates LK Jr, Ulrich C, Martin SP, Post JC, Ehrlich HP. A gene for hereditary pancreatitis maps to chromosome 7q35. Gastroenterology 1996;110:1975–1980. 2. Le Bodic L, Bignon J-D, Raguenes O, Mercier B, Georgelin T, Schnee M, Soulard F, Gagne K, Bonneville F, Muller J-V, Bachner L, Ferec C. The hereditary pancreatitis gene maps to long arm of chromosome 7. Hum Mol Genet 1996;5:549–554. 3. Weeks DE, Lathrop GM. Polygenic disease: methods for mapping complex disease traits. Trends Genet 1995;11:513–519. 4. Royer-Pokora B, Kunkel LM, Monaco AP, Goff SC, Newburger PE, Baehner RL, Cole FS, Curnutte JT, Orkin SH. Cloning the gene for an inherited human disorder—chronic granulomatous disease— on the basis of its chromosomal location. Nature 1986;322: 32–38. 5. Collins FS. Positional cloning moves from perditional to traditional. Nat Genet 1995;9:347–350. 6. Hugot J-P, Laurent-Pulg P, Gower-Rousseau C, Olson JM, Lee JC, Beaugerie L, Naom I, Dupas J-L, VanGossum A, Groupe d’Etude Therap Affect Inflam Dis, Orholm M, Bonaiti-Pelle C, Weissenbach J, Mathew CG, Lennard-Jones JE, Cortot A, Colombel J-F, Thomas G. Mapping of a susceptibility locus for Crohn’s disease on chromosome 16. Nature 1996;379:821–823. 7. Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou JL, Drumm ML, Iannuzzi MC, Collins, FS, Tsui LC. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989;245:1066–1073. 8. Nakamura Y, Nishisho I, Kinzler KW, Vogelstein B, Miyoshi Y, Miki Y, Ando H, Horii A. Mutations of the APC (adenomatous polyposis coli) gene in FAP (familial polyposis coli) patients and in sporadic colorectal tumors. Tohoku J Exp Med 1992;168: 141–147. 9. Thomas GR, Forbes JR, Roberts EA, Walshe JM, Cox DW. The Wilson disease gene: spectrum of mutations and their consequences. Nat Genet 1995;9:210–217. 10. Edery P, Lyonnet S, Mulligan LM, Pelet A, Dow E, Abel L, Holder S, Nihoul-Fekete C, Ponder BA, Munnich A. Mutations of the RET proto-oncogene in Hirschsprung’s disease. Nature 1994;367: 378–380. 11. Liu B, Parsons R, Papadopoulos N, Nicolaides NC, Lynch HT, Watson P, Jass JR, Dunlop M, Wyllie A, Peltomaki P, Delachapelle A, Hamilton SR, Vogelstein B, Kinzler KW. Analysis of mismatch
WBS-Gastro
June 1996
12.
13.
14. 15.
EDITORIALS 2017
repair genes in hereditary non-polyposis colorectal cancer patients. Nature Med 1996;2:169–174. Hahn SA, Schutte M, Shamsul Hoque ATM, Moskaluk CA, daCosta LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 1996;271:350–353. Lynch HT, Smyrk T, Lynch JF. Overview of natural history, pathology, molecular genetics and management of HNPCC (Lynch syndrome). Int J Cancer 1996;69:38–43. Petersen GM. Genetic counseling and predictive testing for colorectal cancer risk. Int J Cancer 1996;69:53–54. Fisher KJ, Choi H, Burda J, Chen SJ, Wilson JM. Recombinant
/ 5e0e$$0048
05-17-96 17:39:14
gasa
adenovirus deleted of all viral genes for gene therapy of cystic fibrosis. Virology 1996;217:11–22. 16. Steer ML, Meldolesi J. The cell biology of experimental pancreatitis. N Engl J Med 1987;316:144–150. Address requests for reprints to: Laurence J. Miller, M.D., Center for Basic Research in Digestive Diseases, Guggenheim 17, Mayo Clinic, Rochester, Minnesota 55905. Fax: (507) 284-0762. Supported by grants from the National Institutes of Health (DK32878 and DK46577). 䉷 1996 by the American Gastroenterological Association 0016-5085/96/$3.00
WBS-Gastro
EDITORIALS 2015
The Power and Promise of Molecular Genetics in Gastroenterology See article on page 1975.
L
ike many areas of medicine, gastroenterology is ideally positioned to take advantage of modern molecular medicine. However, often those basic advances that are potentially most relevant are not reported in clinical journals. In the ever more complex and competitive environments of clinical medicine and clinical investigation, there is increasing difficulty in finding time and in maintaining the skills to sift through basic science literature. At the moment when science is at a most exciting and powerful point, this substantial impediment impairs the effective integration of basic scientific advances into clinical disciplines. In this issue of GASTROENTEROLOGY, we include a Rapid Communication that represents a basic advance of substantial interest to the gastroenterologist. In it, Whitcomb et al. report the mapping of the locus of the defective gene responsible for familial pancreatitis.1 Consistent with the ‘‘timeliness hypothesis,’’ Le Bodic et al.2 have also concurrently reported the mapping of a similar locus in a large French kindred with this disease. The mapping and cloning of new and relevant genes and the launching and application of novel strategies for gene therapy are typical of advances that are becoming common and reflect the power and excitement of molecular medicine. We are convinced that such advances have an important place in the journal and that they will ultimately have substantial impact on our clinical practice. We are delighted to be able to attract such reports and to offer them to our readership in a timely way. This also provides us with the opportunity to review the current status and future promise of molecular genetics to gastroenterology. Identification of specific molecular defects that are associated with and responsible for human disease has never been easier. With the resources provided by initiatives like the Human Genome Project, investigators can now take advantage of extraordinary technological advances and detailed databases that have substantially changed the approaches to the identification of genes associated with disease. The time necessary to clone such genes has been impressively reduced over the last several years as a function of these resources. Ten years ago, the identification of such a gene was almost entirely dependent on fundamental information about the biochemical basis of / 5e0e$$0048
05-17-96 17:39:14
gasa
a disease. Clearly, the number of diseases in which such detailed information and insights exist is extremely small, making this route for gene discovery quite limited. With the rapid expansion of a catalogue of normal genes, the candidate gene approach to disease gene identification has become more popular and productive. This method uses a simple and directed analysis of the candidate gene in a disease population when knowledge of the pathogenesis of that process implicates a particular gene or gene family. This approach will continue to be popular and ever more successful as our database of human genes continues to expand. Because both of the former methods of disease gene identification require insights into the functional and/or biochemical nature of the suspected defect, they have been most effectively applied to disorders with clear and simple patterns of Mendelian inheritance. It has therefore become important to develop additional approaches to disease gene identification that are more broadly applicable. Positional cloning is such an approach that requires no functional information about a potential defect to ensure success. While this approach is fully applicable to disorders with simple inheritance, it also has great potential in complex polygenic disease, where multiple genes are postulated to interact with each other or with environmental factors to create a gradient of genetic susceptibility to disease. In positional cloning approaches, linkage is initially explored within a particularly large kindred (such as those studied by Whitcomb et al.1 and Le Bodic et al.2) or for multiple affected families. Other positional clues, such as visible cytogenetic rearrangements or large and evident deletions, can greatly facilitate the effort. Expanded trinucleotide repeat domains is a special condition that is also quite helpful in localizing a disease locus. The statistical analysis of linkage has become routine for disorders that follow simple inheritance patterns, but linkage is typically much less clear for complex multifactorial diseases. To help identify these loci, a number of specialized statistical methodologies, such as affected sibpair, affected pedigree member, regressive models, and linkage-disequilibrium–based approaches have been developed.3 As the density of available gene maps and markers increases, so will the facility and success of positional cloning. As this occurs, using the positional and candidate gene approaches as complementary methods should provide tremendous power to search for any significant inherited component of any disease process. WBS-Gastro
2016 EDITORIALS
GASTROENTEROLOGY Vol. 110, No. 6
The first successful application of positional cloning resulted in the identification of the X-linked gene for chronic granulomatous disease in 1986.4 By 1995, there were 42 successful applications of this approach,5 and other examples are accumulating at a rapid rate. A noted example of positional cloning in a complex and likely polygenic disorder that is of particular interest to the gastroenterologist is the recent report by Hugot et al.6 These investigators reported that a locus on chromosome 16 was linked to the development of Crohn’s disease. The list of specific gene defects that have been identified and are relevant to the gastroenterologist is rapidly expanding. This list already includes the genes responsible for cystic fibrosis,7 familial polyposis coli,8 Wilson’s disease,9 Hirschsprung’s disease,10 and several tumorsuppressor genes involved in hereditary nonpolyposis colon cancer and pancreatic cancer syndromes.11,12 What does disease gene identification make possible? Perhaps the most direct and simple application relates to improved diagnostic capabilities, with resultant new approaches to genetic counseling and preventive medicine. Already, such efforts are active for some of the gastrointestinal disease genes listed above.13,14 Disease gene identification also has the potential to confirm or redirect explorations toward the elucidation of the molecular pathogenesis of these disorders. Molecular themes responsible for the development and progression of malignancy are being proposed and refined at an extraordinary pace as a function of some of these observations.11 Finally, and perhaps most importantly, such observations should facilitate the eventual development of strategies to repair or circumvent the deleterious impact of the identified gene defects. These strategies may involve conventional drug therapies made relevant by greater insights into pathogenesis or could even take the form of gene therapy. Here, too, there has already been substantial progress in applying gene therapy to some of these disorders.15 While it is too early to understand the impact of the ultimate identification of the hereditary pancreatitis gene (or genes), this will have the potential to add new insights into the pathogenesis and treatment of this elusive and serious disorder. It is of interest that two distinct kindreds both map to the same chromosomal locus,1,2 supporting the possibility that the same gene is defective in both. If the defect is in a pancreatic protease gene or in a gene for a protein that regulates protease activity, a genetic basis for intrapancreatic protease activation could be implicated. This would add complementary evidence to support previous physiological and cell biological studies showing intracellular activation of zymogens in experimental pancreatitis.16 This might also support at least one potential therapeutic approach to use cell-per/ 5e0e$$0048
05-17-96 17:39:14
gasa
meant protease inhibitors in some subset of these patients. Even if the process responsible for the rare hereditary form of this disease is not responsible for or active in the majority of cases of pancreatitis, the information coming from these efforts could be valuable to help engineer a new transgenic animal model of this disease to further explore its pathogenesis and therapy. The availability and power of disease gene cloning methodologies should make all of us ever more vigilant to recognize opportunities for their application. We will all be that much wiser and more effective as a result. LAURENCE J. MILLER
Center for Basic Research in Digestive Diseases Mayo Clinic and Foundation Rochester, Minnesota
References 1. Whitcomb DC, Preston RA, Aston CE, Sossenheimer MJ, Barua PS, Zhang Y, Wong-Chong A, While GJ, Wood PG, Gates LK Jr, Ulrich C, Martin SP, Post JC, Ehrlich HP. A gene for hereditary pancreatitis maps to chromosome 7q35. Gastroenterology 1996;110:1975–1980. 2. Le Bodic L, Bignon J-D, Raguenes O, Mercier B, Georgelin T, Schnee M, Soulard F, Gagne K, Bonneville F, Muller J-V, Bachner L, Ferec C. The hereditary pancreatitis gene maps to long arm of chromosome 7. Hum Mol Genet 1996;5:549–554. 3. Weeks DE, Lathrop GM. Polygenic disease: methods for mapping complex disease traits. Trends Genet 1995;11:513–519. 4. Royer-Pokora B, Kunkel LM, Monaco AP, Goff SC, Newburger PE, Baehner RL, Cole FS, Curnutte JT, Orkin SH. Cloning the gene for an inherited human disorder—chronic granulomatous disease— on the basis of its chromosomal location. Nature 1986;322: 32–38. 5. Collins FS. Positional cloning moves from perditional to traditional. Nat Genet 1995;9:347–350. 6. Hugot J-P, Laurent-Pulg P, Gower-Rousseau C, Olson JM, Lee JC, Beaugerie L, Naom I, Dupas J-L, VanGossum A, Groupe d’Etude Therap Affect Inflam Dis, Orholm M, Bonaiti-Pelle C, Weissenbach J, Mathew CG, Lennard-Jones JE, Cortot A, Colombel J-F, Thomas G. Mapping of a susceptibility locus for Crohn’s disease on chromosome 16. Nature 1996;379:821–823. 7. Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou JL, Drumm ML, Iannuzzi MC, Collins, FS, Tsui LC. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989;245:1066–1073. 8. Nakamura Y, Nishisho I, Kinzler KW, Vogelstein B, Miyoshi Y, Miki Y, Ando H, Horii A. Mutations of the APC (adenomatous polyposis coli) gene in FAP (familial polyposis coli) patients and in sporadic colorectal tumors. Tohoku J Exp Med 1992;168: 141–147. 9. Thomas GR, Forbes JR, Roberts EA, Walshe JM, Cox DW. The Wilson disease gene: spectrum of mutations and their consequences. Nat Genet 1995;9:210–217. 10. Edery P, Lyonnet S, Mulligan LM, Pelet A, Dow E, Abel L, Holder S, Nihoul-Fekete C, Ponder BA, Munnich A. Mutations of the RET proto-oncogene in Hirschsprung’s disease. Nature 1994;367: 378–380. 11. Liu B, Parsons R, Papadopoulos N, Nicolaides NC, Lynch HT, Watson P, Jass JR, Dunlop M, Wyllie A, Peltomaki P, Delachapelle A, Hamilton SR, Vogelstein B, Kinzler KW. Analysis of mismatch
WBS-Gastro
June 1996
12.
13.
14. 15.
EDITORIALS 2017
repair genes in hereditary non-polyposis colorectal cancer patients. Nature Med 1996;2:169–174. Hahn SA, Schutte M, Shamsul Hoque ATM, Moskaluk CA, daCosta LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 1996;271:350–353. Lynch HT, Smyrk T, Lynch JF. Overview of natural history, pathology, molecular genetics and management of HNPCC (Lynch syndrome). Int J Cancer 1996;69:38–43. Petersen GM. Genetic counseling and predictive testing for colorectal cancer risk. Int J Cancer 1996;69:53–54. Fisher KJ, Choi H, Burda J, Chen SJ, Wilson JM. Recombinant
/ 5e0e$$0048
05-17-96 17:39:14
gasa
adenovirus deleted of all viral genes for gene therapy of cystic fibrosis. Virology 1996;217:11–22. 16. Steer ML, Meldolesi J. The cell biology of experimental pancreatitis. N Engl J Med 1987;316:144–150. Address requests for reprints to: Laurence J. Miller, M.D., Center for Basic Research in Digestive Diseases, Guggenheim 17, Mayo Clinic, Rochester, Minnesota 55905. Fax: (507) 284-0762. Supported by grants from the National Institutes of Health (DK32878 and DK46577). 䉷 1996 by the American Gastroenterological Association 0016-5085/96/$3.00
WBS-Gastro