- Email: [email protected]
Genetic linkage and physical mapping of a cancer gene
EDITORIAL Genetic Linkage and Physical Mapping of a Cancer Gene Ataxia-Telangiectasia
The contribution to this issue by Wet et al. [1] is one directed at the physical mapping of a sector of the human genome. It is perhaps more reflective of the dawning of a new era in the genetics of human cancer than any article that has yet appeared in Cancer Genetics and Cytogenetics. This new era will involve genetic linkage, gene localization, and physical mapping of the genome. The aims at this strategy are not obscure. The initial aim is to identify a cancer gene locus. This can be done in established ways: for example the disease ataxiatelangiectasia (AT) must be described and its role in causing malignancy must be delineated. Now the stage is set. The second act is different from the first. The first act was in clinical language. The second is in genetic language, a distinctive tongue containing probabilities, LOD (log of the odds) scores, maximum likelihoods, theta, and additional terms not in everyday usage among most investigators. The aim of this second act using the example of AT, is to locate a gene for AT. A gene locus for AT has been located. Let us say, for example, that this AT gene is on the long (q) arm of chromosome 11 in the region of bands 11q22 and 11q23. We might know this new fact because the AT gene' under study segregates with gene markers in 11q22-2312]. The third act now begins. Little is known about the 11q22-23 region. It may have been identified hitherto but its precise arrangement is not known. The culprit in the crime of cancer, AT, has been recognized and we have learned its neighborhood of residence. The neighborhood now needs to be charted in physical terms. This requires physical mapping of the neighborhood [1]. The fourth and final act will be to isolate and sequence the cancer gene itself. In the case of AT this denouement has not yet been written. AT is not a simple disease. It involves multiple systems. It does not just predispose to malignancy. On a clinical level there are abnormalities in the brain, vessels carrying blood, the blood itself, the eyes, the sinuses, speech, coodination, gait, the lungs, the immune system, the liver, the skin, and other organs, systems, and functions. To tie all these aberrations together into one pathogenetic package is not yet feasible. The sequence of events, even after the gene has been isolated and sequenced, may and probably will still be unknown. On a laboratory level, AT is also complex. The immunoglobulin system is deranged and IGA is low or absent. Conversely, the a-fetoprotein (AFP) is more than ample. The AT liver makes AFP to an excess and exports it into the blood stream. Chromosomes are not normal. There are often elevated chromosome breakages and rearrangements. AT is one of the genetic chromosome instability syndromes. How the chromosome rearrangements in AT fit into cancer is conjectural. One can see clones of cells in blood lymphocytes with marker rearrangements in AT. Some of these marked clones appear benign while others are malignant. 133 © 1990 Elsevier Science Publishing Co., Inc.
Cancer Genet Cytogenet 46:133-134 (1990)
655 Avenueof the Americas,New York,NY 10010
0165-4606/90/$03.50
134
Genetic Linkage and Physical Mapping The chromosome breakpoints in AT clones are not random. By preference they involve chromosomes 7 and 14. Neither are the breakpoints in these chromosomes random. They involve loci of immunological importance, namely genes in the T-cell receptor system and genes for the immunoglobulin heavy chain. The big question concerns the nature of the AT gene on 11q. Wet et al. [1] take note of the concept that a cellular adhesion molecule may have been the ancient genetic ancestor of the immunoglobulin supergene family. They propose that the human gene cluster in 11q23 and the homologous inverted cluster of genes on chromosome 9 in the mouse may contain loci from this extraordinary clan of genes concerned with differentiation of both the immune and the nervous systems. The AT gene in 11q23 may thus be a member of the immunoneural family. Some molecular geneticists believe that all of the answers to questions posed by medical genetics can come from sequencing the human genome. The Genome Project has been likened to the Manhattan Project. The Manhattan Project in World War II created awesome atomic weaponry. The Genome Project would yield genetic weaponry with which to "win the war" against genetic disease and cancer. This is illusory. The physical mapping of the human genome is important. Valuable information will be gained, without a doubt. But all the ingenuity of reverse genetics cannot put together all of the pieces in genetic diseases (such as AT) and cancer. Once reverse genetics had its day, forward genetics must again move ahead to learn how each gene acts to produce the final phenotype. The AT gene under study by Gatti et al. [2] and Wet et al. [1] is from complementation group A. Recently patients with the Nijmegen breakage syndrome, a similar disorder, were reported [3] to have distinctive complementation patterns. The 11q23 region is coming under intensive analysis. Another team of investigators [4] studying this region has found the most likely gene order, going from the centremere toward the telomere, to be neural cellular adhesion molecule (NCAM), CD3, and ETS2 or THY1, with the relative order of ETS1 and THY1 yet to be determined. Wet et al. [1] make a number of good adobe blocks for the pueblo of AT. This research team has already done a brilliant bit of gene mapping with AT [2]. We now know where an AT gene is located. We now know more about its neighborhood [1]. The mystery of AT is being solved and we will, we hope, soon know how AT is connected to cancer. FREDERICK HECHT
The Genetics Center and The Cancer Center Southwest Biomedical Research Institute of Genetrix, Inc., Scottsdale, Arizona, and Jacksonville, Florida
REFERENCES
1. Wet S, Rocchi M, Archidiacono N, Sacchi N, Romeo G, Gatti RA (1990): Physical mapping of the human chromosome 11q23 region containing the ataxia-telangiectasia locus. Cancer Genet Cytogenet 46:1-8. 2. Gatti RA, Berkel I, Boder E, Braedt G, Charmley P, Concannon P, Ersoy F, Foroud T, Jaspers NGJ, Lange K, Lathrop GM, Leppert M, Nakamura Y, O'Connell P, Paterson M, Salser W, Sanal O, Silver j, Sparkes RS, Susi E, Weeks DE, Wet S, White R, Yoderr F (1988):Localization of an ataxia-telangiectasia gene to chromosome 11q22-23. Nature 336:577-580. 3. Jaspers NGJ, Gatti RA, Baan C, Linssen PCML, Bootsma D (1988): Genetic complementation analysis of ataxia telangiectasia and Nijmegen breakage syndrome: A survey of 50 patients. Cytogenet Cell Genet 49:259-263. 4. Savagge PD, Jones C, Silver J, Geurts van Kessel AHM, Gonzalez-Sarmiento R, Palm L, Hanson CA, Kersey JH (1988): Mapping studies and expression of genes located on human chromosome 11, band q23. Cytogenet Cell Genet 49:289-292.
The contribution to this issue by Wet et al. [1] is one directed at the physical mapping of a sector of the human genome. It is perhaps more reflective of the dawning of a new era in the genetics of human cancer than any article that has yet appeared in Cancer Genetics and Cytogenetics. This new era will involve genetic linkage, gene localization, and physical mapping of the genome. The aims at this strategy are not obscure. The initial aim is to identify a cancer gene locus. This can be done in established ways: for example the disease ataxiatelangiectasia (AT) must be described and its role in causing malignancy must be delineated. Now the stage is set. The second act is different from the first. The first act was in clinical language. The second is in genetic language, a distinctive tongue containing probabilities, LOD (log of the odds) scores, maximum likelihoods, theta, and additional terms not in everyday usage among most investigators. The aim of this second act using the example of AT, is to locate a gene for AT. A gene locus for AT has been located. Let us say, for example, that this AT gene is on the long (q) arm of chromosome 11 in the region of bands 11q22 and 11q23. We might know this new fact because the AT gene' under study segregates with gene markers in 11q22-2312]. The third act now begins. Little is known about the 11q22-23 region. It may have been identified hitherto but its precise arrangement is not known. The culprit in the crime of cancer, AT, has been recognized and we have learned its neighborhood of residence. The neighborhood now needs to be charted in physical terms. This requires physical mapping of the neighborhood [1]. The fourth and final act will be to isolate and sequence the cancer gene itself. In the case of AT this denouement has not yet been written. AT is not a simple disease. It involves multiple systems. It does not just predispose to malignancy. On a clinical level there are abnormalities in the brain, vessels carrying blood, the blood itself, the eyes, the sinuses, speech, coodination, gait, the lungs, the immune system, the liver, the skin, and other organs, systems, and functions. To tie all these aberrations together into one pathogenetic package is not yet feasible. The sequence of events, even after the gene has been isolated and sequenced, may and probably will still be unknown. On a laboratory level, AT is also complex. The immunoglobulin system is deranged and IGA is low or absent. Conversely, the a-fetoprotein (AFP) is more than ample. The AT liver makes AFP to an excess and exports it into the blood stream. Chromosomes are not normal. There are often elevated chromosome breakages and rearrangements. AT is one of the genetic chromosome instability syndromes. How the chromosome rearrangements in AT fit into cancer is conjectural. One can see clones of cells in blood lymphocytes with marker rearrangements in AT. Some of these marked clones appear benign while others are malignant. 133 © 1990 Elsevier Science Publishing Co., Inc.
Cancer Genet Cytogenet 46:133-134 (1990)
655 Avenueof the Americas,New York,NY 10010
0165-4606/90/$03.50
134
Genetic Linkage and Physical Mapping The chromosome breakpoints in AT clones are not random. By preference they involve chromosomes 7 and 14. Neither are the breakpoints in these chromosomes random. They involve loci of immunological importance, namely genes in the T-cell receptor system and genes for the immunoglobulin heavy chain. The big question concerns the nature of the AT gene on 11q. Wet et al. [1] take note of the concept that a cellular adhesion molecule may have been the ancient genetic ancestor of the immunoglobulin supergene family. They propose that the human gene cluster in 11q23 and the homologous inverted cluster of genes on chromosome 9 in the mouse may contain loci from this extraordinary clan of genes concerned with differentiation of both the immune and the nervous systems. The AT gene in 11q23 may thus be a member of the immunoneural family. Some molecular geneticists believe that all of the answers to questions posed by medical genetics can come from sequencing the human genome. The Genome Project has been likened to the Manhattan Project. The Manhattan Project in World War II created awesome atomic weaponry. The Genome Project would yield genetic weaponry with which to "win the war" against genetic disease and cancer. This is illusory. The physical mapping of the human genome is important. Valuable information will be gained, without a doubt. But all the ingenuity of reverse genetics cannot put together all of the pieces in genetic diseases (such as AT) and cancer. Once reverse genetics had its day, forward genetics must again move ahead to learn how each gene acts to produce the final phenotype. The AT gene under study by Gatti et al. [2] and Wet et al. [1] is from complementation group A. Recently patients with the Nijmegen breakage syndrome, a similar disorder, were reported [3] to have distinctive complementation patterns. The 11q23 region is coming under intensive analysis. Another team of investigators [4] studying this region has found the most likely gene order, going from the centremere toward the telomere, to be neural cellular adhesion molecule (NCAM), CD3, and ETS2 or THY1, with the relative order of ETS1 and THY1 yet to be determined. Wet et al. [1] make a number of good adobe blocks for the pueblo of AT. This research team has already done a brilliant bit of gene mapping with AT [2]. We now know where an AT gene is located. We now know more about its neighborhood [1]. The mystery of AT is being solved and we will, we hope, soon know how AT is connected to cancer. FREDERICK HECHT
The Genetics Center and The Cancer Center Southwest Biomedical Research Institute of Genetrix, Inc., Scottsdale, Arizona, and Jacksonville, Florida
REFERENCES
1. Wet S, Rocchi M, Archidiacono N, Sacchi N, Romeo G, Gatti RA (1990): Physical mapping of the human chromosome 11q23 region containing the ataxia-telangiectasia locus. Cancer Genet Cytogenet 46:1-8. 2. Gatti RA, Berkel I, Boder E, Braedt G, Charmley P, Concannon P, Ersoy F, Foroud T, Jaspers NGJ, Lange K, Lathrop GM, Leppert M, Nakamura Y, O'Connell P, Paterson M, Salser W, Sanal O, Silver j, Sparkes RS, Susi E, Weeks DE, Wet S, White R, Yoderr F (1988):Localization of an ataxia-telangiectasia gene to chromosome 11q22-23. Nature 336:577-580. 3. Jaspers NGJ, Gatti RA, Baan C, Linssen PCML, Bootsma D (1988): Genetic complementation analysis of ataxia telangiectasia and Nijmegen breakage syndrome: A survey of 50 patients. Cytogenet Cell Genet 49:259-263. 4. Savagge PD, Jones C, Silver J, Geurts van Kessel AHM, Gonzalez-Sarmiento R, Palm L, Hanson CA, Kersey JH (1988): Mapping studies and expression of genes located on human chromosome 11, band q23. Cytogenet Cell Genet 49:289-292.