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Anti-Oncogenes
Anti-Oncogenes F Latif and E Maher, University of Birmingham, Birmingham, UK © 2013 Elsevier Inc. All rights reserved.
Introduction Cancer results, at least in part, from mutations in three classes of genes: 1.
2.
3.
Oncogenes: These are genes whose action positively promotes cell proliferation or growth. The normal nonmutant versions are known as proto-oncogenes. The mutant versions are excessively or inappropriately active leading to tumor growth. Tumor suppressor genes (TSGs) or anti-oncogenes: These are genes that normally suppress cell division or growth. Loss of TSG function promotes uncontrolled cell division and tumor growth. DNA damage repair genes (mutator genes): These genes are not directly involved in cell growth. Their inactivation leads to increase in the rate of mutations in oncogenes and TSGs.
TSGs negatively regulate cell proliferation and growth. The existence of TSGs was originally demonstrated by Harris and colleagues, who found that when tumorigenic and nontumori genic cells were fused in culture, the resulting hybrids were generally nontumorigenic. When some of these hybrids reverted back to the tumorigenic stage, this was accompanied by the loss of chromosomal material.
Two-Hit Model In the early 1970s, Alfred Knudson put forward a theory, ‘the two-hit model’, to explain how mutations in TSGs can lead to cancer. This theory postulates that mutations occurring at the same genetic locus on each of two homologous chromosomes within a single cell leads to tumor formation. In the case of inherited cancer, one mutation may be inher ited (germline mutation) and one acquired (somatic mutation), or both may be acquired in the case of sporadic cancers (nonhereditary). In the case of inherited cancer syn dromes, individuals who are gene carriers are born with the ‘first hit’ in each of their constitutional cells. Hence, one copy of the gene will be defective throughout their life. Then, during the individual’s lifetime, a ‘second hit’ would occur at the same locus on the homologous chromosome within one or more cells, and tumorigenesis will be initiated. In the case of common sporadic tumors, both hits are acquired during the individual’s lifetime. Knudson’s model also explains that the inherited and common forms of the same cancer are caused by mutations in the same gene. It therefore follows that the onset of inherited cancer would be earlier in an individual’s lifetime than in the case of sporadic cancer, since only one further mutation is required in inherited cases to initiate cancer as compared to two mutations required in the event of sporadic tumors. TSG inactivation may occur by mutation (missense,
Brenner’s Encyclopedia of Genetics, 2nd edition, Volume 1
nonsense, splice site, and so on), loss, or epigenetic silencing (methylation). Many, but not all, TSGs comply with the ‘two-hit model’ of tumorigenesis (Table 1). However, though for the past four decades, Knudsen’s ‘two-hit model’ has pro vided a very useful framework for the study of TSG inactivation; in recent years, it has become clear that mutations in TSGs are not always completely recessive. Thus, there is a growing list of haploinsufficient TSGs; for these genes, loss of only one allele is sufficient to produce a malignant phenotype. This can be directly due to the reduction in gene dosage or it may require additional oncogenic or haploinsufficient events. p27Kip1 involved in cell cycle control was one of the early and definitive examples of a haploinsufficient TSG. The list of haploinsuffi cient TSGs is expanding and includes genes such as PTCH and PTEN, which are inactivated in inherited human cancer syndromes. Nontranslated RNAs (e.g., H19 and microRNAs (miRNAs)) represent another class of tumor suppressors. miRNAs are ~22 nucleotide-long noncoding RNAs that hinder gene expression by promoting mRNA degradation or by inhibiting mRNA translation. miRNAs may act as oncogenes or as TSGs in human cancer. In the past decade, there have been major advances in three strategies related to the identification and character ization of cancer-related disease genes: (1) the sequencing of the human genome, (2) epigenetic evaluation of TSGs, and (3) discovery of tumor suppressor pathways using ani mal models.
Human Genome Project and Disease Gene Identification The draft sequence of the human genome was published in February 2001. More recently, second-generation sequencing approaches, such as whole genome, whole exome, and whole transcriptome sequencing, have allowed the identification of disease-related genes, including TSGs in an unprecedented manner, and have helped determine the genomic/transcrip tomic landscape of individual cancer genomes to a high degree of resolution. A recent example using exome and tran scriptome sequencing approaches identified mutations in the ARID1A TSG in a high frequency of ovarian clear cell carcinoma and in endometrioid carcinomas. A cancer-specific database at the Wellcome Trust Sanger Institute aims to catalogue all available information with regard to DNA sequence changes reported in the literature thus far.
Epigenetic Inactivation Inactivation of TSGs can occur by genetic and/or epigenetic mechanisms. The epigenetic silencing of genes is achieved through interplay between histone modifications and DNA
doi:10.1016/B978-0-12-374984-0.00076-0
149
150
Table 1
Anti-Oncogenes
Selected tumor suppressor genes
Gene
Chromosomal locus
Neoplasm
Function
RB1 APC P53 NF1 NF2 WT1 BRCA1 BRCA2 VHL P16
13q14 5q21 17p13 17q11.2 22q12 11p12 17q21 13q12 3p25 9p21
Retinoblastoma Colorectal cancer Sarcomas, gliomas, carcinomas Neurofibromatosis type 1 Neurofibromatosis type 2 Wilm’s tumor Familial breast and ovarian cancer Familial breast and ovarian cancer Von Hippel–Lindau disease Familial melanoma
DPC4/SMAD4 PTC
18q21.1 9q22.3
Pancreatic carcinoma Nevoid basal cell carcinoma syndrome
TSC1 TSC2 CDH1 PTEN
9q34 16p13.3 16q22.1 10q23.3
Tuberous sclerosis Tuberous sclerosis Diffuse gastric cancer Breast cancer, thyroid cancer
Cell cycle regulation Cell adhesion, Wnt pathway Cell cycle regulation, apoptosis Ras-GTPase-activating protein Cell adhesion Transcription factor DNA repair DNA repair Regulation hypoxia response pathways Cell cycle regulation, inhibitor of CDK4/CDK6 cyclin-dependent kinases Cell growth inhibitor Negative regulator of Sonic Hedgehog/Smoothened signal pathway Regulator mTOR pathway Regulator mTOR pathway Cell adhesion Regulation of phosphatidylinositol 3-kinase pathway
mTOR, mammalian target of rapamycin.
methylation and their effect on the chromatin structure and promoter accessibility. In mammals, the major target for DNA methylation (addition of a methyl group to the 5′-carbon of cytosine) is a cytosine located next to a guanine forming what is known as a CpG dinucleotide. The nonrandom distribution of this CpG dinucleotide often results in its clustering in CpG islands. A typical CpG island is >200 base pairs with a GC content >50% and an observed:expected ratio of CpG ≥ 0.6. CpG islands are often found in the 5′-regions of housekeeping genes or to a lesser extent in tissue-specific regulated genes. Most CpG islands are unmethylated in normal cells with few exceptions that include imprinted genes. Introduction of bisul fite treatment of genomic DNA expedited the discovery of novel TSGs that are silenced by CpG island hypermethylation. Polymerase chain reaction (PCR)-based assays were developed to discriminate between methylated and unmethylated alleles and facilitated the identification of de novo promoter region methylation in human cancers. Tumor-specific hypermethyla tion of promoters has been described for an increasing number of TSGs. The RASSF1A TSG is notable as it is almost exclusively inactivated by tumor-specific hypermethylation of its promoter region. Genes silenced by promoter hypermethylation can be reactivated by treatment with the demethylating drug 5-aza-2′-deoxycytidine, either alone or in combination with histone deacetylase (HDAC) inhibitors such as trichostatin A. Therefore, unlike genetic inactivation, which is irreversible, epigenetic inactivation of TSGs is a reversible process. This fact potentially renders tumors treatable by DNA-demethylating agents and/or HDAC inhibitors (epigenetic therapy). Some of these drugs were recently approved for clinical trails in humans including patients with leukemia/myelodysplastic syndromes. Using recently developed high-throughput approaches (methylated DNA immunoprecipitation (MeDIP), methylated CpG island recovery assay (MIRA), and methylation arrays), one can map individual cancer genomes for methylation modifications.
Tumor Suppressor Pathway Discovery Using Animal Models The rapid technological innovations made in sequencing approaches have allowed whole genome sequencing of many simpler organisms such as the yeast (Saccharomyces cerevisiae), the fruitfly (Drosophila melanogaster), the nematode (Caenorhabditis elegans), zebrafish (Danio rerio), mouse, rat, and many more. Analyses of these relatively simpler organ isms have helped to identify new tumor suppressor pathways that are conserved in humans and have helped reveal function of genes implicated in human disease. One such recently discovered pathway was first identified in Drosophila – Salvador–Warts–Hippo (SWH) signaling network involved in tissue growth control in Drosophila. This SWH pathway is highly conserved in mammals and members of the pathway act as TSGs in Drosophila as well as in mammalian cells.
Protein Products The first TSG (RBI) cloned was the gene causing retinoblastoma in children. Since then, many further TSGs have been isolated (e.g., p53, APC, and VHL; see Table 1). These genes are also known as ‘gatekeepers’, preventing cancer through direct con trol of cell growth. The protein products of TSGs are known to play various roles in cell cycle control (RBI prevents cells that are in G0/G1 phase going into S phase of the cell cycle, while p53 acts in late G1 phase, preventing the cells progressing to the S phase), apoptosis (p53; in response to DNA damage, there is a rapid increase in the level of p53 which causes arrest of the cell cycle during G1 phase allowing the cell to repair its DNA; if repair is not possible, p53 induces programmed cell death or apoptosis), and transcription regulation (WT1 protein is a transcription factor and can bind to specific DNA sequences causing transcriptional activation or repression).
Anti-Oncogenes
Clinical Implications In addition to providing insights into the mechanisms that regulate normal cell proliferation, the study of TSGs should eventually lead to novel therapies and better clinical manage ment of cancer patients. An example of this is the use of tyrosine kinase inhibitors (e.g., sorafenib and sunitinib) in metastatic clear cell kidney cancers (most of which will harbor VHL gene mutations and have activation of hypoxia response pathways, some of which are targeted by the drugs). Genetic and epigenetic changes in TSGs mark cancer cells as distinct from their normal counterparts. The study of TSGs will provide molecular markers that can be used for early detection of specific cancers as well as prognostic applications and will provide surrogate markers for chemoprevention trials and help design tumor-specific therapies.
See also: Oncogenes; Retinoblastoma.
Further Reading Bock C, Tomazou EM, Brinkman AB, et al. (2010) Quantitative comparison of genome-wide DNA methylation mapping technologies. Nature Biotechnology 28(10): 1106–1114. Burkhart DL and Sage J (2008) Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nature Reviews Cancer 8(9): 671–682. Croce CM (2009) Causes and consequences of microRNA dysregulation in cancer. Nature Reviews Genetics 10(10): 704–714. Dammann R, Li C, Yoon JH, et al. (2000) Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3. Nature Genetics 25(3): 315–319.
151
Ding L, Ellis MJ, Li S, et al. (2010) Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature 464(7291): 999–1005. Esteller M (2008) Epigenetics in cancer. The New England Journal of Medicine 358(11): 1148–1159. Harvey K and Tapon N (2007) The Salvador–Warts–Hippo pathway – An emerging tumour-suppressor network. Nature Reviews Cancer 7(3): 182–191. Herman JG, Graff JR, Myöhänen S, Nelkin BD, and Baylin SB (1996) Methylationspecific PCR: A novel PCR assay for methylation status of CpG islands. Proceedings of the National Academy of Sciences of the United States of America 93(18): 9821–9826. Jones S, Wang TL, Shih IM, et al. (2010) Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 330(6001): 228–231. Knudson AG (1993) Antioncogenes and human cancer. Proceedings of the National Academy of Sciences of the United States of America 90: 10914–10921. Lander ES, Linton LM, Birren B, et al. (2001) Initial sequencing and analysis of the human genome. Nature 409(6822): 860–921. Lee SB and Haber DA (2001) Wilms tumor and the WT1 gene. Experimental Cell Research 264(1): 74–99. Levine AJ and Oren M (2009) The first 30 years of p53: Growing ever more complex. Nature Reviews Cancer 9(10): 749–758. Parmigiani G, Boca S, Lin J, et al. (2009) Design and analysis issues in genome-wide somatic mutation studies of cancer. Genomics 93(1): 17–21. Payne SR and Kemp CJ (2005) Tumor suppressor genetics. Carcinogenesis 26(12): 2031–2045. Wiegand KC, Shah SP, Al-Agha OM, et al. (2010) ARID1A mutations in endometriosis-associated ovarian carcinomas. The New England Journal of Medicine 363(16): 1532–1543. Venter JC, Myers EW, Li PW, et al. (2001) The sequence of the human genome. Science 291(5507): 1304–1351.
Relevant Websites http://www.sanger.ac.uk/genetics/CGP/cosmic – COSMIC, Catalogue Of Somatic Mutations in Cancer. http://cancergenome.nih.gov/
Introduction Cancer results, at least in part, from mutations in three classes of genes: 1.
2.
3.
Oncogenes: These are genes whose action positively promotes cell proliferation or growth. The normal nonmutant versions are known as proto-oncogenes. The mutant versions are excessively or inappropriately active leading to tumor growth. Tumor suppressor genes (TSGs) or anti-oncogenes: These are genes that normally suppress cell division or growth. Loss of TSG function promotes uncontrolled cell division and tumor growth. DNA damage repair genes (mutator genes): These genes are not directly involved in cell growth. Their inactivation leads to increase in the rate of mutations in oncogenes and TSGs.
TSGs negatively regulate cell proliferation and growth. The existence of TSGs was originally demonstrated by Harris and colleagues, who found that when tumorigenic and nontumori genic cells were fused in culture, the resulting hybrids were generally nontumorigenic. When some of these hybrids reverted back to the tumorigenic stage, this was accompanied by the loss of chromosomal material.
Two-Hit Model In the early 1970s, Alfred Knudson put forward a theory, ‘the two-hit model’, to explain how mutations in TSGs can lead to cancer. This theory postulates that mutations occurring at the same genetic locus on each of two homologous chromosomes within a single cell leads to tumor formation. In the case of inherited cancer, one mutation may be inher ited (germline mutation) and one acquired (somatic mutation), or both may be acquired in the case of sporadic cancers (nonhereditary). In the case of inherited cancer syn dromes, individuals who are gene carriers are born with the ‘first hit’ in each of their constitutional cells. Hence, one copy of the gene will be defective throughout their life. Then, during the individual’s lifetime, a ‘second hit’ would occur at the same locus on the homologous chromosome within one or more cells, and tumorigenesis will be initiated. In the case of common sporadic tumors, both hits are acquired during the individual’s lifetime. Knudson’s model also explains that the inherited and common forms of the same cancer are caused by mutations in the same gene. It therefore follows that the onset of inherited cancer would be earlier in an individual’s lifetime than in the case of sporadic cancer, since only one further mutation is required in inherited cases to initiate cancer as compared to two mutations required in the event of sporadic tumors. TSG inactivation may occur by mutation (missense,
Brenner’s Encyclopedia of Genetics, 2nd edition, Volume 1
nonsense, splice site, and so on), loss, or epigenetic silencing (methylation). Many, but not all, TSGs comply with the ‘two-hit model’ of tumorigenesis (Table 1). However, though for the past four decades, Knudsen’s ‘two-hit model’ has pro vided a very useful framework for the study of TSG inactivation; in recent years, it has become clear that mutations in TSGs are not always completely recessive. Thus, there is a growing list of haploinsufficient TSGs; for these genes, loss of only one allele is sufficient to produce a malignant phenotype. This can be directly due to the reduction in gene dosage or it may require additional oncogenic or haploinsufficient events. p27Kip1 involved in cell cycle control was one of the early and definitive examples of a haploinsufficient TSG. The list of haploinsuffi cient TSGs is expanding and includes genes such as PTCH and PTEN, which are inactivated in inherited human cancer syndromes. Nontranslated RNAs (e.g., H19 and microRNAs (miRNAs)) represent another class of tumor suppressors. miRNAs are ~22 nucleotide-long noncoding RNAs that hinder gene expression by promoting mRNA degradation or by inhibiting mRNA translation. miRNAs may act as oncogenes or as TSGs in human cancer. In the past decade, there have been major advances in three strategies related to the identification and character ization of cancer-related disease genes: (1) the sequencing of the human genome, (2) epigenetic evaluation of TSGs, and (3) discovery of tumor suppressor pathways using ani mal models.
Human Genome Project and Disease Gene Identification The draft sequence of the human genome was published in February 2001. More recently, second-generation sequencing approaches, such as whole genome, whole exome, and whole transcriptome sequencing, have allowed the identification of disease-related genes, including TSGs in an unprecedented manner, and have helped determine the genomic/transcrip tomic landscape of individual cancer genomes to a high degree of resolution. A recent example using exome and tran scriptome sequencing approaches identified mutations in the ARID1A TSG in a high frequency of ovarian clear cell carcinoma and in endometrioid carcinomas. A cancer-specific database at the Wellcome Trust Sanger Institute aims to catalogue all available information with regard to DNA sequence changes reported in the literature thus far.
Epigenetic Inactivation Inactivation of TSGs can occur by genetic and/or epigenetic mechanisms. The epigenetic silencing of genes is achieved through interplay between histone modifications and DNA
doi:10.1016/B978-0-12-374984-0.00076-0
149
150
Table 1
Anti-Oncogenes
Selected tumor suppressor genes
Gene
Chromosomal locus
Neoplasm
Function
RB1 APC P53 NF1 NF2 WT1 BRCA1 BRCA2 VHL P16
13q14 5q21 17p13 17q11.2 22q12 11p12 17q21 13q12 3p25 9p21
Retinoblastoma Colorectal cancer Sarcomas, gliomas, carcinomas Neurofibromatosis type 1 Neurofibromatosis type 2 Wilm’s tumor Familial breast and ovarian cancer Familial breast and ovarian cancer Von Hippel–Lindau disease Familial melanoma
DPC4/SMAD4 PTC
18q21.1 9q22.3
Pancreatic carcinoma Nevoid basal cell carcinoma syndrome
TSC1 TSC2 CDH1 PTEN
9q34 16p13.3 16q22.1 10q23.3
Tuberous sclerosis Tuberous sclerosis Diffuse gastric cancer Breast cancer, thyroid cancer
Cell cycle regulation Cell adhesion, Wnt pathway Cell cycle regulation, apoptosis Ras-GTPase-activating protein Cell adhesion Transcription factor DNA repair DNA repair Regulation hypoxia response pathways Cell cycle regulation, inhibitor of CDK4/CDK6 cyclin-dependent kinases Cell growth inhibitor Negative regulator of Sonic Hedgehog/Smoothened signal pathway Regulator mTOR pathway Regulator mTOR pathway Cell adhesion Regulation of phosphatidylinositol 3-kinase pathway
mTOR, mammalian target of rapamycin.
methylation and their effect on the chromatin structure and promoter accessibility. In mammals, the major target for DNA methylation (addition of a methyl group to the 5′-carbon of cytosine) is a cytosine located next to a guanine forming what is known as a CpG dinucleotide. The nonrandom distribution of this CpG dinucleotide often results in its clustering in CpG islands. A typical CpG island is >200 base pairs with a GC content >50% and an observed:expected ratio of CpG ≥ 0.6. CpG islands are often found in the 5′-regions of housekeeping genes or to a lesser extent in tissue-specific regulated genes. Most CpG islands are unmethylated in normal cells with few exceptions that include imprinted genes. Introduction of bisul fite treatment of genomic DNA expedited the discovery of novel TSGs that are silenced by CpG island hypermethylation. Polymerase chain reaction (PCR)-based assays were developed to discriminate between methylated and unmethylated alleles and facilitated the identification of de novo promoter region methylation in human cancers. Tumor-specific hypermethyla tion of promoters has been described for an increasing number of TSGs. The RASSF1A TSG is notable as it is almost exclusively inactivated by tumor-specific hypermethylation of its promoter region. Genes silenced by promoter hypermethylation can be reactivated by treatment with the demethylating drug 5-aza-2′-deoxycytidine, either alone or in combination with histone deacetylase (HDAC) inhibitors such as trichostatin A. Therefore, unlike genetic inactivation, which is irreversible, epigenetic inactivation of TSGs is a reversible process. This fact potentially renders tumors treatable by DNA-demethylating agents and/or HDAC inhibitors (epigenetic therapy). Some of these drugs were recently approved for clinical trails in humans including patients with leukemia/myelodysplastic syndromes. Using recently developed high-throughput approaches (methylated DNA immunoprecipitation (MeDIP), methylated CpG island recovery assay (MIRA), and methylation arrays), one can map individual cancer genomes for methylation modifications.
Tumor Suppressor Pathway Discovery Using Animal Models The rapid technological innovations made in sequencing approaches have allowed whole genome sequencing of many simpler organisms such as the yeast (Saccharomyces cerevisiae), the fruitfly (Drosophila melanogaster), the nematode (Caenorhabditis elegans), zebrafish (Danio rerio), mouse, rat, and many more. Analyses of these relatively simpler organ isms have helped to identify new tumor suppressor pathways that are conserved in humans and have helped reveal function of genes implicated in human disease. One such recently discovered pathway was first identified in Drosophila – Salvador–Warts–Hippo (SWH) signaling network involved in tissue growth control in Drosophila. This SWH pathway is highly conserved in mammals and members of the pathway act as TSGs in Drosophila as well as in mammalian cells.
Protein Products The first TSG (RBI) cloned was the gene causing retinoblastoma in children. Since then, many further TSGs have been isolated (e.g., p53, APC, and VHL; see Table 1). These genes are also known as ‘gatekeepers’, preventing cancer through direct con trol of cell growth. The protein products of TSGs are known to play various roles in cell cycle control (RBI prevents cells that are in G0/G1 phase going into S phase of the cell cycle, while p53 acts in late G1 phase, preventing the cells progressing to the S phase), apoptosis (p53; in response to DNA damage, there is a rapid increase in the level of p53 which causes arrest of the cell cycle during G1 phase allowing the cell to repair its DNA; if repair is not possible, p53 induces programmed cell death or apoptosis), and transcription regulation (WT1 protein is a transcription factor and can bind to specific DNA sequences causing transcriptional activation or repression).
Anti-Oncogenes
Clinical Implications In addition to providing insights into the mechanisms that regulate normal cell proliferation, the study of TSGs should eventually lead to novel therapies and better clinical manage ment of cancer patients. An example of this is the use of tyrosine kinase inhibitors (e.g., sorafenib and sunitinib) in metastatic clear cell kidney cancers (most of which will harbor VHL gene mutations and have activation of hypoxia response pathways, some of which are targeted by the drugs). Genetic and epigenetic changes in TSGs mark cancer cells as distinct from their normal counterparts. The study of TSGs will provide molecular markers that can be used for early detection of specific cancers as well as prognostic applications and will provide surrogate markers for chemoprevention trials and help design tumor-specific therapies.
See also: Oncogenes; Retinoblastoma.
Further Reading Bock C, Tomazou EM, Brinkman AB, et al. (2010) Quantitative comparison of genome-wide DNA methylation mapping technologies. Nature Biotechnology 28(10): 1106–1114. Burkhart DL and Sage J (2008) Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nature Reviews Cancer 8(9): 671–682. Croce CM (2009) Causes and consequences of microRNA dysregulation in cancer. Nature Reviews Genetics 10(10): 704–714. Dammann R, Li C, Yoon JH, et al. (2000) Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3. Nature Genetics 25(3): 315–319.
151
Ding L, Ellis MJ, Li S, et al. (2010) Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature 464(7291): 999–1005. Esteller M (2008) Epigenetics in cancer. The New England Journal of Medicine 358(11): 1148–1159. Harvey K and Tapon N (2007) The Salvador–Warts–Hippo pathway – An emerging tumour-suppressor network. Nature Reviews Cancer 7(3): 182–191. Herman JG, Graff JR, Myöhänen S, Nelkin BD, and Baylin SB (1996) Methylationspecific PCR: A novel PCR assay for methylation status of CpG islands. Proceedings of the National Academy of Sciences of the United States of America 93(18): 9821–9826. Jones S, Wang TL, Shih IM, et al. (2010) Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 330(6001): 228–231. Knudson AG (1993) Antioncogenes and human cancer. Proceedings of the National Academy of Sciences of the United States of America 90: 10914–10921. Lander ES, Linton LM, Birren B, et al. (2001) Initial sequencing and analysis of the human genome. Nature 409(6822): 860–921. Lee SB and Haber DA (2001) Wilms tumor and the WT1 gene. Experimental Cell Research 264(1): 74–99. Levine AJ and Oren M (2009) The first 30 years of p53: Growing ever more complex. Nature Reviews Cancer 9(10): 749–758. Parmigiani G, Boca S, Lin J, et al. (2009) Design and analysis issues in genome-wide somatic mutation studies of cancer. Genomics 93(1): 17–21. Payne SR and Kemp CJ (2005) Tumor suppressor genetics. Carcinogenesis 26(12): 2031–2045. Wiegand KC, Shah SP, Al-Agha OM, et al. (2010) ARID1A mutations in endometriosis-associated ovarian carcinomas. The New England Journal of Medicine 363(16): 1532–1543. Venter JC, Myers EW, Li PW, et al. (2001) The sequence of the human genome. Science 291(5507): 1304–1351.
Relevant Websites http://www.sanger.ac.uk/genetics/CGP/cosmic – COSMIC, Catalogue Of Somatic Mutations in Cancer. http://cancergenome.nih.gov/