Gene Mutations in Cancer

Mutations affecting a variety of genes have been characterized in cancer. Some of these mutations represent activating mutations of proto-oncogenes (or other positive mediators of cell proliferation) and others represent inactivating mutations of tumor suppressor genes (or other negative mediators of cell proliferation). Mutations in these genes synergize with other genetic (chromosomal) and epigenetic abnormalities to drive neoplastic transformation and tumorigenesis in affected cells and tissues. This review focuses on the mutation of ras and p53 in cancer.

Mutation of the ras Gene Family in Cancer

Three genes constitute the ras gene family: H-ras, K-ras, and N-ras. The ras protein functions in cell signaling as a hete-rotrimeric G protein, toggling between inactive and active forms. In response to a specific cell stimulus, inactive ras protein releases bound guanosine diphosphate (GDP) and binds a guanosine triphosphate (GTP) molecule. 1 26127 In this GTP-bound active configuration, cell signaling occurs until the intrinsic GTPase activity of the ras protein itself cleaves the GTP to GDP, resulting in reacquisition of the inactive configuration. 126 127 Mutant K-ras proteins lack intrinsic GTPase activity and remain in a continuously active form.128 The constitutive activation of K-ras through this mutational mechanism leads to the induction of multiple signaling pathways involved with cell proliferation and cell survival.129

Each of these ras family of oncogenes have been found to be mutated with varying frequencies in major forms of human cancer. 1 30 K-ras is mutated in cancers of the lung, colon, and pancreas, as well as in myelodysplastic syndrome and some other cancers (such as seminoma). The frequency of K-ras mutation in pancreatic cancer is estimated to be 90%,130 suggesting that this gene mutation is very important in the malignant conversion of this tissue. H-ras is mutated in cancers of the bladder, kidney, and thyroid, and N-ras is mutated in seminoma, thyroid, and acute myelogenous leu-kemia.130 In lung cancer, the majority of ras mutations occur in the K-ras gene. 1 31132 K-ras is mutated in 15-20% of all NSCLC and in 30-50% of lung adenocarcinomas,29 131 133-137 but it is infrequently mutated in other lung cancer types.29134 In lung adenocarcinomas, 85% of K-ras mutations affect codon 12. 1 32 Certain carcinogens found in cigarette smoke, such as benzo[a]pyrene, have been shown to preferentially adduct codon 12 of K-ras, and this adduct is not effectively repaired.138 139 No K-ras mutations are found in adenocarcinomas of nonsmokers, supporting a specific role of tobacco carcinogens in the mutation of K-ras.140 The majority of K-ras codon 12 mutations are G to T transversions,141 resulting in either glycine to cysteine (GGT to TGT) or glycine to valine (GGT to GTT) amino acid substitutions in the mutant protein.

Mutation of the p53 Tumor Suppressor Gene in Cancer

The p53 tumor suppressor gene is one of the most frequently mutated genes in cancer.142,143 The p53 protein functions as a transcriptional regulator and mediator of cellular responses to DNA damage and stress. 1 44 Point mutation of p53 leads to synthesis of mutant forms of the protein that do not fold properly, i 45 resulting in a nonfunctional protein that will not bind DNA.146,147 When this mutant protein oli-gomerizes with other p53 molecules (normal or mutant), the resultant tetramers (or higher-order oligomers) are nonfunc-tional.148 Thus, cells with mutant p53 (or p53 deficiency due to chromosomal deletion) become susceptible to progressive genomic instability and accumulation of additional genetic damage.149,150 Mutational inactivation of p53 has been intensely studied since the discovery of the gene two decades ago. The IARC TP53 Mutation Database (http://www-p53. iarc.fr)151,152 catalogues reported mutations in the p53 gene. The most recent compilation (Release 12, November 2007) contained 24,819 mutations, including germline and somatic mutations. Of these mutations, 23,544 were characterized as somatic mutations, the majority (17,358, or 74%) of which were missense mutations. Although missense mutations represent the prevalent mutation type affecting p53, numerous other mutation types have been documented, including frameshift, nonsense, and splice site mutations among others. p53 mutations have been documented in subsets of most major forms of human cancer, including cancers of the colorectal, lung, breast, head and neck, esophagus, brain, liver, skin, pancreas, and bladder, as well as in hematological malignancies.

Inactivation of the p53 protein can result from mutations of the p53 gene affecting codons encompassing the majority of the gene, with most of the mutations falling within the highly conserved region of the gene that includes exons 5-9. i 43,153 155 Nevertheless, a few hotspots for mutation have been identified. These mutational hotspots correspond to the codons that encode amino acids which are important for the functional interaction of the p53 protein with the DNA molecule.156 The mutational spectrum of the p53 gene is also known to reflect the carcinogenic insults encountered by various tissues. For example, consider p53 mutations in liver cancers and lung cancers. In hepatocellu-lar carcinoma, p53 is frequently the target of chromosomal deletion involving 17p13.1, perhaps occurring in as many as 41% of liver cancers examined. 157 However, p53 mutation occurs in conjunction with chromosomal deletion of the p53 locus in hepatocellular carcinoma. A summary of numerous studies of p53 mutation in hepatocellular carcinoma suggests that mutations occur in approximately 27% (547/2029) of these tumors.157 Point mutation of codon 249 of the p53 gene represents a hotspot in hepatocellular carcinoma, accounting for approximately 30% of p53 mutations in hepatocellular carcinoma.157 This mutation, which results in a G to T transversion (AGG to AGT, arginine to serine), was first recognized in patients from Qidong, China, 1 58-160 but it has also been recognized in hepatocellular carcinomas from Africa and North America.1 61-163 The p53 codon 249 mutation has been attributed to exposure to aflatoxin B1.164 Hence, the mutational spectrum of the p53 gene in hepatocellular carcinoma differs significantly between geographic areas with high aflatoxin exposure and those with low exposures.162,165,166 Similar to liver cancer, the p53 gene may be involved in the molecular pathogenesis of lung cancer through chromosomal deletion of 17p13.1, as well as through gene mutation. Approximately 50% of NSCLCs and 90% of SCLCs harbor mutations in the p53 gene.167-169 The p53 mutational spectrum in lung cancer indicates that G to T transversions dominate and that specific hotspot codons are frequently mutated (including codons 157, 158, 175, 245, 248, 249, and 273).170 The types of mutations detected may reflect the interaction of the DNA with specific carcinogens found in cigarette smoke.171,172

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