Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Carcinogens 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 1,2-dimethylhydrazine (DMH) induce colon tumors in the rat that contain mutations in beta-catenin, but the pattern of mutation differs from that found in human colon cancers. In both species, mutations affect the glycogen synthase kinase-3beta consensus region of beta-catenin, but whereas they directly substitute critical Ser/Thr phosphorylation sites in human colon cancers, the majority of mutations cluster around Ser33 in the rat tumors. Two dietary phytochemicals, chlorophyllin and indole-3-carbinol, given post-initiation, shifted the pattern of beta-catenin mutations in rat colon tumors induced by IQ and DMH. Specifically, 17/39 (44%) of the beta-catenin mutations in groups given carcinogen plus modulator were in codons 37, 41 and 45, and substituted critical Ser/Thr residues directly, as seen in human colon cancers. None of the tumors from groups given carcinogen alone had mutations in these codons. Interestingly, many of the mutations that substituted critical Ser/Thr residues in beta-catenin were from a single group given DMH and 0.001% chlorophyllin, in which a statistically significant increase in colon tumor multiplicity was observed compared with the group given DMH only. These tumors had marked over-expression of cyclin D1, c-myc and c-jun mRNA and c-Myc and c-Jun proteins were strongly elevated compared with tumors containing wild-type beta-catenin. The results indicate that the pattern of beta-catenin mutations in rat colon tumors can be influenced by exposure to dietary phytochemicals administered post-initiation, and that the mechanism might involve the altered expression of beta-catenin/Tcf/Lef target genes.
Carcinogenesis 2001 Feb
PMID:beta-Catenin mutation in rat colon tumors initiated by 1,2-dimethylhydrazine and 2-amino-3-methylimidazo[4,5-f]quinoline, and the effect of post-initiation treatment with chlorophyllin and indole-3-carbinol. 1118 54

Ultraviolet light A (UVA) plays an important role in the etiology of human skin cancer, and UVA-induced signal transduction has a critical role in UVA-induced skin carcinogenesis. The upstream signaling pathways leading to p70(S6K) phosphorylation and activation are not well understood. Here, we observed that UVA induces phosphorylation and activation of p70(S6K). Further, UVA-stimulated p70(S6K) activity and phosphorylation at Thr(389) were blocked by wortmannin, rapamycin, PD98059, SB202190, and dominant negative mutants of phosphatidylinositol (PI) 3-kinase p85 subunit (DNM-Deltap85), ERK2 (DNM-ERK2), p38 kinase (DNM-p38), and JNK1 (DNM-JNK1) and were absent in Jnk1-/- or Jnk2-/- knockout cells. The p70(S6K) phosphorylation at Ser(411) and Thr(421)/Ser(424) was inhibited by rapamycin, PD98059, or DNM-ERK2 but not by wortmannin, SB202190, DNM-Deltap85, or DNM-p38. However, Ser(411), but not Thr(421)/Ser(424) phosphorylation, was suppressed in DNM-JNK1 and abrogated in Jnk1-/- or Jnk2-/- cells. In vitro assays indicated that Ser(411) on immunoprecipitated p70(S6K) proteins is phosphorylated by active JNKs and ERKs, but not p38 kinase, and Thr(421)/Ser(424) is phosphorylated by ERK1, but not ERK2, JNKs, or p38 kinase. Moreover, p70(S6K) co-immunoprecipitated with PI 3-kinase and possibly PDK1. The complex possibly possessed a partial basal level of phosphorylation, but not at MAPK sites, which was available for its activation by MAPKs in vitro. Thus, these results suggest that activation of MAPKs, like PI 3-kinase/mTOR, may be involved in UVA-induced phosphorylation and activation of p70(S6K).
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PMID:Signal transduction pathways involved in phosphorylation and activation of p70S6K following exposure to UVA irradiation. 1127 32

Steroid hormones, especially testosterone, play important roles in the carcinogenesis of prostate cancer, and several studies have reported changes in risk with polymorphisms of genes involved in steroid metabolism. One example is the CYP17 gene, which has a polymorphic T-to-C substitution in the 5'-untranslated region giving rise to A1 (T) and A2 (C) alleles. Steroid 5alpha-reductase type II (SRD5A2), which converts testosterone to the metabolically more active dihydrotestosterone, exhibits 2 polymorphisms: V89L, which substitutes leucine for valine at codon 89, and A49T, which substitutes threonine for alanine at codon 49. We therefore designed a case-control study of 105 prostate-cancer patients and 210 controls with benign prostatic hyperplasia for the purpose of investigating the association between prostate-cancer risk and polymorphisms in the SRD5A2 and CYP17 genes among the Japanese. The frequency of the CYP17 A2/A2 genotype in cases (18.8%) was higher than in controls (14.5%). Compared with the A1/A1 genotype, the odds ratio for the A2/A2 genotype was 2.39 (95% confidence interval 1.04-5.46, p = 0.04). The frequency of the SRD5A2 LL genotype in cases (29.3%) was also slightly higher than in controls (24.6%), but this was not significant. Regarding the A49T polymorphism of SRD5A2, we could not detect the T allele in any of the examined samples. These data suggest a significant association between the CYP17 polymorphism and prostate-cancer risk among the Japanese.
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PMID:Impact of genetic polymorphisms of 17-hydroxylase cytochrome P-450 (CYP17) and steroid 5alpha-reductase type II (SRD5A2) genes on prostate-cancer risk among the Japanese population. 1134 May 72

Apart from the RET proto-oncogene (RET) no other genes have been found to be involved in medullary thyroid carcinoma (MTC) tumorigenesis. Germline RET mutations are seen virtually in all familial forms of MTC and somatic RET mutations are often detected in sporadic MTC. In sporadic MTCs the RET gene is mutated in codon 918, where a methionine is substituted to a threonine (M918T). In this study 24 MTCs were analyzed by comparative genomic hybridization (CGH) for chromosomal imbalances. Overall, alterations were detected in approximately 60% of the samples. The most common aberrations were gains on chromosome 19q (29%), 19p (21%), 11c-q12 (12.5%), and 22q (12.5%) and losses on 13q21 (21%) and 3q23-qter (12.5%). Gain of chromosome 11c-q12 was only detected in samples from patients whom died of MTC (p=0.001). These MTCs also harbored the somatic RET M918T mutation and also showed the highest numbers of CGH alterations in the series (p<0.003). Although there was a tendency towards a higher number of CGH imbalances in the tumors with RET M918T mutation, this difference was not significant. The results indicate that MTC is a comparatively genetically stable tumor, and that chromosomal regions 19q, 19p, 13q and 11q may be involved in MTC carcinogenesis.
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PMID:CGH alterations in medullary thyroid carcinomas in relation to the RET M918T mutation and clinical outcome. 1135 Dec 54

Although several variants of DNA repair genes have been identified, their functional significance has not been determined. Using samples collected from 135 cancer-free women, this study evaluated whether amino acid substitution variants of DNA repair genes contribute to ionizing radiation (IR) susceptibility as measured by prolonged cell cycle G2 delay. PCR-restriction fragment length polymorphism (RFLP) assays were used to determine four genotypes: X-ray repair cross complementing group 1 (XRCC1, exon 6, C/T, 194 Arg/Trp and exon 10, G/A, 399 Arg/Gln), XRCC group 3 (XRCC3, exon 7, C/T, 241 Thr/Met) and apurinic/apyrimidinic endonuclease 1 (APE1, exon 5, T/G, 148 Asp/Glu). Fluorescence-activated cell sorter (FACS) analysis was used to measure cell cycle delay. APE1 (exon 5) genotype was significantly associated with mitotic delay (P = 0.01), with the Glu/Glu genotype having prolonged delay compared with the other two genotypes. The mitotic delay index (mean +/- SD) in women with the APE1 codon 148 Asp/Asp, Asp/Glu and Glu/Glu genotypes was 30.95 +/- 10.15 (n = 49), 30.65 +/- 10.4 (n = 60) and 39.56 +/- 13.12 (n = 21), respectively. There was a significant interaction between family history (FH) and APE1 (exon 5) genotype (P = 0.007) as well as FH and XRCC1 (exon 10) genotype (P = 0.005) in mitotic delay. Lastly, prolonged cell cycle delay was significantly associated with number of variant alleles when APE1 Asp148Glu and XRCC1 Arg399Gln genotypes were evaluated in a four-level model (chi(2) for linear trend = 10.9; P = 0.001). These results suggest that amino acid substitution variants of XRCC1 and APE1 may contribute to IR hypersensitivity.
Carcinogenesis 2001 Jun
PMID:Amino acid substitution variants of APE1 and XRCC1 genes associated with ionizing radiation sensitivity. 1137 99

Mutations in the ras gene are key events in the process of carcinogenesis; in particular, point mutations in codon 61 of exon 2 of the N-ras gene occur frequently in malignant melanoma (MM). We searched for point mutations in the N-ras gene in a large series of primary and metastatic MM from 81 different retrospectively selected patients using the very sensitive denaturing gradient gel electrophoresis technique, followed by sequencing. The classical codon 12 and codon 61 mutations were found in 21 and 17% of the cases, respectively. No codon 13 mutation was found. A novel mutation at codon 18 of exon 1, consisting of a substitution of alanine (GCA) by threonine (ACA), was found in 15% of the primary MMs but in none of the metastatic MMs. All of the other cases were free of mutations. Using microdissected cells from distinctive MM growth phases as source of DNA for mutation analysis, this particular N-ras exon 1 mutation at codon 18 was already present in the radial growth phase and preserved throughout the successive growth phases; it was also found in a dysplastic nevi in continuity with a MM, indicating a clonal relationship between both lesions. Our findings also illustrate the clonal relationship between the distinctive growth phases in MM and suggest the codon 18 mutation to occur early in MM development. The MM in patients with this mutation were significantly thinner than those without a codon 18 mutation (P = 0.0257). Statistical analysis, comparing the group of codon 18 patients with the group of patients with the classical mutations and without mutations, revealed a highly significant difference in overall outcome. The cumulative probability of developing metastasis was significantly lower for the group patients with a codon 18 mutation (P = 0.0130). We can thus conclude that this codon 18 mutation identifies a group of patients with better prognosis than patients with melanoma that harbor wild-type sequence or classical activating point mutations in codon 12 or 61. Preliminary nucleotide binding measurements could not detect a difference between wild-type Ras protein and the mutant Ras(A18T) protein. However, for a precise elucidation of the role of the N-Ras(A18T) mutant in melanoma, additional studies aimed to measure the affinity to guanine nucleotide exchange factors and GTPase-activating proteins are needed.
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PMID:A novel N-ras mutation in malignant melanoma is associated with excellent prognosis. 1140 71

Using PCR, type A Epstein-Barr virus (EBV) infection was demonstrated in a squamous cell carcinoma of the maxilla (in a 52-year-old man) and the tongue of the same patient 18 years later (at the age of 70). Furthermore, at the age of 72, this patient developed an EBV-infected anaplastic large cell lymphoma. Analysis of the terminal regions of the EBV genome revealed a monoclonal proliferation of EBV-infected lymphoma cells. However, sequence analysis of the EBV revealed a slight difference in the EBNA2 regions between the virus-infected lymphoma and the squamous cell carcinomas. The mutations at 48991 (G-->T) and 48998 (C-->A) were demonstrated in the lymphoma. Although the squamous cell carcinoma of the tongue occurred after an interval of 18 years, the mutation site in the carcinomas was the same, 49137 (A-->G), as compared with B95-8 strain EBV EBNA2. The mutations at 48991 and at 49137 were associated with amino acid changes, Arg-->Met and Thr-->Ala, respectively, but the alteration at 48998 was a silent mutation. Thirty-bp deletion in the LMP-1 carboxy terminal region was demonstrated in the virus-infected lymphoma, but not in the squamous cell carcinomas. On the other hand, HTLV-1 proviral DNA (tax, gag and env) was not detected in the lymphoma, nor was HPV demonstrated in the squamous cell carcinomas, although Okinawa is known as an HTLV-1 and HPV prevalence region. The T-cell receptor beta gene rearrangement was demonstrated in the lymphoma, but the t(2;5) fusion transcript was not detected using PCR. Cytogenetic analysis of the lymphoma cells showed a complex hypertriploid karyotype with 76XY. The type A EBV infection might play a role in the carcinogenesis of the tumors of our patient. Interestingly, the infected virus genome sequences, the EBNA2 and LMP-1 regions, which were closely associated with carcinogenesis in the squamous cell carcinomas and the lymphoma, showed slight differences.
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PMID:Differences in EBNA2 and LMP-1 carboxy terminal region sequences of Epstein-Barr virus type A between the tumors in a multiple cancer patient. 1143 67

The exposure of mammalian cells to UV irradiation leads to the activation of transcription factors and protein kinases, which are believed to be responsible for the carcinogenic effects of excessive sun exposure. The present study investigated the effect of UV exposure on reactive oxygen species (ROS) generation and protein kinase B (Akt) phosphorylation in epidermal cells and determined if a relationship exists between these UV responses. Exposure of mouse epidermal JB6 Cl 41 cells to UV radiation led to specific phosphorylation of Akt at Ser-473 and Thr-308 in a time-dependent manner. This phosphorylation was confirmed by the observation that overexpression of Akt mutant, Akt-T308/S473A, attenuated phosphorylation of Akt at Ser-473 and Thr-308. UV radiation also generated ROS as measured by electron spin resonance (ESR) in JB6 Cl 41 cells. The generation of ROS by UV radiation was measured further by H(2)O(2) and O(-.2) fluorescence staining assays. The mechanism of ROS generation involved reduction of molecular oxygen to O(-.2), which generated H(2)O(2) through dismutation. H(2)O(2) produced .OH via a metal-independent pathway. The scavenging of UV-generated H(2)O(2) by N-acety-l-cyteine (NAC, a general antioxidant) or catalase (a specific H(2)O(2) inhibitor) inhibited Akt phosphorylation at Ser-473 and Thr-308, whereas the pretreatment of cells with sodium formate (an .OH radical scavenger) or superoxide dismutase (an O(-.2) radical scavenger) did not show any inhibitory effects. Furthermore, treatment of cells with H(2)O(2) increased UV-induced phosphorylation of Akt at Ser-473 and Thr-308. These results demonstrate that UV radiation generates a whole spectrum of ROS including O(-.2), .OH, and H(2)O(2) and induces phosphorylation of Akt at Ser-473. Among the various ROS, H(2)O(2) seems most potent in mediating UV-induced phosphorylation of Akt at Ser-473 and Thr-308. It is possible that Akt may play a role in the carcinogenesis effects by UV radiation.
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PMID:UV Induces phosphorylation of protein kinase B (Akt) at Ser-473 and Thr-308 in mouse epidermal Cl 41 cells through hydrogen peroxide. 1150 90

DNA repair genes have an important role in protecting individuals from cancer-causing agents. Polymorphisms in several DNA repair genes have been identified and individuals with non-dramatic reductions in the capacity to repair DNA damage are observed in the population, but the impact of specific genetic variants on repair phenotype and cancer risk has not yet been clarified. In 308 healthy Italian individuals belonging to the prospective European project EPIC, we have investigated the relationship between DNA damage, as measured by (32)P-DNA adduct levels, and three genetic polymorphisms in different repair genes: XRCC1-Arg399Gln (exon 10), XRCC3-Thr241Met (exon 7) and XPD-Lys751Gln (exon 23). DNA adduct levels were measured as relative adduct level (RAL) per 10(9) normal nucleotides by DNA (32)P-post-labelling assay in white blood cells from peripheral blood. Genotyping was performed by PCR-RFLP analysis. The XRCC3-241Met variant was significantly associated with higher DNA adduct levels, whereas XRCC1-399Gln and XPD-751Gln were associated with higher DNA adduct levels only in never-smokers. XRCC3-241Met homozygotes had an average DNA adduct level of 11.44 +/- 1.48 (+/-SE) compared with 7.69 +/- 0.88 in Thr/Met heterozygotes and 6.94 +/- 1.11 in Thr/Thr homozygotes (F = 3.206, P = 0.042). Never-smoking XRCC1-399Gln homozygotes had an average DNA adduct level of 15.60 +/- 5.42 compared with 6.16 +/- 0.97 in Gln/Arg heterozygotes and 6.78 +/- 1.10 in Arg/Arg homozygotes (F = 5.237, P = 0.007). A significant odds ratio (3.81, 95% CI 1.02-14.16) to have DNA adduct levels above median value was observed for XPD-751Gln versus XPD-751Lys never-smoking homozygotes after adjustment for several confounders. These data show that all the analysed polymorphisms could result in deficient DNA repair and suggest a need for further investigation into the possible interactions between these polymorphisms, smoking and other risk factors.
Carcinogenesis 2001 Sep
PMID:XRCC1, XRCC3, XPD gene polymorphisms, smoking and (32)P-DNA adducts in a sample of healthy subjects. 1153 66

Several studies have investigated polymorphisms in CYP1A1 and breast cancer risk with inconsistent results. We have carried out a population based case-control study of the Thr461Asn and Ile462Val polymorphisms in CYP1A1 to clarify their importance in determining breast cancer susceptibility. A total of 1873 cases and 712 controls were genotyped for Thr461Asn and 1948 cases and 1355 controls were genotyped for Ile462Val. We have also investigated a putative interaction between smoking and CYP1A1 genotype and breast cancer risk using a case only study design. The genotype distribution of Thr461Asp in controls was close to that expected under Hardy-Weinberg equilibrium (HWE). We detected no significant differences in genotype frequencies between breast cancer cases and controls (P = 0.68). Compared with the Thr/Thr homozygotes there was no significant risk for either the Thr/Asp heterozygote [OR = 1.1 (95% CI 0.8-1.4)] or the Asp/Asp homozygote [OR = 0.4 (0.02-6.1)]. The genotype distribution of Ile462Val in controls was also close to that expected under HWE with no significant differences between breast cancer cases and the controls (P = 0.44). No significant risk was found for either the Ile/Val heterozygote [OR = 0.8 (0.6-1.1)] or the Val/Val homozygote [OR = 2.7 (0.3-24)] compared with the Ile/Ile homozygotes. Furthermore, subgroup analyses revealed no effect of age or menopausal status on genotypic risks, and we found no evidence for an interaction between genotype and smoking habit or alcohol consumption and susceptibility to breast cancer. We combined our data for the Ile462Val polymorphism with those from four other published studies, but even with >5000 subjects, none of the genotype-associated risks achieved statistical significance, and there was no consistent pattern to the risks associated with increasing Val allele dosage [Ile/Val OR = 0.9 (0.7-1.1), Val/Val OR = 2.3 (0.4-12), and Val carrier OR = 1.0 (0.9-1.1)].
Carcinogenesis 2001 Nov
PMID:Polymorphisms in CYP1A1 and smoking: no association with breast cancer risk. 1169 41


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