Tumor mutations

Culp, S. J., Warbritton, A. R., Smith, B. A., Li, E. E. Beland, F. A. (2000). DNA adduct measurements, cell proliferation and tumor mutation induction in relation to tumor formation in B6C3F1 mice fed coal tar or benzo[a]pyrene. Carcinogenesis, 21, 1433 0. 

SAFETY PROFILE Confirmed human carcinogen producing lung tumors. Mutation data reported. See also CHROMIUM COMPOUNDS and ZINC COMPOUNDS. 

Miyoshi Y, Nagase H, Ando H, Horii A, Ichii S, Nakatsuru S, et al. Somatic mutations of the APC gene in colorectal tumors mutation cluster region in the ARC gene. Hum Molec Genet 1992 1 229-33. 

Recio L. 1997. Oncogene and tumor suppressor gene alterations in nasal tumors. Mutat Res 380 27-31. 

Studies of heritable tumor syndromes have provided considerable insight into the molecular basis of the corresponding sporadic tumors. Mutations of the HRPT2 gene are responsible for the development of the hyperparathyroidism-jaw tumor (HPT-JT) syndrome, which is inherited as an autosomal dominant trait. The commonest manifestations of this syndrome include primary hyperparathyroidism, fibro-osseous lesions of the mandible and maxilla, and a variety of renal lesions. In this syndrome, hyperparathyroidism occurs as a result of neoplasms of one or more parathyroid glands, which... 

Eew studies have been done on the molecular features of gastrointestinal endocrine tumors. Allelic loss of llq has been detected in GI endocrine tumors associated with MENl, and LOH of 1 Iq is also present in a subset of sporadic GI endocrine tumors. Mutations of the MENl gene are present in approximately 30% of sporadic gastrinomas and in occasional midgut and hindgut endocrine tumors. In contrast to pancreatic endocrine tumors, the CpG island methylator phenotype is frequent in GI endocrine tumors. Beta-catenin exon 3 mutations are relatively common (38%) in these tumors, and up to 80% of the tumors show nuclear and cytoplasmic localization of the corresponding protein. Other studies, however, reported absence of exon 3 mutations, but nuclear f5-catenin was found in 30% of cases. In contrast, extra-GI endocrine tumors were negative for nuclear f5-catenin. 

Li EE, Culp SJ, Beland FA. 1994. Tumor mutational spectrum in relation to DNA adduct profile in forestomachs of mice fed coal tar or benzo[a]pyrene. Proc Am Assoc Cancer Res 35 148. 

Yoon, J.H., Lee, C.S., and Pfeifer, G.P. (2003) Simulated sunlight and benzo[o]pyrene diol epoxide induced mutagenesis in the human p53 gene evaluated by the yeast functional assay lack of correspondence to tumor mutation spectra. Carcinogenesis, 24, 113-119. 

C. Role of Environment in Shaping Tumor Mutation Patterns... 

Among the human tumor mutations identified by sequencing, 87.2% are single base substitutions and 12.8% are complex mutations and short deletions or insertions. Missense mutations have been observed at 231 of the 393 codons, including all the codons of the DNA-binding domain except codon 123. This codon (ATC, threonine) is well conserved in evolution, but experimental mutation (to Alanine) at this codon has been shown to activate, rather than suppress DNA-binding activity (Freeman et al., 1994). The vast majority of the mutated codons are recurrent mutation sites that are likely to result in dysfunctional p53. Silent mutations represent up to 3.9% of the mutations in the database and it is possible that mutations occurring at rare... 

Fig. 3A Role of exogenous and endogenous factors in shaping tumor mutation patterns. Mini-hotspots in the p53 coding sequence. Distribution of four mutation types in the coding sequence, GC to AT transitions at CpG (representing 23% of all mutations), GC to TA transversions (15%), GC to CG (8%), and AT to GC (12%). CpG transitions primarily appear as the consequence of an endogenous mutation mechanism and form well-defined mutation hotspots. Because of these major hotspots, the mini-hotspots corresponding to other mutation types are difficult to detect. Only sites that contain more than 1 % of a specific mutation type are shown. Hotspot codons for each mutation type are indicated. Some of the non-CpG hotspots are well-characterized sites of alteration induced by exogenous carcinogens (see Fig. 5).

Fig. 4 Percentage of tumor mutations at p53 base pairs with purine on the nontranscribed strand. The strand bias of several types of mutations affecting purines is shown in several common human cancers. A strong strand bias is indicative of a possible perturbation of the transcription-repair complex at an adducted DNA base. CpG transitions show almost equal distribution on both strands. GC to TA transversions show a strong strand bias in most cancers. The strong bias of AT to GC transitions in lung and bladder cancer is a clue to the involvement of carcinogens in the genesis of these mutations.

Inheritance of a mutation in p53 leads to Li-Fraumeni syndrome, which is characterized by multiple types of tumors. Mutations in p53 are present in more than 50% of human tumors. These are secondary mutations within the cell, and if p53 is mutated the overall rate of cellular mutation will increase because there is no p53 to check for DNA damage, to initiate the repair of the damaged DNA, or to initiate apoptosis if the damage is not repaired. Thus, damaged DNA is replicated, and the frequency of additional mutations within the same cell increases remarkably. 

Tumorigenic - Carcinogenic by RTECS criteria Endocrine - thyroid tumors Mutation in mammalian somatic cells (mouse lymphocyte) = 1500 mg/L... 

---