p53 mutation and cancer
p53 MUTATIONS IN LUNG CANCER
Lung cancer is the most frequently encountered tumor in the industrial world with increasing incidence in both men and women linked to tobacco smoking epidemics. All investigations have shown a clear-cut dose-response relationship between the amount of tobacco smoked daily and the subsequent risk of lung cancer. It is now thought that cigarette smoking is responsible for 80-90% of lung cancers. In experimental animals, cigarette smoke induces malignant tumours of the respiratory tract. This smoke is a complex mixture of several hundred different molecules, including well characterized carcinogens such as polycyclic aromatic hydrocarbons (benzo(a)pyrene) and N-nitrosamines. Benzo(a)pyrene is a highly carcinogenic compound and was one of the molecules found in coal tar that was implicated in the scrotal cancer identified during the 19th century. Exposure to coal tar is no longer a public health hazard, but benzo(a)pyrene from sources such as cigarette smoke and automobile exhaust fumes is highly prevalent in the environment.
Non-small cell lung cancer (NSCLC) is a heterogeneous aggregate of at least 3 distinct histologies of lung cancer including epidermoid or squamous carcinoma, adenocarcinoma, and large cell carcinoma. These histologies are often classified together because, when localized, all have the potential for cure with surgical resection. Systemic chemotherapy can produce objective partial responses and palliation of symptoms for short durations in patients with advanced disease. Local control can be achieved with radiation in a large number of patients with unresectable disease, but cure is seen only in a small minority of patients. Without treatment, small cell carcinoma of the lung has the most aggressive clinical course of any type of pulmonary tumor, with median survival from diagnosis of only 2 to 4 months. Compared with other cell types of lung cancer, small cell carcinoma has a greater tendency to be widely disseminated by the time of diagnosis, but is much more responsive to chemotherapy and irradiation.
Extensive analysis has revealed several types of genetic alterations that contribute to either small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC): myc gene activation, ras gene mutation and loss of heterozygosity in chromosomes regions 3p, 13q and 17p2. The two first alterations result from amplifications and/or mutations of dominant oncogenes. Allele loss is highly suggestive of the presence of a tumor suppressor gene at the deleted chromosomal site. Two well-known tumor suppressor genes, RB and p53, have been identified in 13q14 and 17p13 respectively. More recently, alteration of a new gene named FHIT, localized in 3p14.2, have been described in lung cancer3 but due to the heterogeneity of the LOH on 3p, it is possible that more than one locus is the targets for these deletions. Analysis of the timing of these molecular events indicates that 3p alteration in one of the earliest genetic change detected in lung cancer. p53 alterations have also been detected in early lung lesions such as mild dysplasia.
p53 mutations are common in lung cancer and range from 33% in adenocarcinomas to 70% in small cell lung cancers. These mutations are mostly GC to TA transversions, with a rate of transition mutations lower than in other cancers. A strong correlation has been detected between the frequency of these GC to TA transversions and lifetime cigarette smoking. This high frequency of GC to TA transversions has not been detected for other cancers such as colon, breast, ovary or brain cancer, which are not directly associated with smoking (Figure below). This observation is compatible with the role of exogenous carcinogens such as benzo(a)pyrene in lung cancer. Experimentally, it has been shown that after metabolic activation, one of the derivative products of benzo(a)pyrene binds predominantly to guanine and gives rise to specific G-C to T-A transversions. A recent study has shown that exposure of cells to benzo(a)pyrene lead to the formation of adducts at codon 157, 248 and 273 in the p53 gene. These position are the major mutational hotspots in human lung cancer but not in other cancer (figures below).Thus, these studies clearly show that the p53 gene is one of the targets of carcinogens found in tobacco.