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p53 mutation and cancer

p53 MUTATIONS IN BREAST CANCER

Borresen-Dale, A.L. (2003) TP53 and breast cancer. Hum Mutat, 21, 292-300.-> Download

Gasco, M., Yulug, I.G. and Crook, T. (2003) TP53 mutations in familial breast cancer: functional aspects. Hum Mutat, 21, 301-306 -> Download

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Breast cancer

Breast cancer is the third most common tumor in the world and represents 9% of the global cancer burden. This percentage varies considerably around the world: in high-risk areas, such as North America and western Europe, breast cancer accounts for one in four female cancers, while in low-risk areas such as China and Japan, it accounts for only one in eight to one in 16. The importance of environmental factors in the etiology of breast cancer is demonstrated by the change in risk in migrant populations. Rates of breast cancer in European migrants to the USA evolve relatively rapidly toward those of the US population, but changes in migrant populations from China and Japan are less rapid.

Analyses of the pattern of p53 mutations in breast cancer have led to the discovery of substantial diversity of the mutational pattern among cohorts from various areas in the world (table 1). This heterogenity concerns i) the frequency of p53 mutations ii) the frequency of frameshift mutation (deletions and insertion) and iii) the frequency of transversions.

The frequency of the p53 mutation could reflect the sensitivity of the various methods used in these studies. Nevertheless, different frequencies and patterns were found among 6 populations analyzed by the same laboratory using the same methodology, suggesting that other factors could be involved. Blaszyk et al. reported some striking differences in mutation frequency within Japanese populations, but the reasons for such observations are unclear. The unusually high frequency of deletions and insertions in rural Caucasian midwestern women compared to other populations is also difficult to explain, and could reflect exposure to particular environmental carcinogens. A similar explanation can be advanced for the heterogenous frequency of transition and transversions (table1).

The pattern of p53 mutations in breast cancer is highly complex. The differences in these patterns of mutation in geographically and/or racially diverse populations reflect an intrinsic (endogenous) pattern of mutation plus exposure to particular environmental carcinogens.

 Spectrum of p53 mutations in breast cancer

DISTRIBUTION OF p53 MUTATIONS IN BREAST CANCER

MUTATIONAL EVENTS IN BREAST CANCER

Meta-analysis of p53 loss of function in breast cancer. Points ; mean p53 activity as measured by transactivation with the WAF1promoter ; bars , 95 % CI. The mean and 95 % CI of p53 activity for all studies combined for a specific type of cancer is shown on the far left of each graph. Horizontal line, mean of the combined studies. The publication code is indicated on the x-axis : the first number is an anonymous ID for the publication and the second number indicates the number of p53 mutants included in this study. Studies are presented from left to right in decreasing order of number of p53 mutants. The y-axis corresponds to p53 transactivation activity, with a value of 1.5 for the negative control and a value of 2.5 for 100 % of wild-type activity. Only studies with 5 or more p53 mutations are shown on the graph. More information about this statistical analysis can be found in this article: Soussi, T., Asselain, B., Hamroun, D., Kato, S., Ishioka, C., Claustres, M. and Beroud, C. (2006) Meta-analysis of the p53 mutation database for mutant p53 biological activity reveals a methodologic bias in mutation detection. Clin Cancer Res, 12, 62-69. Download the pdf more information for problems in the analysis of p53 mutations in breast cancer.