Novel pattern of P53 mutation in breast cancers from Austrian women.

Hartmann, Arndt; Rosanelli, G.; Blaszyk, Hagen; Cunningham, Julie M.; McGovern, Renee M.; Schroeder, Jennifer J.; Schaid, Daniel J.; Kovach, John S.; Sommer, Steve S.

doi:10.1172/jci117714

Cited by 31 publications

(19 citation statements)

References 23 publications

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“…We assume that the patterns of mutation in high-risk populations reflect the superimposition of a pattern caused by a unique or enhanced exposure to a particular environmental toxin(s) upon an intrinsic (endogenous) pattern of mutation characteristic of low-risk groups. We have shown that the pattern of p53 gene mutations in primary breast cancers in a white, largely rural Midwestern US population (Sommer et al, 1992;Saitoh et al, 1994) and in a population from Graz, Austria (Hartmann et al, 1995a), differs significantly from the pattern present in African -American women from Detroit and from the patterns in Scottish (Coles et al, 1992) and French (Mazars et al, 1992) women. The major differences among these populations are: a predominance of transversions, particularly G:C-+T:A transversions in the Scottish population; a high frequency of microdeletions in the rural white US population; a high frequency of A:T-+T:A transversions in the Austrian population; and a high frequency of transitions, particularly A:T-+G:C transitions, in the African-American population.…”

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confidence: 84%

High frequency of p53 gene mutations in primary breast cancers in Japanese women, a low-incidence population

Hartmann

Blaszyk

Saitoh³

et al. 1996

Br J Cancer

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Summary The pattern of acquired mutations in the p53 tumour-suppressor gene is potentially useful for determining factors contributing to carcinogenesis in diverse populations differing in incidence and/or mortality from the disease. We previously reported differences in mutational patterns of the p53 gene in primary breast cancers from Midwest US Caucasian, African-American and Austrian women. Herein, we report 16 mutations in 27 primary breast cancers from Japanese women from Hirosaki, a population with a low incidence of breast cancer. The frequency of 59.3% of p53 mutations is the highest reported in breast cancers from a particular ethnic group thus far. A relatively high number of mutations (7/16) were heterozygous in at least some tumour cell clusters. Intergroup comparisons of the mutational pattern between this population and several other US, European and Japanese populations do not show any statistically significant differences. There were recurrent mutations at two sites, codon 273 (R-.H; three mutations), a common hotspot of mutations in breast and other cancers, and codon 183 (S-Stop; two mutations), a very rare location for p53 mutations. These mutations were shown to be independent and presumably not in the germ line. The highest frequency of p53 mutations raises the possibility that p53 mutagenesis is a predominant factor for breast cancer development in this low-risk Japanese group, whereas in other cohorts different mechanisms are likely to account for the higher proportion of breast cancer. Further studies are needed to confirm the present observations.

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confidence: 84%

High frequency of p53 gene mutations in primary breast cancers in Japanese women, a low-incidence population

Hartmann

Blaszyk

Saitoh³

et al. 1996

Br J Cancer

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“…Many of the differences are substantial because statistical significance was often observed with only relatively few mutations divided among the eight mutational types. The differences are unlikely to be attributed to methodological biases because different patterns were found among six populations analyzed by one laboratory using identical methods Saitoh et al, 1994;Hartmann et al, 1995bHartmann et al, , 1996. The differences between populations with breast cancer are unlikely to represent varying mixtures of just two or three mutagens in diverse populations, given that subanalyses by the Fisher exact test reveal that the differences are attributed to highly distinct patterns of mutations (Table II).…”

Section: P53 Mutation Patterns Vary Among 15 Populationsmentioning

confidence: 97%

p53 As a mutagen test in breast cancer

Hill

Sommer

2002

Environ and Mol Mutagen

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The p53 gene is mutated in about half of all tumors. The p53 gene can be used as a “mutagen test,” that is, the relative frequencies of the different types of mutation can be used as an epidemiological tool to explore the contribution of exogenous mutagens vs. endogenous processes in particular cancers. p53 has been used as a mutagen test in breast cancer. Surprisingly, the pattern of p53 mutations differs among 15 geographically and ethnically diverse populations. In contrast, mutation patterns in the human factor IX gene are similar in geographically and ethnically diverse populations. Diverse p53 mutation patterns in breast cancer are consistent with a significant contribution by a diversity of exogenous mutagens. Breast tissue may be uniquely sensitive to lipophilic mutagens because of its unique architecture, characterized by tiny islands of cancer‐prone mammary epithelial cells surrounded by a sea of adipocytes. Mammary epithelial cells may be differentially susceptible to released lipophilic mutagens preferentially concentrated in adjacent adipocytes and originating in the diet. To test this hypothesis, we developed a method for measuring mutation load from ethanol‐fixed, paraffin‐embedded human tissues immunohistochemically stained with anti‐p53 antibodies. Single cells staining positively for p53 overabundance are microdissected and the gene is sequenced. It is possible to identify individuals with a high mutation load in normal breast tissue and who are presumably at increased risk for breast cancer. In addition, analysis of the p53 gene with appropriate mutation detection methodology markedly improves the prediction of early recurrence, treatment failure, and death in breast cancer patients. Mutagen tests and mutation load measurements are useful tools to identify the role of mutagens in breast cancer. Environ. Mol. Mutagen. 39:216–227, 2002. © 2002 Wiley‐Liss, Inc.

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“…However, Lehman et al, (1993) had previously sequenced the highly conserved region of p53 known as the mutational hot-spot region (exons 4 ± 9) in HMEC184, HMEC184A1 and HMEC184B5 and found a wildtype p53 sequence. However, p53 mutations have been found outside of the hot-spot region in some breast cancers (Hartmann et al, 1995). Therefore, to determine whether HMEC184 contained mutations in p53 outside of the hot-spot region, four primer sets were used to clone the complete p53 coding sequence in HMEC184.…”

Section: Hmec184 Contain Wild-type P53mentioning

confidence: 99%

Human mammary epithelial cells exhibit a differential p53-mediated response following exposure to ionizing radiation or UV light

et al. 1999

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The tumor suppressor protein, p53, plays a critical role as a transcriptional activator of downstream target genes involved in the cellular response to DNA damaging agents. We examined the cell cycle checkpoint response of human mammary epithelial cells (HMEC) and their isogenic ®broblast counterparts to ionizing (IR) and ultraviolet (UV) radiation, two genotoxic agents whose DNA damage response pathways involve p53. Using¯ow cytometric analysis, we found that both mortal and immortalized HMEC, which contain wild-type p53 sequence, do not exhibit a G1 arrest in response to IR, but show an intact G2 checkpoint. Supportive evidence from Western analyses revealed that there was neither an increase in p53 nor one of its downstream targets, p21 WAF1 , in HMEC exposed to IR. In contrast, isogenic mammary ®broblasts arrest at the G1 checkpoint and induce the p53 and p21 WAF1 proteins following IR. By comparison, HMEC exposed to UV displayed an S phase arrest and induced the expression of p53 and p21 WAF1 . Our results show that the cellular response to DNA damage depends on both the type of damage introduced into the DNA and the speci®c cell type.

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Novel pattern of P53 mutation in breast cancers from Austrian women.

Cited by 31 publications

References 23 publications

High frequency of p53 gene mutations in primary breast cancers in Japanese women, a low-incidence population

High frequency of p53 gene mutations in primary breast cancers in Japanese women, a low-incidence population

p53 As a mutagen test in breast cancer

Human mammary epithelial cells exhibit a differential p53-mediated response following exposure to ionizing radiation or UV light

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