The molecular epidemiology of P53 gene mutations in human breast cancer

doi:10.1016/S0168-9525(96)10043-3

Trends in Genetics

Volume 13, Issue 1, January 1997, Pages 27-33

https://doi.org/10.1016/S0168-9525(96)10043-3 Get rights and content

Abstract

The P53 tumor-suppressor gene is an advantageous tool for analyzing the molecular epidemiology of cancer. We describe the utility of the P53 gene as a ‘mutagen test’ and a prognostic indicator in breast cancer. Aspects of study design and methodology are discussed. Two major conclusions emerge: (1) there is an extraordinary diversity of mutational patterns among coborts, binding that the unique biology of mammary cells results in exposure to high doses of a diversity of ingested lipophilic mutagens; and (2) mutations in the P53 gene predict poor outcome in breast cancer.

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Cited by (123)

Advances in carcinogenesis: A historical perspective from observational studies to tumor genome sequencing and TP53 mutation spectrum analysis
2011, Biochimica et Biophysica Acta - Reviews on Cancer
Citation Excerpt :
The spectrum of TP53 mutations in breast cancer is very heterogeneous among the various published studies, a feature that is not observed for other types of cancer. An analysis of the TP53 mutation spectrum in breast tumors from 15 geographically and ethnically diverse populations showed a significantly distinct pattern [38]. It is possible that the profile in low-risk populations (Japan) predominantly reflects a baseline, endogenous process, while mutagens present in high-risk populations might result in another spectrum indicating that a fraction of breast cancer mutations occur as a result of environmental exposure.
Tumor sequencing projects have been initiated over the last decade with the promising goal of identifying novel cancer genes and potential therapeutic targets. One of the unexpected findings of these projects was the discovery that cancer genomes contain thousands of passenger mutations that are irrelevant to tumor development and are coselected by a small number of driver mutations that constitute the true selection power in cancer progression. Although often discarded and considered to be irrelevant, the value of passenger mutations should not be underestimated, as they are the most important markers of the exposure to various carcinogens and are essential to assess the etiology of individual tumors.
Over the last century, the history of cancer epidemiology evolved in different stages and concepts from occupational observational studies beginning in the 18th century, in vitro and in vivo experimental analyses and cancer gene analyses, such as Ha-ras or TP53. Mutation spectra of passenger mutations from various types of cancers not only confirm the findings of molecular epidemiology analysis, but also reveal novel profiles that will extend this knowledge to single tumors in all types of cancer.
Protein molecular function influences mutation rates in human genetic diseases with allelic heterogeneity
2011, Biochemical and Biophysical Research Communications
Citation Excerpt :
Therefore, there is a keen interest in testing for differences among mutational spectra across different populations and understanding the potential effects of such mutations at the molecular level. Molecular epidemiology studies employ genes with allelic heterogeneity as ‘mutagen test’, for identifying putative mutagens [1–3]. Such studies use counts of different mutational types like transitions, transversions, etc. as a measure for comparison, with little reference to gene organization and structure–function aspects of the translated product, yielding mixed results.
Molecular epidemiology studies have used the counts of different mutational types like transitions, transversions, etc. to identify putative mutagens, with little reference to gene organization and structure–function of the translated product. Moreover, geographical variation in the mutational spectrum is not limited to the mutational types at the nucleotide level but also have a bearing at the functional level. Here, we developed a novel measure to estimate the rate of spontaneous detrimental mutations called “mutation index” for comparing the mutational spectra consisting of all single base, missense, and non-missense changes. We have analyzed 1609 mutations occurring in 38 exons in 24 populations in three diseases viz. hemophilia B (F9 gene – 420 mutations in 9 populations across 8 exons), hemophilia A (F8 gene – 650, 8 and 26, respectively) and ovarian carcinoma (TP53 gene – 539, 7 and 4, respectively). We considered exons as units of evolution instead of the entire gene and observed feeble differences among populations implying lack of a mutagen-specific effect and the possibility of mutation causing endogenous factors. In all the three genes we observed elevated rates of detrimental mutations in exons encoding regions of significance for the molecular function of the protein. We propose that this can be extended to the entire exome with implications in exon-shuffling and complex human diseases.
Cytotoxic response of breast cancer cell lines, MCF 7 and T 47 D to triphala and its modification by antioxidants
2006, Cancer Letters
The cytotoxic effects of Triphala (TPL), an Indian Ayurvedic formulation with known anti-cancer properties, has been investigated on two human breast cancer cell lines differing in their p53 status. In vitro studies showed that MCF 7 with wild type p53 was more sensitive to TPL than T 47 D, which is p53 negative. TPL induced loss of cell viability was determined by MTT assay. After 72 h incubation, the IC 50 values for MCF 7 was found to be ∼8 μg/ml and that for T 47 D was ∼26 μg/ml. Moreover, TPL inhibited the clonogenic growth of MCF 7 cells, which was significantly recovered by pifithrin-α, the p53 inhibitor. However, pifithrin-α, did not modify TPL induced cytotoxicity in T 47 D cells. Exogenous addition of antioxidants, glutathione (GSH) and N-Acetyl-Cysteine (NAC) inhibited the anti-proliferative ability of TPL in both MCF 7 and T47 D. Annexin-V and propidium iodide double staining of cells treated with TPL for 2 h revealed that TPL induced significant apoptosis in both the cell lines in a dose dependant manner but magnitude of apoptosis was significantly higher in MCF 7 than in T 47-D cells. TPL was also found to induce dose and time dependent increase in intracellular reactive oxygen species in both the cell lines. Present results have demonstrated that MCF 7 and T 47 D cells exhibited differential sensitivity to TPL, which seems to be dependant on their p53 status. Inhibition of anti-proliferative ability of TPL by antioxidants suggests a role for TPL induced ROS in the induction of apoptosis. It is concluded that p53 status of cancer cells formed an important factor in predicting the response of cancer cells to prooxidant drugs.
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2022, npj Breast Cancer
Arg72Pro polymorphism in P53 gene and Breast Cancer Risk Population: a meta-analysis of case-control studies matched
2019, Research Square
Role of p53 gene in breast cancer: Focus on mutation spectrum and therapeutic strategies
2018, Current Pharmaceutical Design

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Trends in Genetics

ReviewThe molecular epidemiology of P53 gene mutations in human breast cancer

Abstract

Adv. Cancer Res.

Lancet

Lancet

Trends Genet.

Cancer Lett.

Cell

Lancet

Lancet

Genomics

IARC Scientific Publications

Br. J. Cancer

Nat. Genet.

Nat. Genet.

Nature

Oncogene

Nature

J. Am. Med. Assoc.

Cancer Res.

Am. J. Surg. Pathol.

Int. J. Cancer

Int. J. Cancer

Am. J. Pathol.

Nature

Cancer Res.

Oncogene

Nature

Nature

Carcinogenesis

Oncogene

J. Natl. Cancer Inst.

J. Natl. Cancer Inst.

Cancer Res.

Lancet

Oncogene

Review
The molecular epidemiology of P53 gene mutations in human breast cancer