Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
Absence of association with cancer risk and low frequency of alterations at a p53 responsive PIG3 gene polymorphism in breast and lung carcinomas
Introduction
Apoptosis is a vital process for tissue homeostasis that is frequently disturbed in several pathological conditions, including cancer. It has been shown that p53-dependent apoptosis involves the induction of a series of genes called PIGs (p53-inducible gene(s)) [1]. These genes participate in this process through reactive oxygen species (ROS) modulation [1]. Interestingly, for one of them, assigned as PIG3 [1], induction has been shown to be mediated by p53 mainly through a microsatellite present in its 5′-upstream regulatory region and not through a classical El-Deiry consensus sequence [2]. This microsatellite acquired its polymorphic structure and p53-dependent functional ability to induce this gene, recently in the evolutionary history of biological species [3]. Specifically, although it is present in lower primates its full length and function appears only in Hominoidea (apes and humans).
In humans this microsatellite represents a pentanucleotide (TGYCC)n polymorphism, where Y = C or T, and with four alleles of 10, 15, 16 and 17 repetitions [2]. Furthermore, the extent of transcriptional activation of PIG3 by p53 correlates directly with the number of repeats. Given that PIG3 is associated with reactive oxygen species-dependent apoptosis [1], the recent evolutionary control of this gene by p53 raises two important points, as Contente et al. comment [3]. First, they suggest that the evolutionary appearance of this polymorphism represents a continuous adaptation of tumor suppressor mechanism(s), and second, they draw caution on the comparative interpretation of gene expression results from animal models and human cancers. However, what is not clear yet, is first if there is any potential mechanism(s) by which this gene may be implicated in human carcinogenesis, and second what is its exact role during tumorigenesis.
As previously hypothesized, the nature of this polymorphism indicates two possible ways that may account for PIG3 involvement in tumorigenesis [2]. In neoplasias, as it is well known, microsatellites are frequently prone to alterations emerging from instability at these loci. Microsatellite instability (MI) usually involves a change in the number of repetitions at a polymorphic locus in the neoplastic areas. Therefore, any aberrations affecting the structural integrity of this polymorphism should affect the ability to induce PIG3 by p53 and maybe consequently the ROS-dependent apoptotic process. A second mechanism that is cancer-prone represents the genetic constitution of an individual. Taking into consideration that alleles with low number of repetitions (specifically the 10 repetitions one) are less able to induce PIG3 expression by p53 [2], it is expected that combination(s) of such alleles provide an increased cancer risk for an individual. Therefore, cancer patient cohorts may have a different frequency distribution as compared to control cases, with low repetition alleles expected to have a higher penetrance.
Intrigued by these collective results and observations we have investigated this polymorphism in two common human cancers, lung and breast, but characterized by their different tumor biology. Furthermore, two different populations of lung cancer patients, Greek and British, where examined to assess possible ethnical differences.
Section snippets
Patients and sample collection
For our analysis individuals from Greek and British populations were enrolled. The Greek population consisted of 330 healthy case controls (173 females and 157 males), 210 female breast cancer patients and 72 lung cancer patients (5 females and 67 males), while from the British 190 healthy case controls (64 females and 126 males) and 176 lung cancer patients (71 females and 105 males) were used. DNA was extracted from blood samples with the QIAamp Blood kit (Qiagen) following the manufacturer's
Allelotype and genotype analysis of the PIG polymorphism in Greek and British populations
- (1)
Greek population. Our analysis showed the presence of the previously described four alleles at this locus, in the samples examined [2] (Table 1). The most interesting and unexpected result was the presence of 7 control cases that where homozygous for allele 10 (10/10). On the other hand no such cases were found in the breast or lung cancer patients examined (Table 3). Analysis of allele frequency distribution in the control and cancer groups, after gender correction, showed that the proportion
Discussion
The mechanisms underlying the development of p53-dependent apoptosis are largely unknown. Recently, a set of genes has been shown to be markedly induced by p53 in this process [1]. One of them PIG3, has the unique feature to be induced by p53 through a microsatellite in its promoter region [2]. Despite the presence of PIG3 gene homologs in other species, including plants [1], [2], [3], this microsatellite appears evolutionary in a functional form only in Hominoidea (apes and humans) [3].
Acknowledgments
We would like to thank Ms Virginia Stogia for her expert help during collection and processing of the blood samples. We also wish to acknowledge the support of the Hellenic Anticancer Institute.
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Identification of prohibitin and prohibiton as novel factors binding to the p53 induced gene 3 (PIG3) promoter (TGYCC)<inf>15</inf> motif
2014, Biochemical and Biophysical Research CommunicationsCitation Excerpt :Inspired by the inconsistent findings for the role of the PIG3 promoter (TGYCC)n motif in modifying transcriptional activity and cancer susceptibility [2–5], we initiated the present study to screen for other potential molecules that may bind to the PIG3 promoter (TGYCC)15 motif and to assess their role in the transcriptional regulation of PIG3. The identification of novel molecules interacting with this PIG3 promoter (TGYCC)15 motif may provide the underlying molecular mechanisms to help explain the reported inconsistent findings and add to our knowledge of mechanisms regulating PIG3 and cancer risk associated with the PIG3 promoter (TGYCC)15 [2–5]. The UM-SCC-17B, UM-SCC-22B, and MDA886 cell lines were from the collection in the Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA [6].
PIG3: A novel link between oxidative stress and DNA damage response in cancer
2012, Cancer LettersCitation Excerpt :Nevertheless, subsequent PIG3 promoter analysis showed that a polymorphic microsatellite located at positions between +442 and +517 downstream of the transcription start site was the main p53 responsive element [14]. Population analysis of this polymorphic locus showed that in Caucasians it consists of alleles of 10, 15, 16 and 17 repetitions of a pentanucleotide core TGYCC (Y: C or T) [14,15]. In contrast, in a Japanese cohort seven alleles were found at this locus comprising 10, 12, 14, 15, 16, 17 and 18 repetitions [16].
A novel variable number of tandem repeats (VNTR) polymorphism containing Sp1 binding elements in the promoter of XRCC5 is a risk factor for human bladder cancer
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