A Polymorphic p53 Response Element in KIT Ligand Influences Cancer Risk and Has Undergone Natural Selection

Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
Cell (Impact Factor: 32.24). 10/2013; 155(2):410-422. DOI: 10.1016/j.cell.2013.09.017
Source: PubMed


The ability of p53 to regulate transcription is crucial for tumor suppression and implies that inherited polymorphisms in functional p53-binding sites could influence cancer. Here, we identify a polymorphic p53 responsive element and demonstrate its influence on cancer risk using genome-wide data sets of cancer susceptibility loci, genetic variation, p53 occupancy, and p53-binding sites. We uncover a single-nucleotide polymorphism (SNP) in a functional p53-binding site and establish its influence on the ability of p53 to bind to and regulate transcription of the KITLG gene. The SNP resides in KITLG and associates with one of the largest risks identified among cancer genome-wide association studies. We establish that the SNP has undergone positive selection throughout evolution, signifying a selective benefit, but go on to show that similar SNPs are rare in the genome due to negative selection, indicating that polymorphisms in p53-binding sites are primarily detrimental to humans.

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Available from: Jorge Zeron-Medina, Nov 02, 2014
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    • "However, the modus operandi of these polymorphisms' function has not been demonstrated. Most recently, a study using genome-wide data sets of cancer susceptibility loci and systematically biological function experiments identified a novel genetic polymorphism, rs4590952, which is located in the p53 response element of KITLG, associated with testicular cancer risk6. Intriguingly, this polymorphism was highly correlated to these three polymorphisms, rs995030, rs3782181 and rs4474514. "
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    ABSTRACT: Recently, a functional polymorphism in KITLG, rs4590952, was identified to be associated with testicular cancer susceptibility through increasing the p53-dependent KITLG expression and disrupting the function of p53. We performed a hospital-based case-control study, including 1241 breast cancer (BC) patients and 1259 cancer-free controls, to investigate the role of this polymorphism in the risk of BC in Chinese Han population. However, no significant association between rs4590952 and BC risk was identified in allelic model with the odds ratio (OR) of 1.04 (95% confidence interval (CI) = 0.73-1.46, P = 0.839) or in any other genetic models. When performed stratified analysis according to the Estrogen Receptor (ER) and Progesterone Receptor (PR) status, rs4590952 was neither associated with ER+/PR+ nor ER-PR- subgroups. Our results suggested that rs4590952 was not associated with the risk of BC in Chinese population, implying that heterogeneous distinct mechanisms might exist in the etiology of different cancers.
    Full-text · Article · Sep 2014 · Scientific Reports
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    • "In targeted studies specific genomic risk loci/Single Nucleotide Polymorphisms (SNPs) were identified at the Y chromosome (gr/gr microdeletion) [130] [131] and in the FSH [132]/androgen receptors [133]. Risk loci were also found in PTEN [134] and loci related to genes involved in steroid hormone metabolism [135] [136], cAMP signaling [137], insulin like growth factor signaling [138], DNA damage response [139] [140], estrogen metabolism/signaling [141] [142] [143], gonadotropin regulation [144], TP53-KITL interaction [145], sex determination [146] and prostate/colorectal/breast cancer (8q24 locus) [147]. Larger scale GWAS studies consistently identified a number of (other) risk SNPs [148] [149] [150] [151] [152] [153] [154] [155] which were validated in additional (targeted) studies: [156] [157] [158]. "
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    ABSTRACT: Germ cell tumors (GCTs) represent a diverse group of tumors presumably originating from (early fetal) developing germ cells. Most frequent are the testicular germ cell cancers (TGCC). Overall, TGCC is the most frequent malignancy in Caucasian males (20-40yr) and remains an important cause of (treatment related) mortality in these young men. The strong association between the phenotype of TGCC stem cell components and their totipotent ancestor (fetal primordial germ cell or gonocyte) makes these tumors highly relevant from an onco-fetal point of view. This review subsequently discusses the evidence for the early embryonic origin of TGCCs, followed by an overview of the crucial association between TGCC pathogenesis, genetics, environmental exposure and the (fetal) testicular micro-environment (genvironment). This culminates in an evaluation of three genvironmentally modulated hallmarks of TGCC directly related to the oncofetal pathogenesis of TGCC: (1) maintenance of pluripotency, (2) cell cycle control/cisplatin sensitivity and (3) regulation of proliferation/migration/apoptosis by KIT-KITL mediated receptor tyrosine kinase signaling. Briefly, TGCC exhibit identifiable stem cell components (seminoma and embryonal carcinoma) and progenitors that show large and consistent similarities to primordial/embryonic germ cells, their presumed totipotent cells of origin. TGCC pathogenesis depends crucially on a complex interaction of genetic and (micro-)environmental, i.e. genvironmental risk factors that have only been partly elucidated despite significant effort. TGCC stem cell components also show a high degree of similarity with embryonic stem/germ cells (ES) in the regulation of pluripotency and cell cycle control, directly related to their exquisite sensitivity to DNA damaging agents (e.g. cisplatin). Of note, (ES specific) micro-RNAs play a pivotal role in the crossover between cell cycle control, pluripotency and chemosensitivity. Moreover, multiple consistent observations reported TGCC to be associated with KIT-KITL mediated receptor tyrosine kinase signaling, a pathway crucially implicated in proliferation, migration and survival during embryogenesis including germ cell development. In conclusion, TGCCs are a fascinating model for onco-fetal developmental processes especially with regard to studying cell cycle control, pluripotency maintenance and KIT-KITL signaling. The knowledge presented here contributes to better understanding of the molecular characteristics of TGCC pathogenesis, translating to identification of at risk individuals and enhanced quality of care for TGCC patients (diagnosis, treatment and follow-up).
    Full-text · Article · Jul 2014 · Seminars in Cancer Biology
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    ABSTRACT: The term "human germ cell tumors" (GCTs) refers to a heterogeneous group of neoplasms, all with a defined histological appearance. They have specific epidemiological characteristics, clinical behavior, and pathogenesis. Histologically, GCTs contain various tissue elements, which are homologs of normal embryogenesis. We have proposed a subclassification of GCTs in five subtypes, three of which preferentially occur in the testis. These include teratomas and yolk sac tumors of neonates and infants (type I), seminomas and nonseminomas of (predominantly) adolescents and adults (type II), and spermatocytic seminomas of the elderly (type III). Both spontaneous and induced animal models have been reported, of which the relevance for human GCTs is still to be clarified. Multidisciplinary studies have recently shed new light on the (earliest steps in the) pathogenesis of GCTs, mainly in regard of malignant type II GCTs (germ cell cancer (GCC)). This review discusses novel understanding of the pathogenesis of (mainly) GCC, focusing on identification of informative diagnostic markers suitable for application in a clinical setting. These include OCT3/4, SOX9/FOXL2, SOX17/SOX2, as well as embryonic microRNAs. These markers have been identified through studies on normal embryogenesis, specifically related to the gonads, including the germ cell lineage. Their strengths and limitations are discussed as well as the expected future approach to identify the group of individuals at highest risk for development of a GCC. The latter would allow screening of defined populations, early diagnosis, optimal follow-up, and potentially early treatment, preventing long-term side effects of systemic treatment.
    No preview · Article · Feb 2014 · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin
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