A Polymorphic p53 Response Element in KIT Ligand Influences Cancer Risk and Has Undergone Natural Selection.
ABSTRACT 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.
Full-textDOI: · Available from: Jorge Zeron-Medina, Nov 02, 2014
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ABSTRACT: Single nucleotide polymorphisms (SNPs) occur within chromatin-modulating factors; however, little is known about how these variants within the coding sequence impact cancer progression or treatment. Therefore, there is a need to establish their biochemical and/or molecular contribution, their use in sub-classifying patients and their impact on therapeutic response. In this report, we demonstrate that coding SNP-A482 within the lysine tri-demethylase KDM4A/JMJD2A has different allelic frequencies across ethnic populations, associates with differential outcome in non-small cell lung cancer (NSCLC) patients and promotes KDM4A protein turnover. Using an unbiased drug screen against 87 preclinical and clinical compounds, we demonstrate that homozygous SNP-482 cells have increased mTOR inhibitor sensitivity. mTOR inhibitors significantly reduce SNP-A482 protein levels, which parallels the increased drug sensitivity observed with KDM4A depletion. Our data emphasize the importance of using variant status as candidate biomarkers and highlight the importance of studying SNPs in chromatin modifiers to achieve better targeted therapy. Copyright © 2014, American Association for Cancer Research.Cancer Discovery 01/2015; DOI:10.1158/2159-8290.CD-14-1159 · 15.93 Impact Factor
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ABSTRACT: The pigmentation of mammalian skin and hair develops through the interaction of two basic cell types — pigment donors and recipients. The pigment donors are melanocytes, which produce and distribute melanin through specialized structures. The pigment recipients are epithelial cells, which acquire melanin and put it to use, collectively yielding the pigmentation visible to the eye. This review will focus on the pigment recipients, the historically less understood cell type. These end-users of pigment are now known to exert a specialized control over the patterning of pigmentation, as they identify themselves as melanocyte targets, recruit pigment donors, and stimulate the transfer of melanin. As such, this review will discuss the evidence that the skin is like a coloring book: the pigment recipients create a “picture,” a blueprint for pigmentation, which is colorless initially but outlines where pigment should be placed. Melanocytes then melanize the recipients and “color in” the picture.This article is protected by copyright. All rights reserved.Pigment Cell & Melanoma Research 08/2014; 27(6). DOI:10.1111/pcmr.12301 · 5.64 Impact Factor
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ABSTRACT: Testicular germ cell tumour (TGCT) is the most common cause of cancer in young men (aged 15–45 years) in many populations. Multiple genome-wide association studies (GWAS) of TGCT have now been conducted, yielding over 25 disease-associated single-nucleotide polymorphism (SNP)s at 19 independent loci. The genes at these loci have provided rich biological and genetic insight into possible mechanisms underlying testicular germ cell oncogenesis. In this review, we summarize these mechanisms which can be grouped into five distinct categories: KIT/KITLG signalling, other pathways of male germ cell development/differentiation, telomerase function, microtubule assembly and DNA damage repair. The TGCT risk markers identified through GWAS include individual SNPs carrying per allele odds ratios (OR) in excess of 2.5. These ORs are among the highest reported in GWAS of any cancer type, hence suggesting a potential clinical utility in risk determination. Here, we present analysis of such an approach, using polygenic risk scores to calculate the combined effect of all risk loci on overall TGCT risk and discuss how a potential screening strategy may fit within a broader clinical context.Andrology 01/2015; 3(1). DOI:10.1111/andr.304 · 3.37 Impact Factor