Tumor suppressor p53 (
            <i>TP53</i>
            ) at the crossroads of the exposome and the cancer genome

Schetter, Aaron J.; Harris, Curtis C.

doi:10.1073/pnas.1205457109

Cited by 12 publications

(15 citation statements)

References 20 publications

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“…In most cancers, TP53 is mutated, indicating the important role played by TP53 as a tumor suppressor2223. TP53 was reported the most frequently mutated gene in HNSCC by Agarwal et.al11.…”

Section: Resultsmentioning

confidence: 99%

“…The change of TP53 status had effects on its downstream miRNA. The expression status of the following five miRNAs in HNSCC, from HNOCDB22 and PhenomiR224, were: miRNA-107, miRNA-215, miRNA-34b/c and miRNA-125b were downregulated, but miRNA-155 was augmented in the absence of TP53. Notice the unexpected result for miRNA-125b: it was anticipated to be upregulated in TP53's dearth.…”

Section: Resultsmentioning

confidence: 99%

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Anomalous altered expressions of downstream gene-targets in TP53-miRNA pathways in head and neck cancer

Mitra

Mukherjee

Das

et al. 2014

Sci Rep

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The prevalence of head and neck squamous cell carcinoma, HNSCC, continues to grow. Change in the expression of TP53 in HNSCC affects its downstream miRNAs and their gene targets, anomalously altering the expressions of the five genes, MEIS1, AGTR1, DTL, TYMS and BAK1. These expression alterations follow the repression of TP53 that upregulates miRNA-107, miRNA- 215, miRNA-34 b/c and miRNA-125b, but downregulates miRNA-155. The above five so far unreported genes are the targets of these miRNAs. Meta-analyses of microarray and RNA-Seq data followed by qRT-PCR validation unravel these new ones in HNSCC. The regulatory roles of TP53 on miRNA-155 and miRNA-125b differentiate the expressions of AGTR1 and BAK1in HNSCC vis-à-vis other carcinogenesis. Expression changes alter cell cycle regulation, angiogenic and blood cell formation, and apoptotic modes in affliction. Pathway analyses establish the resulting systems-level functional and mechanistic insights into the etiology of HNSCC.

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“…In most cancers, TP53 is mutated, indicating the important role played by TP53 as a tumor suppressor2223. TP53 was reported the most frequently mutated gene in HNSCC by Agarwal et.al11.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Anomalous altered expressions of downstream gene-targets in TP53-miRNA pathways in head and neck cancer

Mitra

Mukherjee

Das

et al. 2014

Sci Rep

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“…Among the several environmental agents that have been investigated, ingestion of aristolochic acid (AA) found in Aristolochia plants proved to be the causal agent of UUT in both of these high-risk populations. Mutational analysis of tumors in these two cohorts, coupled with DNA adduct studies [17–21], has provided definitive molecular epidemiologic evidence for incriminating AA in the etiology of UUT [17;19–26]. No such strong molecular, clinical or epidemiologic evidence exists for the myotoxin ochratoxin A (OTA), one of many environmental agents hypothesized as playing a role in the etiology of BEN [27].…”

Section: Introductionmentioning

confidence: 99%

Analysis of TP53 mutation spectra reveals the fingerprint of the potent environmental carcinogen, aristolochic acid

Hollstein

Moriya

Grollman

et al. 2013

Mutation Research/Reviews in Mutation Research

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Genetic alterations in cancer tissues may reflect the mutational fingerprint of environmental carcinogens. Here we review the evidence that support the role of aristolochic acid (AA) in inducing a mutational fingerprint in the tumor suppressor gene TP53 in urothelial carcinomas of the upper urinary tract (UUT). Exposure to AA, a nitrophenathrene carboxylic acid present in certain herbal remedies and in flour prepared from wheat grain contaminated with seeds of Aristolochia clematitis, has been linked to chronic nephropathy and UUT. TP53 mutations in UUT of individuals exposed to AA reveal a unique pattern of mutations characterised by A to T transversions on the non-transcribed strand, which cluster at hotspots rarely mutated in other cancers. This unusual pattern, originally discovered in UUTs from two different populations, one in Taiwan, and one in the Balkans, has been reproduced experimentally by treating mouse cells that harbour human TP53 sequences with AA. The convergence of molecular epidemiological and experimental data establishes a clear causal association between exposure to the human carcinogen AA and UUT cancer. Despite bans on the sale of herbs containing AA, their use continues, raising global public health concern and an urgent need to identify populations at risk.

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“…Genotoxic exposures to environmental carcinogens and endogenous mutagens promote specific sequence base changes that provide clues to the etiological origins of cancer (Hollstein et al 1991;Hussain and Harris 1999;Olivier et al 2010;Schetter and Harris 2012). TP53 somatic mutations and the exposome were first linked with the discovery that dietary exposure to aflatoxin B1, a chemical carcinogen found in crops contaminated with the mold Aspergilla flavus, caused a specific G:C .…”

Section: The Tp53 Mutation Landscape As a Footprint Of The Exposomementioning

confidence: 99%

Clinical Outcomes of TP53 Mutations in Cancers

Robles

Jen

Harris

2016

Cold Spring Harb Perspect Med

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High-throughput sequencing of cancer genomes is increasingly becoming an essential tool of clinical oncology that facilitates target identification and targeted therapy within the context of precision medicine. The cumulative profiles of somatic mutations in cancer yielded by comprehensive molecular studies also constitute a fingerprint of historical exposures to exogenous and endogenous mutagens, providing insight into cancer evolution and etiology. Mutational signatures that were first established by inspection of the TP53 gene somatic landscape have now been confirmed and expanded by comprehensive sequencing studies. Further, the degree of granularity achieved by deep sequencing allows detection of low-abundance mutations with clinical relevance. In tumors, they represent the emergence of small aggressive clones; in normal tissues, they signal a mutagenic exposure related to cancer risk; and, in blood, they may soon become effective surveillance tools for diagnostic purposes and for monitoring of cancer prognosis and recurrence.

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Tumor suppressor p53 ( TP53 ) at the crossroads of the exposome and the cancer genome

Cited by 12 publications

References 20 publications

Anomalous altered expressions of downstream gene-targets in TP53-miRNA pathways in head and neck cancer

Anomalous altered expressions of downstream gene-targets in TP53-miRNA pathways in head and neck cancer

Analysis of TP53 mutation spectra reveals the fingerprint of the potent environmental carcinogen, aristolochic acid

Clinical Outcomes of TP53 Mutations in Cancers

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