Strength of association
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The stronger the association, the more likely a causal component
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TP53 is the most frequently mutated gene in cancer. Mutations are found in 6–47% of tumors from 25 important cancer sites (Table 1), but mutation rates can be much higher for specific cancers.21
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Consistency
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A relationship is observed repeatedly
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More studies have found an association between cancer and TP53 mutations than any other genetic mutation1,18
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Specificity
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A factor influences specifically a particular outcome or population
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TP53 mutations elevate cancer susceptibility of many tumors, and are also a inherited characteristic of the Li-Fraumeni syndrome24
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Temporality
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The factor must precede the outcome it is assumed to affect
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Preneoplastic TP53 mutations confer a growth advantage in mouse mammary tumors25 and human esophageal cancers,26 but evidence is less convincing for human gastric tumors27
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Biological gradient (dose–response relationship)
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The outcome increases monotonically with increasing exposure to the factor
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Figure 2A shows that the cancer exponent for all cancers, evaluated from worldwide incidence rates, increases with the presence of TP53 mutations. In Li-Fraumeni syndrome, age of onset of cancer is directly related to the TP53 transactivation functionality28
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Biological plausibility
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The observed association can be plausibly explained by biological explanations
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TP53 mutations increase glycolysis29 and reduce apoptosis of neoplastic cells, and are also associated with genomic instability leading to cancer in mice and humans30-32
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Biological coherence
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A causal association should not fundamentally contradict present substantive knowledge
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There are only a few exceptions11,12 to the general finding that inactivating TP53 mutations are associated with cancer. Results given here show 2.5-fold higher TP53 mutation rate in epithelial tumor sites than in less-common, non-epithelial cancers.
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Experimental evidence (including reversibility)
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Cause is best shown by randomized experiments (or removal of cause leads to reduced effect)
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In vivo evidence supports a causal role for TP53 deficiencies in decreasing cancer latency and increasing susceptibility.33,34 Reversibility has been demonstrated in two recent studies.9,10 However, there is an absence of randomized experiments involving preneoplastic TP53 mutations.
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| Analogy |
An effect has already been shown for analogous factors, exposures, and outcomes |
Overexpression of anti-apoptotic proteins (e.g., Bcl2, Mdm2)35 and genes that induce genomic instability (e.g., MYC and RAS)36,37 increase susceptibility to many cancers. Other gene deficiencies that, like mutated TP53, disable p53 function (e.g., PTEN) also increase cancer risk.19
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