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The p53 protein plays a passive and an active role in stem cells. The transcriptional activities of p53 for cell-cycle arrest and DNA repair are largely turned off in stem cells, but there is some indication that long-term stem-cell viability may require other p53-regulated functions. When p53 is activated in stem cells, it stops cell division and promotes the commitment to a differentiation pathway and the formation of progenitor cells. In the absence of any p53 activity, stem-cell replication continues and mistakes in the normal epigenetic pathway occur at a higher probability. In the presence of a functionally active p53 protein, epigenetic stability is enforced and stem-cell replication is regulated by commitment to differentiation. Over a lifetime of an organism, stem-cell clones compete in a tissue niche for Darwinian replicative advantages and in doing so accumulate mutations that permit stem-cell replication. Mutations in the p53 gene give stem cells this advantage, increase the clonal stem-cell population, and lower the age at which cancers can occur. Li-Fraumeni patients that inherit p53 mutations develop tumors in a tissue-type-specific fashion at younger ages. Throughout the life of a Li-Fraumeni patient, the tumor types that arise occur in tissues where stem cells are active and cell division is most rapid. Thus, p53 mutations that are inherited or occur during developmental life act in stem cells of the mesenchymal and epithelial lineages, whereas p53 mutations that occur in progenitor or differentiated (somatic) cells later in life function in tissues of endodermal origins, indicating that p53 may function differently in different developmental lineages., (Copyright © 2016 Cold Spring Harbor Laboratory Press; all rights reserved.)

Recent studies have demonstrated abundant transcription of a set of noncoding RNAs (ncRNAs) preferentially within tumors as opposed to normal tissue. Using an approach from statistical physics, we quantify global transcriptome-wide motif use for the first time, to our knowledge, in human and murine ncRNAs, determining that most have motif use consistent with the coding genome. However, an outlier subset of tumor-associated ncRNAs, typically of recent evolutionary origin, has motif use that is often indicative of pathogen-associated RNA. For instance, we show that the tumor-associated human repeat human satellite repeat II (HSATII) is enriched in motifs containing CpG dinucleotides in AU-rich contexts that most of the human genome and human adapted viruses have evolved to avoid. We demonstrate that a key subset of these ncRNAs functions as immunostimulatory "self-agonists" and directly activates cells of the mononuclear phagocytic system to produce proinflammatory cytokines. These ncRNAs arise from endogenous repetitive elements that are normally silenced, yet are often very highly expressed in cancers. We propose that the innate response in tumors may partially originate from direct interaction of immunogenic ncRNAs expressed in cancer cells with innate pattern recognition receptors, and thereby assign a previously unidentified danger-associated function to a set of dark matter repetitive elements. These findings potentially reconcile several observations concerning the role of ncRNA expression in cancers and their relationship to the tumor microenvironment.

The Li-Fraumeni syndrome (LFS) and its variant form (LFL) is a familial predisposition to multiple forms of childhood, adolescent, and adult cancers associated with germ-line mutation in the TP53 tumor suppressor gene. Individual disparities in tumor patterns are compounded by acceleration of cancer onset with successive generations. It has been suggested that this apparent anticipation pattern may result from germ-line genomic instability in TP53 mutation carriers, causing increased DNA copy-number variations (CNVs) with successive generations. To address the genetic basis of phenotypic disparities of LFS/LFL, we performed whole-genome sequencing (WGS) of 13 subjects from two generations of an LFS kindred. Neither de novo CNV nor significant difference in total CNV was detected in relation with successive generations or with age at cancer onset. These observations were consistent with an experimental mouse model system showing that trp53 deficiency in the germ line of father or mother did not increase CNV occurrence in the offspring. On the other hand, individual records on 1,771 TP53 mutation carriers from 294 pedigrees were compiled to assess genetic anticipation patterns (International Agency for Research on Cancer TP53 database). No strictly defined anticipation pattern was observed. Rather, in multigeneration families, cancer onset was delayed in older compared with recent generations. These observations support an alternative model for apparent anticipation in which rare variants from noncarrier parents may attenuate constitutive resistance to tumorigenesis in the offspring of TP53 mutation carriers with late cancer onset.

Cells from some tumors use an altered metabolic pattern compared with that of normal differentiated adult cells in the body. Tumor cells take up much more glucose and mainly process it through aerobic glycolysis, producing large quantities of secreted lactate with a lower use of oxidative phosphorylation that would generate more adenosine triphosphate (ATP), water, and carbon dioxide. This is the Warburg effect, which provides substrates for cell growth and division and free energy (ATP) from enhanced glucose use. This metabolic switch places the emphasis on producing intermediates for cell growth and division, and it is regulated by both oncogenes and tumor suppressor genes in a number of key cancer-producing pathways. Blocking these metabolic pathways or restoring these altered pathways could lead to a new approach in cancer treatments.