Insights into Wild-Type and Mutant p53 Functions Provided by Genetically Engineered Mice

Donehower, Lawrence A.

doi:10.1002/humu.22507

Cited by 28 publications

(30 citation statements)

References 106 publications

(121 reference statements)

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“…A study of over 100 breeding Trp53 knockout mice over 15 generations has not revealed evidence for increased accumulation of CNV and of germ-line genetic instability. In mice deficient for Trp53, age at onset and type of cancer is remarkably dependent upon genetic background (15) as well as of the presence of germ-line mutations in other genes such as BRCA1 (16) or RB1 (17)(18)(19). We anticipate that the variants involved in modulating heterogeneity may be complex and may differ from one family to the other.…”

Section: Discussionmentioning

confidence: 99%

Whole-genome sequencing analysis of phenotypic heterogeneity and anticipation in Li–Fraumeni cancer predisposition syndrome

Ariffin

Hainaut

Puzio-Kuter

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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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.Li-Fraumeni syndrome | whole genome sequencing | genetic anticipation | p53 mutation | copy number variation

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Section: Discussionmentioning

confidence: 99%

Whole-genome sequencing analysis of phenotypic heterogeneity and anticipation in Li–Fraumeni cancer predisposition syndrome

Ariffin

Hainaut

Puzio-Kuter

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Despite the fact that mutp53 GOF leading to chemoresistance has been confirmed in basic investigations and verified in genetically engineered mouse models with mutp53 [8] or in patients with Li-Fraumeni syndrome [60], the role of mutp53 in clinical chemotherapy response has not been well defined nor has mutp53 been recommended as a chemoresistance marker for clinical use. Clinical application of mutp53 analysis is lagging in part because the various methods and protocols for p53 mutation detection in use worldwide have dramatic variations in specificity and sensitivity.…”

Section: The Role Of Mutp53 In Response To Clinical Chemotherapymentioning

confidence: 99%

“…The most compelling evidence of mutp53 GOF comes from knock-in mice engineered to harbor tumor-associated hot spot p53 mutations. Knock-in mice exhibited a broader tumor spectrum with a more invasive and metastatic phenotype than p53-/- or p53+/- mice [8]. …”

Section: Mutp53 Gofmentioning

confidence: 99%

Mutant p53 Gain of Function and Chemoresistance: The Role of Mutant p53 in Response to Clinical Chemotherapy

Li²,

Guan³

et al. 2016

Chemotherapy

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Purpose: To review mechanisms underlying mutant p53 (mutp53) gain of function (GOF) and mutp53-induced chemoresistance, and to investigate the role of mutp53 in response to clinical chemotherapy. Methods: We searched the PubMed database for clinical studies from the past decade, including data evaluating the impact of mutp53 in clinical chemotherapy response. Results: Interactions between mutp53 and transcriptional factors, proteins or DNA structures, as well as epigenetic regulation, contribute to mutp53 GOF. Major mechanisms of mutp53-induced chemoresistance include enhanced drug efflux and metabolism, promoting survival, inhibiting apoptosis, upregulating DNA repair, suppressing autophagy, elevating microenvironmental resistance and inducing a stem-like phenotype. Clinically, mutp53 predicted resistance to chemotherapy in diffuse large B-cell lymphoma, and esophageal and oropharyngeal cancers, but its impact on chronic lymphocytic leukemia was unclear. In bladder cancer, mutp53 did not predict resistance, whereas in some breast and ovarian cancers, it was associated with sensitivity to certain chemotherapeutic agents. Conclusion: mutp53 has an intricate role in the response to clinical chemotherapy and should not be interpreted in isolation. Furthermore, when predicting tumor response to chemotherapy based on the p53 status, the drugs used should also be taken into consideration. These concepts require further investigation.

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“…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.…”

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confidence: 76%

TheTP53Gene Network in a Postgenomic Era

Soussi

2014

Human Mutation

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Inactivation of TP53 pathways are the most common defects observed in human cancer. Although missense mutations remain the most frequent genetic event, it is now evident that dysfunction of several members of this network such as MDM2, MDM4 (mdmX), or miR125b can substitute for TP53 mutations. This special issue on TP53 brings the TP53 gene into the post-genomic era. Several (Soussi, 2003; http://onlinelibrary.wiley.com/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. * Correspondence to: Thierry Soussi, Karolinska Institute, Department of OncologyPathology, Cancer Center Karolinska, Stockholm SE-171 76, Sweden. E-mail: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 c...

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Insights into Wild-Type and Mutant p53 Functions Provided by Genetically Engineered Mice

Cited by 28 publications

References 106 publications

Whole-genome sequencing analysis of phenotypic heterogeneity and anticipation in Li–Fraumeni cancer predisposition syndrome

Whole-genome sequencing analysis of phenotypic heterogeneity and anticipation in Li–Fraumeni cancer predisposition syndrome

Mutant p53 Gain of Function and Chemoresistance: The Role of Mutant p53 in Response to Clinical Chemotherapy

TheTP53Gene Network in a Postgenomic Era

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