Intrinsic tumour suppression

Lowe, Scott W.; Cepero, Enriqué; Evan, Gérard I.

doi:10.1038/nature03098

Cited by 1,173 publications

(965 citation statements)

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“…The location of the germline mutation in APC in a FAP patient and the mode by which the wild‐type allele of the gene is inactivated during adenomagenesis influence the degree to which the WNT pathway is activated 13. The level of WNT pathway activation influences the multiplicity of intestinal polyposis and the growth of the adenomas that form, and is described by the ‘just‐right hypothesis’, which suggests that adenomas aim to have sufficient WNT activation to drive cell growth without tipping cells into apoptosis or evoking cell death 14. Fine‐tuning of the WNT pathway is thus central to colorectal tumourigenesis 15.…”

Section: Introductionmentioning

confidence: 99%

Adenoma development in familial adenomatous polyposis and MUTYH‐associated polyposis: somatic landscape and driver genes

Rashid

Fischer

Wilson

et al. 2015

The Journal of Pathology

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Familial adenomatous polyposis (FAP) and MUTYH‐associated polyposis (MAP) are inherited disorders associated with multiple colorectal adenomas that lead to a very high risk of colorectal cancer. The somatic mutations that drive adenoma development in these conditions have not been investigated comprehensively. In this study we performed analysis of paired colorectal adenoma and normal tissue DNA from individuals with FAP or MAP, sequencing 14 adenoma whole exomes (eight MAP, six FAP), 55 adenoma targeted exomes (33 MAP, 22 FAP) and germline DNA from each patient, and a further 63 adenomas by capillary sequencing (41 FAP, 22 MAP). With these data we examined the profile of mutated genes, the mutational signatures and the somatic mutation rates, observing significant diversity in the constellations of mutated driver genes in different adenomas, and loss‐of‐function mutations in WTX (9%; p < 9.99e‐06), a gene implicated in regulation of the WNT pathway and p53 acetylation. These data extend our understanding of the early events in colorectal tumourigenesis in the polyposis syndromes. © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Section: Introductionmentioning

confidence: 99%

Adenoma development in familial adenomatous polyposis and MUTYH‐associated polyposis: somatic landscape and driver genes

Rashid

Fischer

Wilson

et al. 2015

The Journal of Pathology

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“…Whereas p53 is mutated in almost half of all human cancers (http://.iarc.fr/p53), p73 and p63, despite extensive effort, have been found mutated very rarely in human tumors (Sunahara et al, 1998;Takahashi et al, 1998;Kaelin, 1999;Levrero et al, 2000;Yang and McKeon, 2000;Olivier et al, 2002). Altogether, these findings indicate that among the p53 family members, p53 has been selected as a canonical tumor-suppressor gene whose inactivation certainly gives an advantage to the development and the maintenance of a cancer (Lowe et al, 2004). Unlike other tumor-suppressor genes, whose inactivation results in the absence or in the presence of truncated proteins, p53 generates abundant full-length mutant proteins.…”

Section: Introductionmentioning

confidence: 99%

Mutant p53: an oncogenic transcription factor

Strano¹,

Dell’Orso²,

Agostino³

et al. 2007

Oncogene

243

184

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Inactivation of tumor-suppressor genes is one of the key hallmarks of a tumor. Unlike other tumor-suppressor genes, p53 is inactivated by missense mutations in half of all human cancers. It has become increasingly clear that the resulting mutant p53 proteins do not represent only the mere loss of wild-type p53 tumor suppressor activity, but gain new oncogenic properties favoring the insurgence, the maintenance, the spreading and the chemoresistance of malignant tumors. The actual challenge is the fine deciphering of the molecular mechanisms underlying the gain of function of mutant p53 proteins. In this review, we will focus mainly on the transcriptional activity of mutant p53 proteins as one of the potential molecular mechanisms. To date, the related knowledge is still quite scarce and many of the raised questions of this review are yet unanswered.

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“…In addition, many of the oncogenes that become activated during tumour development push tumour cells closer to the edge of death, revealing a therapeutic window between normal and tumour cells that is the basis for many standard forms of chemotherapy (Green and Evan, 2002;Lowe et al, 2004). As a result, as tumours become more established and particularly following exposure to cell death-inducing therapies, a subset of defective cells carrying genetic aberrations can develop ways to inactivate or uncouple cell death pathways and evade irradication (Hanahan and Weinberg, 2000).…”

Section: Introductionmentioning

confidence: 99%