Prevalence of early onset colorectal cancer in 397 patients with classic Li-Fraumeni syndrome.
ABSTRACT Hereditary colorectal cancer is associated most commonly with the hereditary nonpolyposis colorectal cancer or familial adenomatous polyposis syndromes. We investigated the prevalence of early onset colorectal cancer and the frequency of p53 germline mutations in 64 families from a Li-Fraumeni syndrome (LFS) registry.
Patients with documented colorectal cancer and a diagnosis at or before age 50 were included. P53 analyses were performed through germline mutational analyses using standard molecular techniques.
Among the 397 patients and 64 families in the classic LFS registry, a total of 11 patients (2.8%) from 10 different families (15.6%) met criteria for classic LFS and had documented colorectal cancer at less than 50 years of age. The mean age at diagnosis in this group was 33 years and of these patients 4 developed colorectal cancer before age 21 (ages, 9, 11, 15, and 20 y). All families that were tested for p53 mutations (8 of 10) had evidence of germline mutations by sequence analysis; therefore, 12.5% of the total number of families in the registry had colorectal cancer at age less than 50 years and a documented germline p53 mutation. Mutations primarily were missense or nonsense and were located between exons 4-10.
LFS patients with germline p53 mutations may have an increased susceptibility to colorectal cancer and present up to several decades earlier than the general population. LFS should be considered when a young patient presents with colorectal cancer.
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ABSTRACT: The p53 tumor suppressor gene encodes a homo-tetrameric transcription factor which is activated in response to a variety of cellular stressors, including DNA damage and oncogene activation. p53 mutations occur in more than 50% of human cancers. Although p53 has been shown to regulate Wnt signaling, the underlying mechanisms are not well understood. Here we show that silencing p53 in colon cancer cells led to increased expression of Aha1, a co-chaperone of Hsp90. Increased Aha1 levels were associated with enhanced interactions with Hsp90 resulting in increased Hsp90 ATPase activity. Moreover, increased Hsp90 ATPase activity resulted in increased phosphorylation of Akt and GSK3β, leading to enhanced expression of Wnt target genes including Axin-2, c-Myc and Naked-1. Significantly, levels of Aha1, Hsp90 ATPase activity, Akt and GSK3β phosphorylation and expression of Wnt target genes were increased in the colons of p53 null as compared to p53 wild type mice. Using p53 heterozygous mutant epithelial cells from Li-Fraumeni syndrome patients, we show that a monoallelic mutation of p53 was sufficient to activate the Aha1/Hsp90 ATPase axis leading to stimulation of Wnt signaling and increased expression of Axin-2, c-Myc and Naked-1 in these cells. Pharmacologic intervention with CP-31398, a p53 rescue agent, inhibited recruitment of Aha1 to Hsp90 and suppressed Wnt-mediated gene expression in colon cancer cells. Taken together, this study provides new insights into the mechanism by which p53 regulates Wnt signaling and raises the intriguing possibility that p53 status may affect the efficacy of anti-cancer therapies targeting Hsp90 ATPase.Journal of Biological Chemistry 01/2014; 289(10). DOI:10.1074/jbc.M113.532523 · 4.60 Impact Factor
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ABSTRACT: Since its description by Li and Fraumeni over 40 years ago, Li-Fraumeni syndrome (LFS) remains one of the most striking familial cancer predisposition syndromes. Children and adults are affected by a wide array of cancers that occur predominantly at younger ages. This review discusses LFS, describes its association with TP53, and examines the classic and evolving definitions of the syndrome. The potential implications of multi-gene assessments of individuals at increased cancer risk, which have already begun to identify individuals with very little personal or family cancer history carrying germline TP53 mutations, are considered. Newer options in the management of individuals with LFS are also discussed, highlighting the importance of further clinical trials for cancer detection, prevention and management. Finally, we observe how the clinical criteria for TP53 mutation screening appear to be evolving as our understanding of the impact of germline TP53 mutations continues to expand.This article is protected by copyright. All rights reservedHuman Mutation 06/2014; 35(6). DOI:10.1002/humu.22559 · 5.05 Impact Factor
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ABSTRACT: Carriers of germline mutations in the TP53 gene, encoding the cell-cycle regulator and tumour suppressor p53, have a markedly increased risk of cancer-related morbidity and mortality during both childhood and adulthood, and thus require appropriate and effective cancer risk management. However, the predisposition of such patients to multiorgan tumorigenesis presents a specific challenge for cancer risk management programmes. Herein, we review the clinical implications of germline mutations in TP53 and the evidence for cancer screening and prevention strategies in individuals carrying such mutations, as well as examining the potential psychosocial implications of lifelong management for a ubiquitous cancer risk. In addition, we propose an evidence-based framework for the clinical management of TP53 mutation carriers and provide a platform for addressing the management of other cancer predisposition syndromes that can affect multiple organs.Nature Reviews Clinical Oncology 03/2014; DOI:10.1038/nrclinonc.2014.41 · 15.70 Impact Factor