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Sercin O.,Free University of Colombia | Larsimont J.-C.,Free University of Colombia | Karambelas A.E.,Free University of Colombia | Marthiens V.,University Pierre and Marie Curie | And 8 more authors.
Nature Cell Biology | Year: 2016

Aneuploidy is found in most solid tumours, but it remains unclear whether it is the cause or the consequence of tumorigenesis. Using Plk4 overexpression (PLK4OE) during epidermal development, we assess the impact of centrosome amplification and aneuploidy on skin development and tumorigenesis. PLK4OE in the developing epidermis induced centrosome amplification and multipolar divisions, leading to p53 stabilization and apoptosis of epidermal progenitors. The resulting delayed epidermal stratification led to skin barrier defects. Plk4 transgene expression was shut down postnatally in the surviving mice and PLK4OE mice never developed skin tumours. Concomitant PLK4OE and p53 deletion (PLK4OE/p53cKO) rescued the differentiation defects, but did not prevent the apoptosis of PLK4OE cells. Remarkably, the short-term presence of cells with supernumerary centrosomes in PLK4OE/p53cKO mice was sufficient to generate aneuploidy in the adult epidermis and triggered spontaneous skin cancers with complete penetrance. These results reveal that aneuploidy induced by transient centrosome amplification can accelerate tumorigenesis in p53-deficient cells. Source

Dieudonne A.-S.,Catholic University of Leuven | Lambrechts D.,Vesalius Research Center | Lambrechts D.,Laboratory for Translational Genetics | Smeets D.,Vesalius Research Center | And 15 more authors.
Annals of Oncology | Year: 2014

Background: Tamoxifen remains important in the treatment and prevention of estrogen receptor-positive breast cancer. In postmenopausal women, it can lead to endometrial changes such as cystic appearances, hyperplasia, polyps and endometrial cancer. Tamoxifen is metabolized by cytochrome P450 (CYP450) enzymes to the more active metabolite endoxifen. Several genetic variants in the CYP450 enzymes reduce tamoxifen metabolism, leading to reduced endoxifen levels. We hypothesize that carriers of these variants, which are established poor metabolizers of tamoxifen, do not have the typical tamoxifen-induced increase in endometrial thickness. We test the association between genetic variability in CYP450 enzymes and the increase in double endometrial thickness (DET) as measured through transvaginal ultrasound (TVU). Patients and methods: We carried out a retrospective study on postmenopausal tamoxifen users for which germline DNA was available and at least one DET measurement was made between January 2000 and October 2011. Genotyping of 33 single nucleotide polymorphisms in CYP450 genes involved in tamoxifen metabolism was carried out using Sequenom MassARRAY. The association between these variants and TVU outcome (DET ≥5 mm) was assessed by proportional hazards regression. Results: Data were available for 184 women: 47 with a DET of <5 mm on all ultrasounds and 137 with a DET of ≥5 mm on at least one ultrasound. The rs1800716 variant in CYP2D6 showed a statistically significant association with DET. In particular, mutant carriers of rs1800716 had an increased chance of having a DET of ≥5 mm (P = 0.0022, false discovery rate 0.0179). None of the other variants were associated with DET. Conclusion: Although mutant carriers of rs1800716 are characterized by reduced CYP2D6 enzyme activity and by low levels of endoxifen, we observed that mutant alleles of rs1800716 were associated with an increased chance of having a DET of ≥5 mm in postmenopausal women on tamoxifen. We conclude that the increase in endometrial thickness seen under tamoxifen cannot be used as a marker for favorable genotypes. © The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. Source

De Smedt L.,Catholic University of Leuven | Palmans S.,Catholic University of Leuven | Govaere O.,Catholic University of Leuven | Moisse M.,Vesalius Research Center | And 12 more authors.
Laboratory Medicine | Year: 2015

Background: Forkhead box gene P1 (FOXP1) has proven to be a valuable prognostic biomarker in lymphomas, but little is known about this gene in colorectal cancer (CRC). Objectives: To investigate the expression of FOXP1 in CRC and its potential associations with outcome in CRC. Methods: We studied the expression pattern of FOXP1 retrospectively via immunohistochemistry in a series of 165 - CRC cases. Fluorescent in situ hybridization and RNA sequencing on FOXP1 knockdown cell lines were performed to investigate the mechanism of action and target genes of FOXP1. Results: Complete loss of nuclear FOXP1 expression was observed in 11.5% of the subjects. A total of 70.9% of subjects showed a heterogeneous FOXP1 expression pattern, and 17.6% of them had high FOXP1 expression. Impaired expression of FOXP1 was significantly correlated with reduced survival rates by multivariate analysis (P = .004). We found no chromosomal aberrations involving FOXP1 in individuals with FOXP1 negativity via immunohistochemical testing. RNA sequencing revealed that genes involved in inflammation and cell proliferation were differentially expressed after FOXP1 knockdown. Conclusions: In our case series, loss of FOXP1 was associated with reduced survival rates in CRC tissue. Also, FOXP1 affects proliferation and inflammatory reaction in colorectal neoplasia. Source

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