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Messiaen L.,University of Alabama at Birmingham | Vogt J.,University of Ulm | Bengesser K.,University of Ulm | Fu C.,University of Alabama at Birmingham | And 6 more authors.
Human Mutation | Year: 2011

Mosaicism is an important feature of type-1 neurofibromatosis (NF1) on account of its impact upon both clinical manifestations and transmission risk. Using FISH and MLPA to screen 3500 NF1 patients, we identified 146 individuals harboring gross NF1 deletions, 14 of whom (9.6%) displayed somatic mosaicism. The high rate of mosaicism in patients with NF1 deletions supports the postulated idea of a direct relationship between the high new mutation rate in this cancer predisposition syndrome and the frequency of mosaicism. Seven of the 14 mosaic NF1 deletions were type-2, whereas four were putatively type-1, and three were atypical. Two of the four probable type-1 deletions were confirmed as such by breakpoint-spanning PCR or SNP analysis. Both deletions were associated with a generalized manifestation of NF1. Independently, we identified a third patient with a mosaic type-1 NF1 deletion who exhibited segmental NF1. Together, these three cases constitute the first proven mosaic type-1 deletions so far reported. In two of these three mosaic type-1 deletions, the breakpoints were located within PRS1 and PRS2, previously identified as hotspots for nonallelic homologous recombination (NAHR) during meiosis. Hence, NAHR within PRS1 and PRS2 is not confined to meiosis but may also occur during postzygotic mitotic cell cycles. © 2011 Wiley-Liss, Inc.


Aytes A.,Institute Catala Doncologia Institute Dinvestigacio Biomedica Of Bellvitge Idibell | Mollevi D.G.,Institute Catala Doncologia Institute Dinvestigacio Biomedica Of Bellvitge Idibell | Martinez-Iniesta M.,Institute Catala Doncologia Institute Dinvestigacio Biomedica Of Bellvitge Idibell | Nadal M.,Institute Catala Doncologia Institute Dinvestigacio Biomedica Of Bellvitge Idibell | And 7 more authors.
Molecular Carcinogenesis | Year: 2012

Allelic imbalances at chromosome 4p have been largely documented in many different tumor types. In colorectal cancer, loss of heterozygosity (LOH) at 4p15 has been associated with tumor aggressiveness and poor patient outcome, however no target genes in the region have been identified to date. Since stromal interaction molecule 2 (STIM2) is located at 4p15.2 and has been proposed as a candidate gene for this region in glioblastoma multiforme, we aimed at investigating the role of STIM2 in colorectal cancer. We studied STIM2 transcript expression levels in a collection of xenografted primary colorectal tumors (n=20) and a well-annotated tumor series of colorectal cancer (n=140). We observed an overexpression of STIM2 in 63.5% of the cases that was associated with a less invasive phenotype. In vitro and in vivo functional studies with colon cancer cell lines revealed that overexpression of STIM2 reduced cell proliferation and tumor growth, respectively. Our work presents several lines of evidence indicating that STIM2 overexpression is a frequent trait in colorectal cancer that results in cell growth suppression, certifying that even in the absence of somatic genetic or epigenetic alterations, recurrent regions of LOH should still be considered a hallmark for the presence of relevant genes for tumorigenesis. © 2011 Wiley Periodicals, Inc.


Santos C.,Institute Catala Doncologia Institute Dinvestigacio Biomedica Of Bellvitge Idibell | Lopez-Doriga A.,Institute Catala Doncologia Institute Dinvestigacio Biomedica Of Bellvitge Idibell | Navarro M.,Institute Catala Doncologia Institute Dinvestigacio Biomedica Of Bellvitge Idibell | Mateo J.,Institute Catala Doncologia Institute Dinvestigacio Biomedica Of Bellvitge Idibell | And 12 more authors.
Colorectal Disease | Year: 2013

Aim Adjuvant 5-fluorouracil based chemotherapy has demonstrated benefit in Stage III colon cancer but still remains controversial in Stage II. The aim of this study was to analyse the prognostic impact of clinicopathological factors that may help guide treatment decisions in Stage II colon cancer. Method Between 1996 and 2006 data from patients diagnosed with colorectal cancer at Hospital Universitari Bellvitge and its referral comprehensive cancer centre Institut Català d′Oncologia/L'Hospitalet were prospectively included in a database. We identified 432 patients with Stage II colon cancer operated on at Hospital Universitari Bellvitge. The 5-year relapse-free survival (RFS) and colon-cancer-specific survival (CCSS) were determined. Results The 5-year RFS and CCSS were 83% and 88%, respectively. Lymphovascular or perineural invasion was associated with RFS [hazard ratio (HR) 1.84; 95% CI 1.01-3.35]. Gender (women, HR 0.48; 95% CI 0.23-1) and lymphovascular or perineural invasion (HR 3.51; 95% CI 1.86-6.64) together with pT4 (HR 2.79; 95% CI 1.44-5.41) influenced CCSS. In multivariate analysis pT4 and lymphovascular or perineural invasion remained significantly associated with CCSS. We performed a risk index with these factors with prognostic impact. Patients with pT4 tumours and lymphovascular or perineural invasion had a 5-year CCSS of 61%vs the 93% (HR 5.87; 95 CI 2.46-13.97) of those without any of these factors. Conclusion pT4 and lymphatic, venous or perineural invasion are confirmed as significant prognostic factors in Stage II colon cancer and should be taken into account in the clinical validation process of new molecular prognostic factors. © 2012 The Association of Coloproctology of Great Britain and Ireland.

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