Cancer susceptibility has been attributed to at least one heterozygous genetic alteration in a tumor suppressor gene (TSG)1. It has been hypothesized that subtle variations in TSG expression can promote cancer development2,3. However, this hypothesis has not yet been definitively supported in vivo. PTEN is a TSG frequently lost in human cancer and mutated in inherited cancer-predisposition syndromes4. Here, we analyze Pten hypermorphic mice (Ptenhy/+), expressing 80% normal levels of Pten. Ptenhy/+ mice develop a spectrum of tumors, with breast tumors occurring at the highest penetrance. All breast tumors analyzed here retained two intact copies of Pten and maintained Pten levels above heterozygosis. Notably, subtle downregulation of Pten altered the steady-state biology of the mammary tissues and the expression profiles of genes involved in cancer cell proliferation. We present an alterative working model for cancer development in which subtle reductions in the dose of TSGs predispose to tumorigenesis in a tissue-specific manner.

Lipids, either endogenously synthesized or exogenous, have been linked to human cancer. Here we found that PML is frequently co-deleted with PTEN in metastatic human prostate cancer (CaP). We demonstrated that conditional inactivation of Pml in the mouse prostate morphs indolent Pten-null tumors into lethal metastatic disease. We identified MAPK reactivation, subsequent hyperactivation of an aberrant SREBP prometastatic lipogenic program, and a distinctive lipidomic profile as key characteristic features of metastatic Pml and Pten double-null CaP. Furthermore, targeting SREBP in vivo by fatostatin blocked both tumor growth and distant metastasis. Importantly, a high-fat diet (HFD) induced lipid accumulation in prostate tumors and was sufficient to drive metastasis in a nonmetastatic Pten-null mouse model of CaP, and an SREBP signature was highly enriched in metastatic human CaP. Thus, our findings uncover a prometastatic lipogenic program and lend direct genetic and experimental support to the notion that a Western HFD can promote metastasis.

No abstract

Background:The preventive role of non-steroid anti-inflammatory drugs (NSAIDs) and aspirin, in particular, on colorectal cancer is well established. More recently, it has been suggested that aspirin may also have a therapeutic role. Aim of the present observational population-based study was to assess the therapeutic effect on overall survival of aspirin/NSAIDs as adjuvant treatment used after the diagnosis of colorectal cancer patients.Methods:Data concerning prescriptions were obtained from PHARMO record linkage systems and all patients diagnosed with colorectal cancer (1998–2007) were selected from the Eindhoven Cancer Registry (population-based cancer registry). Aspirin/NSAID use was classified as none, prediagnosis and postdiagnosis and only postdiagnosis. Patients were defined as non-user of aspirin/NSAIDs from the date of diagnosis of the colorectal cancer to the date of first use of aspirin or NSAIDs and user from first use to the end of follow-up. Poisson regression was performed with user status as time-varying exposure.Results:In total, 1176 (26%) patients were non-users, 2086 (47%) were prediagnosis and postdiagnosis users and 1219 (27%) were only postdiagnosis users (total n=4481). Compared with non-users, a survival gain was observed for aspirin users; the adjusted rate ratio (RR) was 0.77 (95% confidence interval (CI) 0.63–0.95; P=0.015). Stratified for colon and rectal, the survival gain was only present in colon cancer (adjusted RR 0.65 (95%CI 0.50–0.84; P=0.001)). For frequent users survival gain was larger (adjusted RR 0.61 (95%CI 0.46–0.81; P=0.001). In rectal cancer, aspirin use was not associated with survival (adjusted RR 1.10 (95%CI 0.79–1.54; P=0.6). The NSAIDs use was associated with decreased survival (adjusted RR 1.93 (95%CI 1.70–2.20; P<0.001).Conclusion:Aspirin use initiated or continued after diagnosis of colon cancer is associated with a lower risk of overall mortality. These findings strongly support initiation of a placebo-controlled trial that investigates the role of aspirin as adjuvant treatment in colon cancer patients.

No abstract

Rett syndrome is a neurodevelopmental disorder that represents one of the most common genetic causes of mental retardation in girls. MECP2 point mutations in exons 2-4 account for about 80% of classic Rett cases and for a lower percentage of variant patients. We investigated the genetic cause in 77 mutation-negative Rett patients (33 classic, 31 variant, and 13 Rett-like cases) by searching missed MECP2 defects. DHPLC analysis of exon 1 and MLPA analysis allowed us to identify the defect in 17 Rett patients: one exon 1 point mutation (c.47_57del) in a classic case and 16 MECP2 large deletions (15/33 classic and 1/31 variant cases). One identical intragenic MECP2 deletion, probably due to gonadal mosaicism, was found in two sisters with discordant phenotype: one classic and one "highly functioning" preserved speech variant. This result indicates that other epigenetic or genetic factors, beside MECP2, may contribute to phenotype modulation. Three out of 16 MECP2 deletions extend to the adjacent centromeric IRAK1 gene. A putative involvement of the hemizygosity of this gene in the ossification process is discussed. Finally, results reported here clearly indicate that MECP2 large deletions are a common cause of classic Rett, and MLPA analysis is mandatory in MECP2-negative patients, especially in those more severely affected (P = 0.044).

The present report describes a 7-year-old girl with a de novo 3 Mb interstitial deletion of chromosome 14q12, identified by oligo array-CGH. The region is gene poor and contains only five genes two of them, FOXG1B and PRKD1 being deleted also in a previously reported case with a very similar phenotype. Both patients present prominent metopic suture, epicanthic folds, bulbous nasal tip, tented upper lip, everted lower lip and large ears and a clinical course like Rett syndrome, including normal perinatal period, postnatal microcephaly, seizures, and severe mental retardation. FOXG1B (forkhead box G1B) is a very intriguing candidate gene since it is known to promote neuronal progenitor proliferation and to suppress premature neurogenesis and its disruption is reported in a patient with postnatal microcephaly, corpus callosum agenesis, seizures, and severe mental retardation.

No abstract