Ptprj is a candidate for the mouse colon-cancer susceptibility locus Scc1 and is frequently deleted in human cancers.

Only a small proportion of cancers result from familial cancer syndromes with Mendelian inheritance. Nonfamilial, 'sporadic' cancers, which represent most cancer cases, also have a significant hereditary component, but the genes involved have low penetrance and are extremely difficult to detect. Therefore, mapping and cloning of quantitative trait loci (QTLs) for cancer susceptibility in animals could help identify homologous genes in humans. Several cancer-susceptibility QTLs have been mapped in mice and rats, but none have been cloned so far. Here we report the positional cloning of the mouse gene Scc1 (Susceptibility to colon cancer 1) and the identification of Ptprj, encoding a receptor-type protein tyrosine phosphatase, as the underlying gene. In human colon, lung and breast cancers, we show frequent deletion of PTPRJ, allelic imbalance in loss of heterozygosity (LOH) and missense mutations. Our data suggest that PTPRJ is relevant to the development of several different human cancers.

p27kip1-838C>A single nucleotide polymorphism is associated with restenosis risk after coronary stenting and modulates p27kip1 promoter activity.

BACKGROUND: The cyclin-dependent kinase inhibitor p27(kip1) is a key regulator of smooth muscle cell and leukocyte proliferation in vascular disease, including in-stent restenosis. We therefore hypothesized that common genetic variations or single nucleotide polymorphisms in p27(kip1) may serve as a useful tool in risk stratification for in-stent restenosis. METHODS AND RESULTS: Three single nucleotide polymorphisms concerning the p27(kip1) gene (-838C>A, rs36228499; -79C>T, rs34330; +326G>T, rs2066827) were determined in a cohort of 715 patients undergoing coronary angioplasty and stent placement. We discovered that the p27(kip1)-838C>A single nucleotide polymorphism is associated with clinical in-stent restenosis; the -838AA genotype decreases the risk of target vessel revascularization (hazard ratio, 0.28; 95% confidence interval, 0.10 to 0.77). This finding was replicated in another cohort study of 2309 patients (hazard ratio, 0.61; 95% confidence interval, 0.40 to 0.93). No association was detected between this end point and the p27(kip1)-79C>T and +326G>T single nucleotide polymorphisms. We subsequently studied the functional importance of the -838C>A single nucleotide polymorphism and detected a 20-fold increased basal p27(kip1) transcriptional activity of the -838A allele containing promoter. CONCLUSIONS: Patients with the p27(kip1)-838AA genotype have a decreased risk of in-stent restenosis corresponding with enhanced promoter activity of the -838A allele of this cell-cycle inhibitor, which may explain decreased smooth muscle cell proliferation.

Five new mouse susceptibility to colon cancer loci, Scc11-Scc15.

Although several genes causing familial cancer syndromes have been identified, susceptibility to sporadic cancer remains unsolved. Animal experiments have demonstrated a large number of quantitative trait loci affecting cancer susceptibility. Previously, we described in mouse strain CcS-19/Dem five susceptibility to colon cancer (Scc) loci, Scc1-Scc5 controlling tumor numbers. In the present study, we performed an independent identical mouse cross using a distinct carcinogen, azoxymethane, to induce colon tumors. We confirmed all five originally described Scc loci and detected five additional new Scc loci; Scc11-Scc15. All these loci were detected in two-way interactions.

The relationship between the number of preprocedural circulating endothelial progenitor cells and angiographic restenosis following coronary artery stent placement.

OBJECTIVE: In animals, endothelial progenitor cells (EPCs) beneficially influence the repair of the coronary vessel wall after damage by stent placement. However, their role in humans is less well understood. In the present study, the authors aimed to evaluate the relationship between the number of preprocedural EPCs defined as CD34+/KDR+/CD133+ cells and angiographic late loss as a measure of the growth of in-stent intimal hyperplasia. DESIGN SETTING PATIENTS AND INTERVENTIONS: The 59 study patients were treated in the authors' clinic with a Genous EPC capturing stent, a bare metal stent (BMS) or a drug-eluting stent, and angiographic follow-up occurred between 6 and 13 months. RESULTS: The authors found no relationship between preprocedural EPCs and angiographic late loss, irrespective of stent type. Though statistically not significant, patients with a high number of preprocedural CD34 cells and treated with a Genous stent or BMS showed a numerically higher late loss (in Genous patients: 1.03±0.76 mm vs 0.71±0.50 mm, p=0.15; in BMS patients: 1.06±0.73 mm vs 0.35±0.62 mm, p=0.08). CONCLUSIONS: Considering these and other varied observations, further studies aimed at identifying the biological mechanism and the individual roles of EPCs and/or CD34 cells in endothelial repair after coronary vessel stenting are needed.