Genome-wide rare copy number variation screening in ulcerative colitis identifies potential susceptibility loci.

BACKGROUND: Ulcerative colitis (UC), a complex polygenic disorder, is one of the main subphenotypes of inflammatory bowel disease. A comprehensive dissection of the genetic etiology of UC needs to assess the contribution of rare genetic variants including copy number variations (CNVs) to disease risk. In this study, we performed a multi-step genome-wide case-control analysis to interrogate the presence of disease-relevant rare copy number variants. METHODS: One thousand one hundred twenty-one German UC patients and 1770 healthy controls were initially screened for rare deletions and duplications employing SNP-array data. Quantitative PCR and high density custom array-CGH were used for validation of identified CNVs and fine mapping. Two main follow-up panels consisted of an independent cohort of 451 cases and 1274 controls, in which CNVs were assayed through quantitative PCR, and a British cohort of 2396 cases versus 4886 controls with CNV genotypes based on array data. Additional sample sets were assessed for targeted and in silico replication. RESULTS: Twenty-four rare copy number variants (14 deletions and 10 duplications), overrepresented in UC patients were identified in the initial screening panel. Follow-up of these CNV regions in four independent case-control series as well as an additional public in silico control group (totaling 4439 UC patients and 15,961 healthy controls) revealed three copy number variants enriched in UC patients; a 15.8 kb deletion upstream of ABCC4 and CLDN10 at13q32.1 (0.43% cases, 0.11% controls), a 119 kb duplication at 7p22.1, overlapping RNF216, ZNF815, OCM and CCZ1 (0.13% cases, 0.01% controls) and a 134 kb large duplication upstream of the KCNK9 gene at 8q24.3 (0.22% carriers among cases, 0.03% carriers among controls). The trend of association with UC was present after the P-values were corrected for combining data from different subpopulations. Break-point mapping of the deleted region suggested non-allelic homologous recombination as the mechanism underlying its formation. CONCLUSION: Our study presents a pragmatic approach for effective rare CNV screening of SNP-array data sets and implicates the potential contribution of rare structural variants in the pathogenesis of UC.

Role of PTEN gene in progression of prostate cancer.

INTRODUCTION: The aim of this study was to clarify the role of PTEN gene in progression of prostate cancer. MATERIALS AND METHODS: A total of 51 formalin-fixed paraffin-embedded specimens of prostate cancer were analyzed for PTEN mutations. Tissue microdissection and polymerase chain reaction/single-strand conformation polymorphism methods were used. Clinical and pathologic data of the patients were reviewed with regard to PTEN mutation. RESULTS: The Gleason score (GS) was less than 7 in 29 (56.8%), 7 in 11 (21.6%), and greater than 7 in 11 (21.6%). Tumor stage was IIa, IIb, IIc, and IV in 14 (27.4%), 4 (7.8%), 21 (41.2%), and 12 (23.6%) patients, respectively. Eleven of 12 stage IV tumors had metastases at the time of presentation. Six of 51 cases (11.6%) showed mutation in PTEN which had involved exones 1, 2, and 5. Two of these cases had localized and the others had advanced prostate cancer. One case of the tumors with PTEN mutation had a GS of 7 and 5 had GSs greater than 7. Patients with a positive mutation of PTEN had a significantly greater GS (P < .001), lower survival rate (P = .001), higher tendency to metastasis (P = .002), and higher prostate-specific antigen (P = .03). Cox proportional hazard model showed that only GS was significantly correlated with mortality (P = .03). CONCLUSION: Patients with prostate cancer who had PTEN mutation had also a significantly greater GS, poorer prognosis, and higher rate of metastasis. However, this mutation cannot predict the prognosis and the GS is a more precise factor.