Analysis of BRCA1 and BRCA2 genes in Turkish breast cancer patients

Ankara : The Department of Molecular Biology and Genetics and the Institute of Engineering and Science of Bilkent Univ., 2000.Thesis (Ph.D.) -- Bilkent University, 2000.Includes bibliographical references leaves 149-165.Breast cancer is the most frequent cancer type and the second cause of death among women. It is estimated that 10 to 15% of breast cancer cases are hereditary. The majority of hereditary breast cancers can be attributed to germ-line mutations in ^Jgeast CAncer susceptibility genes BRCAl and BRCA2. In this study, germ-line BRCAl and/or BRCA2 gene mutations were screened in 50 Turkish breast and/or ovarian cancer patients divided into four groups of hereditary, familial, early onset, and male cancer by heteroduplex analysis and DNA sequencing. Two BRCA2 mutations, one novel (6880insG) and one previously reported (3034delAAAC), were found in the hereditary group. A novel BRCAl (1200insA) mutation was formd in the early onset group. All three mutations cause premature- termination codons. In addition, five BRCAl sequence variants have been identified in 23 patients. K654E (2080 A—>G), D693N (2196 G->A), P871L (2731 C—>T), and K1183R (3667 A—>G) result in a change of amino acids. 1013 T—^>C and 2201 C—>T are silent mutations. One patient in the early onset group was compound heterozygote for K654E and D693N. These results indicate that BRCAl and BRCA2 genes are involved in some but not all hereditary breast cancers in the Turkish population.Özdağ, HilalPh.D

Investigation and comparison of the preprocessing algorithms for microarrayanalysis for robust gene expression calculation and performance analysis of technical replicates

Preprocessing of microarray data involves the necessary steps of background correction, normalization and summarization of the raw intensity data obtained from cDNA or oligo-arrays before statistical analysis. Several algorithms, namely RMA, dChip, and MAS5 exist for the preprocessing of Affymetrix microarray data. Previous studies have identified RMA as one of most accurate algorithms while MAS5 was characterized with lower accuracy and sensitivity levels. In this study, performance of different preprocessing algorithms have been compared in terms of ROC characteristics of pairwise intensity differences of microarray replicates. Our findings indicated that all three algorithms predicted in similar order the quality of the technical replicates obtained from a selected set of latin square experiments [1]. On the other hand, RMA exhibited higher performance in terns of accuracy by maximizing the area under the receiver operating curve. The proposed method also is useful for detection of global and/or local artifacts associated within the technical replicas of a microarray experiment. Therefore this study is unique in the sense that it provides an extensive investigation and comparison of preprocessing algorithms and proposes a novel method for the detection and identification of fine technical replicate pair

A novel approach for small sample size family-based association studies: sequential tests

In this paper, we propose a sequential probability ratio test (SPRT) to overcome the problem of limited samples in studies related to complex genetic diseases. The results of this novel approach are compared with the ones obtained from the traditional transmission disequilibrium test (TDT) on simulated data. Although TDT classifies single-nucleotide polymorphisms (SNPs) to only two groups (SNPs associated with the disease and the others), SPRT has the flexibility of assigning SNPs to a third group, that is, those for which we do not have enough evidence and should keep sampling. It is shown that SPRT results in smaller ratios of false positives and negatives, as well as better accuracy and sensitivity values for classifying SNPs when compared with TDT. By using SPRT, data with small sample size become usable for an accurate association analysis. European Journal of Human Genetics (2011) 19, 915-920; doi:10.1038/ejhg.2011.51; published online 23 March 201

C-type lectin domain family 12, member a: a common denominator in Behcet's syndrome and acute gouty arthritis

C-type lectin domain family 12, member A (CLEC12A) is a C-type lectin-like pattern recognition receptor capable of recognizing monosodium urate crystals. Monosodium urate crystals, the causative agents of gout are also among the danger-associated molecular patterns reflecting cellular injury/cell death. In response to monosodium urate crystals, CLEC12A effectively inhibits granulocyte and monocyte/macrophage functions and hence acts as a negative regulator of inflammation. Behcet's syndrome and gout are autoinflammatory disorders sharing certain pathological (neutrophilic inflammation), clinical (exaggerated response to monosodium urate crystals) and therapeutic (colchicine) features. We propose the hypothesis that decreased expression of CLEC12A is a common denominator in the hyperinflammatory responses observed in Behcet's syndrome and gout. Major lines of evidence supporting this hypothesis are: (1) Downregulation/deficiency of CLEC12A is associated with hyperinflammatory responses. (2) CLEC12A polymorphisms with functional and clinical implications have been documented in other inflammatory diseases. (3) Colchicine, a fundamental therapeutic agent used both in Behcet's syndrome and gout is shown to oppose the downregulation of CLEC12A. (4) Behget's syndrome and gout are characterized by a hyperinflammatory response to monosodium urate crystals and other than gout, Behcet's syndrome is the only inflammatory condition exhibiting this exaggerated response. (5) Genomewide linkage and association studies of Behcet's syndrome collectively point to 12p12-13, the chromosomal region harboring CLEC12A. (6) Patients with severe forms of Behcet's syndrome underexpress CLEC12A with respect to patients with mild forms of the disease. If supported by well-designed, rigorous experiments, the forementioned hypothesis pertinent to CLEC12A will carry important implications for therapy, designing experimental models, and uncovering immunopathogenic mechanisms in Behcet's syndrome and gout. (C) 2015 Elsevier Ltd. All rights reserved