Akut lösemi tanılı olgularda kromozom ve kardeş kromatid değişimi (KKD) analizi

Tez (yüksek lisans) - Anadolu ÜniversitesiAnadolu Üniversitesi, Sağlık Bilimleri Enstitüsü, Tıpta UzmanlıkKayıt no: 99760Akut lösemili olgularda kromozom düzeyinde meydana gelen düzensizlikler ile bu olgularda kardeş kromatid değişim düzeylerini belirlemek amacıyla yapılan bu çalışmada 14 akut lösemili ve biri Hodgkin's hastalığı olan toplam 15 olgu ile toplam 15 sağlıklı kişide periferik kan kültürü yöntemi ile kromozomve kardeş kromatid değişim düzeylerine ilişkin analiz yapıldı. Araştırma ve kontrol grubunda kromozom analizi için GTG bant- lama tekniği uygulandı. Ayrıca araştırma ve kontrol grubu bireylerinde KKD analizi için FPG tekniği uygulandı. İncelenen akut lösemili olgulardan i) ANLL - M2 tipinde olanların ilkinde [46,XY,del(3)(q25)] karyotipi, ikincisinde ise [46,XY,del (2)(q12q14)] saptanırken, üçün- cüsünde ise, [46,XY,-7,mar/46,XY, inv (16)(p;q)]karyotipi belirlendi. ii) Yine ANLL- M3 tipinde olan üç olgudan ilkinde normal karyotip [46,XX],ikircisinde [44, XY, -14,19 t(7;8) (q22;p11) ve üçüncüsünde ise translokasyon tipi düzensizlik[43,XY,-19,t(13q22q), t(21q22q)] saptandı. iii) Araştırma grubundaki olgulardan iki tanesi ANLL-M4 tipin- de olup ilkinde translokasyon [46,XX,+19, t(15;22)(q26;q11) / 46, XX, +19,-22, min] gözlenirken ikinci olguda inversiyon tipi düzen- sizlik [46,XX,inv(3)(p11;q22)/47,XX,+del (22)(q11)] gözlendi. iv) Yine araştırma grubunu oluşturan olgulardan dört tanesi ANLL-M5 tipinde idi. Bu olgulardan ilkinde 13. kromozomun uzun kolunda artış saptandı [46,XY,13q+] saptandı. Bu grubun diğer üç olgusundan ilki M5a tipinde olup 20. kromozom monozomisi [45,XY,-20] gözlenirken geri kalan iki tanesi M5b tipinde olup ilkinde [47,XX,+21] ve ikincisinde ise translokasyon tipi düzensizlik belirlendi [45,XY,-19,t(10;14)(q23;q23)]. v) Araştırmamızda yer alan son üç olgudan biri alt tipi belirlenemiyen ANLL tipinde, bir tanesi ALL-L2 ve sonucusu da Hodgkin's hastalığı tanılı idi. Bunlardan ilkinde 17. kromozom monozomisi ve marker kromozom [46, XY,-17, mar., min.], ikincisinde normal karyotip [46,XX] ve sonuncusunda da translokasyon tipi düzensizlik [46, XY,t (8;19)(q24;q13)] saptandı

Prognostic relevance of acquired uniparental disomy in serous ovarian cancer

BACKGROUND: Acquired uniparental disomy (aUPD) can lead to homozygosity for tumor suppressor genes or oncogenes. Our purpose is to determine the frequency and profile aUPD regions in serous ovarian cancer (SOC) and investigated the association of aUPD with clinical features and patient outcomes.METHODS: We analyzed single nucleotide polymorphism (SNP) array-based genotyping data on 532 SOC specimens from The Cancer Genome Atlas database to identify aUPD regions. Cox univariate regression and Cox multivariate proportional hazards analyses were performed for survival analysis.RESULTS: We found that 94.7% of SOC samples harbored aUPD; the most common aUPD regions were in chromosomes 17q (76.7%), 17p (39.7%), and 13q (38.3%). In Cox univariate regression analysis, two independent regions of aUPD on chromosome 17q (A and C), and whole-chromosome aUPD were associated with shorter overall survival (OS), and five regions on chromosome 17q (A, D-G) and BRCA1 were associated with recurrence-free survival time. In Cox multivariable proportional hazards analysis, whole-chromosome aUPD was associated with shorter OS. One region of aUPD on chromosome 22q (B) was associated with unilateral disease. A statistically significant association was found between aUPD at TP53 loci and homozygous mutation of TP53 (p < 0.0001).CONCLUSIONS: aUPD is a common event and some recurrent loci are associated with a poor outcome for patients with serous ovarian cancer

Association between Acquired Uniparental Disomy and Homozygous Mutations and HER2/ER/PR Status in Breast Cancer

Background: Genetic alterations in cellular signaling networks are a hallmark of cancer, however, effective methods to discover them are lacking. A novel form of abnormality called acquired uniparental disomy (aUPD) was recently found to pinpoint the region of mutated genes in various cancers, thereby identifying the region for next-generation sequencing. Methods/Principal Findings: We retrieved large genomic data sets from the Gene Expression Omnibus database to perform genome-wide analysis of aUPD in breast tumor samples and cell lines using approaches that can reliably detect aUPD. Aupd was identified in 52.29% of the tumor samples. The most frequent aUPD regions were located at chromosomes 2q, 3p, 5q, 9p, 9q, 10q, 11q, 13q, 14q and 17q. We evaluated the data for any correlation between the most frequent aUPD regions and HER2/neu, ER, and PR status, and found a statistically significant correlation between the recurrent regions of aUPD and triple negative (TN) breast cancers. aUPD at chromosome 17q (VEZF1, WNT3), 3p (SUMF1, GRM7), 9p (MTAP, NFIB) and 11q (CASP1, CASP4, CASP5) are predictors for TN. The frequency of aUPD was found to be significantly higher in TN breast cancer cases compared to HER2/neu-positive and/or ER or PR-positive cases. Furthermore, using previously published mutation data, we found TP53 homozygously mutated in cell lines having aUPD in that locus. Conclusions/Significance: We conclude that aUPD is a common and non-random molecular feature of breast cancer that is most prominent in triple negative cases. As aUPD regions are different among the main pathological subtypes, specific aUPD regions may aid the sub-classification of breast cancer. In addition, we provide statistical support using TP53 as an example that identifying aUPD regions can be an effective approach in finding aberrant genes. We thus conclu

High quality copy number and genotype data from FFPE samples using Molecular Inversion Probe (MIP) microarrays

BACKGROUND:A major challenge facing DNA copy number (CN) studies of tumors is that most banked samples with extensive clinical follow-up information are Formalin-Fixed Paraffin Embedded (FFPE). DNA from FFPE samples generally underperforms or suffers high failure rates compared to fresh frozen samples because of DNA degradation and cross-linking during FFPE fixation and processing. As FFPE protocols may vary widely between labs and samples may be stored for decades at room temperature, an ideal FFPE CN technology should work on diverse sample sets. Molecular Inversion Probe (MIP) technology has been applied successfully to obtain high quality CN and genotype data from cell line and frozen tumor DNA. Since the MIP probes require only a small (~40 bp) target binding site, we reasoned they may be well suited to assess degraded FFPE DNA. We assessed CN with a MIP panel of 50,000 markers in 93 FFPE tumor samples from 7 diverse collections. For 38 FFPE samples from three collections we were also able to asses CN in matched fresh frozen tumor tissue.RESULTS:Using an input of 37 ng genomic DNA, we generated high quality CN data with MIP technology in 88% of FFPE samples from seven diverse collections. When matched fresh frozen tissue was available, the performance of FFPE DNA was comparable to that of DNA obtained from matched frozen tumor (genotype concordance averaged 99.9%), with only a modest loss in performance in FFPE.CONCLUSION:MIP technology can be used to generate high quality CN and genotype data in FFPE as well as fresh frozen samples.This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at [email protected]

Genomic sequencing in cancer

Genomic sequencing has provided critical insights into the etiology of both simple and complex diseases. The enormous reductions in cost for whole genome sequencing have allowed this technology to gain increasing use. Whole genome analysis has impacted research of complex diseases including cancer by allowing the systematic analysis of entire genomes in a single experiment, thereby facilitating the discovery of somatic and germline mutations, and identification of the function and impact of the insertions, deletions, and structural rearrangements, including translocations and inversions, in novel disease genes. Whole-genome sequencing can be used to provide the most comprehensive characterization of the cancer genome, the complexity of which we are only beginning to understand. Hence in this review, we focus on whole-genome sequencing in cancer