1. Genomic instability Genomic instability is a prominent characteristic of most cancer types that has an essential role in tumorigenesis by accelerating the accumulation of genetic changes that are responsible for cancer cell evolution

2. Chromosome Organization 3. LINEs (Long Interspersed Nuclear Elements)LINE-1 SINEs (Short Interspersed Nuclear Elements)Alu Segmental duplications are large blocks of the genome (1000 200,000 nucleotide pairs) that are present at 2 or more locations in the genome Simple sequence repeats : short Tandem Repeats (STR) that are repeating sequences of 2-6 bp of DNA . microsatellite DNA for long stretches (arises by unequal crossovers during recombination ) Microsatellite Transposons are all mobile genetic elements that have multiplied in our genome by replicating themselves and inserting new copies in different positions 4. Main pathways implicated in genomic instability Base and nucleotide excision repairExcise & Repair abnormal bases or nucleotides, such as UV radiationinduced pyrimidine dimers* mutations in components of these pathways : predispose people to skin cancers 5. Mismatch repair (MMR)during DNA replication* Loss of function of MSH2 and MLH1, which are required for mismatch repair, results in hypermutation and microsatellite instability 6. Colorectal cancer (CRC) Microsatellite instability (MSI) system MSI in colorectal cancers (CRC)deficient mismatch repair silencing of MLH1Additional mutations accumulateColorectal Cancer: Tumor cells with almost normal karyotype 7. DNA replicationDeregulated DNA replication* Deregulation can occur through oncogene activation , loss of certain tumour suppressors, DNA polymerase inhibition , replication stress 8. Chromosome segregation Defects in chromosome segregation : defects in the mitotic checkpoint , sister chromatid cohesion , spindle geometry and spindle dynamicsAberrant chromosome-spindle attachmentsmissegregation of chromatidsAneuploid 9. Double-strand break repair (DSBR)Homologous recombination repair of double-strand breaks (DSBs) uses the sister DNA molecule as a template to repair the breakimportant for repair of stalled or collapsed replication forks 10. HR 11. Ataxia-telangiectasia (A-T) autosomal mutations in the ATM gene at gene map locus 11q23 ATM is activated in response to double-strand DNA breaksIt has a central role in a network of proteins that regulate cellular responses to DNA damage and recombination 12. NF1 Autosomal dominant 17q11.2 Frequency 1:3500 skeletal deformities Predisposition to tumors of nervous system The mutations are deletions, insertions( Alu ) , base substitutions translocation involving the long arm of chromosome 17 with breakpoints at 17q11.2 and CpG islands 13. Bloom Syndrome (BLM) BLM gene 15q26.1 is a ReqQ helicase involved in DNA replication and repairHelicase deficiency SCE frequency increased (shows increased chromosome breaks) genomic instability The hallmark is a tenfold increase in the spontaneous rate of sister chromatid exchanges Breaks in one or both chromatids and exchanges between homologous chromosomes occur in about 12% of metaphase cells Mainly protein-truncating nonsense mutations are distributed fairly evenly along the gene but some missense mutations exist. 14. Telomers Protect chromosome from degradation Regulate telomerase activity at chromosome ends Essential for chromosome stability 15. Formed by tandem repeats of TTAGGG sequence Bounded by a specialized six-proteins complex known as shelterin Elongated by telomerase 16. Telomere dysfunction and genomic instability One of the important source of genomic instability is telomere shorteningdeficient of telomerasedeficient of shelterin proteinsloss of the telomere protective structure 17. The molecular mechanisms that related to telomere defects 18. TPE & FSHD telomere position effects (TPE) could change gene expression at intermediate telomere lengths in cultured human cells.facioscapulohumeral muscular dystrophy (FSHD) FSHD is a late-onset disease genetically residing only 2560 kilobases from the end of chromosome 4q DUX4, the primary candidate for FSHD pathogenesis, is upregulated over tenfold in FSHD 19. Ring chromosome 1. Two DNA breaks, one in each arm of the same chromosome followed by fusion of the proximal broken ends2. By fusion of dysfunctional telomeres (end-terminal part) from the same chromosome 20. In R20 a little piece of genetic material is missing from each end of one of the number 20 chromosomes and the ends fuse together to form a ring The first symptom of R20 is usually epilepsy and can start at any time from day one of life until 17 yearsNormal chromosome 20 and ring chromosome 20 in an heterozygote patient 21. Thanks For Your AttentionE-mail : reza_sahebi2001@yahoo.com