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Concepts Change on genomic level- DNA sequence Evolutionary process Cell clone Additional genomic processes diversify the population Environmental effectors Immunology Angiogenesis Tissue response

Changes on DNA level are involved and define cancer Cancer can be caused by environmental factors: Chemicals Physical exposures Biological metabolites Viruses (Hep. viruses, papilloma V ) Cellular intrinsic changes and mishaps Point mut, translocations, LOH… SOLID VS. NON-SOLID TUMORS Carcinoma-Epithelial, Sarcoma- Muscle Glioma- Glia (neuron supporting cells) Leukemia Lymphoma

Staging and grading I- differentiated tissue, markers IV- No differentiation markers, marked invasiveness Stage 1-4: involvement of other tissues usually with Lymph nodes (Stage 3- invasiveness) Neoplasia: Cell growth, increased proportion of cell divisions, differentiation--------- malignant NEOPLASMS Benign growth--- Tumor, Angiogenesis, metastasis

The process is exhibited through the development

Cancer Causing genes Oncogenes: GOF, dominant, de-novo (cell signaling to cycling) Tumor suppressors: LOF, both alleles, de-novo/inherited, 2hit? Maintenance/ metabolic functions/cellular communication Reduced DNA repair, increased metabolism, reduced contact Founder mutation Driver Mutations- give advantage to the cell, evidence that implicate them with the cancerous process Gate Keeper Genes Passenger Mutations- no proof for functionality or contribution Clonallity and heterogeneity Signature: typical transcriptome, mutated genes, proteome

Current tumor mutational evolution is very simplistic Current tumor mutational evolution is very simplistic. The one above asses diversity in the cell population without the genomic landscape. Do subgroups always contain the mutational history of their evolution? Analysis methods/ importance?

The most prevalent gene Why more than one gene

AML as an example

Mutation burden and cancer incidence. Mutation burden and cancer incidence. (A) Comparison of the mean number of non-coding mutations per genome in tumours of different tissues (raw data from Lawrence et al., 2013). Error bars show the standard error of the mean. (B) UK annual incidence of various malignancies [Cancer Registry Statistics, 2011; (www.ons.gov.uk) and the Cancer Research UK website (www.cancerresearchuk.org/cancer-info/cancerstats/)]. An asterisk (*) signifies that the incidence data refer to the tissue of origin, rather than the specific cancer subtype shown in A (e.g. lung cancer rather than lung squamous cell or adenocarcinoma). CLL, chronic lymphocytic leukaemia; DLBCL, diffuse large B-cell lymphoma. Carolyn S. Grove, and George S. Vassiliou Dis. Model. Mech. 2014;7:941-951

Open q. Why certain tissues are more prone to tumor- genesis? Why certain people are more prone to tumor- genesis? Are certain cells/ genes/tissues chronological ages more prone to tumor- genesis? ? Half of the coding driver mutations occur outside of known cancer genes