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Cancer Biomarkers )( Diagnosis, Treatment, Disease managements Personalized Medicine فروزنده محجوبی متخصص سیتوژنتیک مولکولی پزشکی دانشیار پژوهشگاه ملی مهندسی ژنتیک مدیر عامل بنیاد ژنتیک آزمایشگاه ژنتیک پزشکی سالله Iran? Same and different story A cancer patient knows he/she has cancer An apparently healthy person doesn’t have cancer yet (screening?/Early detection) Cancer therapy: Surgery Chemotherapy Radiotherapy Immunotherapy etc Cancer therapy 1) Success rate (survivor rate) 2) Side effect 3) Cost The best survivor rate so far in USA Side effects Side effect: Bone density loss Cardiotoxicity (Heart damage) Cognitive (mental) deficits( chemo brain) Distress Fatigue Infertility Pain Pulmonary (lung) dysfunction Drug resistance Cost Cost in Iran for breast cancer معاون درمان وزیر بهداشت: ساالنه در ایران ساالنه بطور مستقیم و غیرمستقیم ،هشت هزارو 500میلیارد تومان صرف هزینه های درمانی سرطان می شود. معاون درمان وزیربهداشت: سرطان سومین علت مرگ و میر در کشور به شمار می رود و یک دوم مرگ های ناش ی ازسرطان با تشخیص به موقع و درمان مناسب قابل پیشگیری است. Cost of care Even the USA can't afford treating 100% to benefit 20% Summary: High incidence Medium/low survival rate Very costly Very bad side effects Biomarkers and Personalized medicine Surgeons /Clinicians Pathologists Oncologist Old Paradigm: Personalized medicine or Precision medicine Precision medicine implies that diseases are defined by underlying molecular mechanisms rather than traditional signs and symptoms. Lancet 378 : 1678, 2011 Toward precision medicine US National Research Council, nov 2011 New Paradigm: Cancer and genetics All cancers are caused by genetic changes 507 patients were subjected to whole-exome sequencing, identifying 30,626 somatic mutations : Average 60 mutations in each breast tumor But only small proportion of cancers are hereditary About 5% to 10% of breast cancers are thought to be hereditary: Meaning? The genetic nature of each tumor may be unique Definition Mutations: a) Pathogenic b) Polymorphism, normal Variant, SNP A frameshift mutation : original In contrast, any insertion or deletion that is evenly divisible by three is termed an in-frame mutation A nonsense mutation : premature stop codon, or a nonsense codon in the transcribed mRNA, and possibly a truncated, and often nonfunctional protein product Missense mutations or nonsynonymous mutations: are types of point mutations substitution of a different amino acid. different translation from the A neutral mutation : results in the use of a different, but chemically similar, amino acid. Silent mutations : do not result in a change to the amino acid sequence of a protein, Different types of SNP Outside genes : no impact In the genes coding sequence : change of base but not of amino acid (cf redundancy of genetic code : GCA et GCC both code for alanine) change of amino acid : more or less impressive modification of function (loss or gain) In the promoter region : or transcription of the gene and protein expression In the mRNA 3’-untranslated region : (or ) sensitivity to miRNA (that inhibit translation and destabilize mRNA). SNP and Personalized Medicine: A particular SNP is more /less frequent in the affected population SNP A SNP B Investigation of C1236T polymorphism in MDR1 gene in children with acute lymphoblastic leukemia F. Mahjoubi et al (AMUJ) 2013; 16(79): 76- 83 SNP and Personalized Medicine: A particular SNP changes the affected response to drug in the Effect of MDR1 polymorphism on multidrug resistance expression in breast cancer patients. Mahjoubi F et al Genet Mol Res. 2010 Jan 12;9(1):34-40 Study of the Possible Correlation between MRP1 Gene Polymorphisms (C2217T, G2168A,T825C, G816A, G1299, G-260C, A-275G, G2268A) and its mRNA Expression in Acute Leukemic Patients with MDR Phenotype Mahjoubi et al SID (2001) Vol (24);1-9 Analysis of VKORC1 and CYP2C9 reveal variable warfarin dose response Needs low-dose Needs high-dose Variants at these two genes account for ~60% of variability in therapeutic dose Prospective trials now underway FDA has added information about genetics to label Slow P450 metabolizers Rieder, M. et al. NEJM 352: 2285-2293, 2005 CYP2C19*2 Polymorphism is Associated with Increased Survival in Breast Cancer Patients Using Tamoxifen Rikje Pharmacogenomics. 2010;11(10):1367- 1375 Definition (con) Epigenetics: Changes in gene expression (active versus inactive genes) that does not involve changes to the underlying DNA sequence Epigenetic can make a gene on ( eg oncogene) or off ( eg tumor-supressor gene) Gene expression Gene Expression: Gene product. Gene Expression up/ down : cancer / changes in survival/ changes in response Personalized medicine Hippocrates: it is far more important to know what person the disease has than what disease the person has National Institutes of Health (NIH), personalized medicine is "an emerging practice of medicine that uses an individual's genetic profile to guide decisions made in regard to the prevention, diagnosis, and treatment of disease". FDA "the best medical outcomes by choosing treatments that work well with a person's genomic profile or with certain characteristics in the person's blood proteins or cell surface proteins". Personalized medicine does not literally mean individuality. “ "Medicine Tailored Just for You." Personalized medicine is "the ability to classify individuals into subpopulations that differ in their susceptibility to a particular disease or their response to a specific treatment" Biomarkers Surgeons /Clinicians Pathologists Oncologist Biomarkers • Molecules or genes found in the body that can provide important information about a disease • FDA definition • A characteristic that is measured as an indicator of normal biology or disease or drug response Types of Biomarkers Biomarkers for: Screening Diagnostic/early detection Staging Prognosis Predication of response to therapy Susceptibility to cancer Personalized medicine Is it a new era ?!!1 New era of personalized medicine: targeting drugs for each unique genetic profile Imatinib (INN) or Gleevec (is a tyrosine-kinase inhibitor used in the treatment of multiple cancers, most notably Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia Personalized medicine New era in personalized medicine: targeting drugs for each unique genetic profile Personalized Medicine Give cancer patients the treatments that are most likely to work on their particular cancer with fewer harmful side effects. Today, many patients have treatment options based on the particular markers in their tumors. These patients can get better, more specific treatments, which might also have fewer side effects. Personalized Medicine in Iran Our goal??? Finding biomarkers suitable for Iranian population with specificity and sensitivity with the cost affordable for our nation (focus on breast cancer & CRC) Over 50 genes (expression study) Plz refer to published papers by F.Mahjoubi et al. Biomarker discovery begins by collecting molecular data in in vitro experiments and then patients Step 1 Data collection Step 2 Quality control Step 3 Step 4 Step 5 Identification of candidate biomarkers Construction od prediction model Independent validation of prediction Preventative BRCA1 (Breast Cancer 1) BRCA2 (Breast Cancer 2) TP53 gene ATM gene etc.. Diagnosis & Early biomarkers detection Prognostic biomarkers Response to therapy Some Genes Which Have Been Studing In CRC Cancer By Our Team M. Golalipour. F. Mahjoubi, * M Sanati, K. Alimogaddam. Gene dosage is not responsible for the upregulation of MRP1 gene expression in adult leukemia patients. Arc Med Res (2007). Apr;38(3):297-304 M. Golalipour. F. Mahjoubi*, M Sanati. RNAi induced inhibition of MRP1 expression and reversal of drug resistance in human promyelocytic HL60 cell line. Iranian Journal of Biotechnology (2007). 38(3):297-304 Akbari S, Mahjoubi F*, Monatzeri M, Nazari Sh, Elahi, E. Comparison between the expression of MRP1 in pediatric leukemic patients with different response to chemotherapy. J of Genetic Novin (2007) , 2; 67-73 Frouzandeh Mahjoubi*, Masoud Golalipour, Kamran Alimoghaddam. Expression of MRP1 gene in acute leukemias. Sao Paolo Med J (2008) 126 ; 172-179 Frouzandeh Mahjoubi*, Masoud Golalipour, Kamran Alimoghaddam. Expression of MRP1 gene in acute leukemias. Sao Paolo Med J (2008) 126 ; 172-179 Frouzandeh Mahjoubi*, Soodeh Akbari, Maryam Montazeree, Farzaneh Moshyree. MRP1 polymorphisms (T2684C, C2007T, C2012T and C2665T) are not associated with multidrug resistance in leukemic patients. Journal of Medical Research (2008);7(4):1369-74 Rezvani S, Montazeri M, Mahjoubi F*. Study of the effect the of MRP1 gene polymorphisms on its mRNA expression in acute leukemic patients. Journal of Zystshenasy (2001) Vol (24);1-9 M Tahery, F. Mahjoubi*, R Omranipour, F Feraidony. Investigation of MDR1 C3435T polymorphism in Patients with breast cancer. Tabeeb Sharg (2009) Vol 11 ;9-17 Taheri M, Mahjoubi F*, Omranipour R. The effect of MDR1 polymorphism on its expression in Breast Cancer Patients. Journal of Medical Research. Genet Mol Res. (2010 ) 12;9(1):34-40 Sara Samanian, Bahar Mahjoubi, Frouzandeh Mahjoubi*, Rezvan Mirzaee, Rasool Azizi. Association between MDR1 and MRP1 expression levels and clinicopathology markers in colorectal patients. Zahedan Journal of Medical Research,(2012) 15 (7):31-34 S. Samanian, F. Mahjoubi. Genotype and allele frequencies of MDR1 gene C3435T and C1236T polymorphisms in an Iranian population. Journal of Genetic Novin (2012) 3:221-226 Mahjoubi F, Akbari S. Multidrug resistance-associated protein 1 predicts relapse in Iranian childhood acute lymphoblastic leukemia.Asian Pac J Cancer Prev. (2012);13(5):2285-9 Mohsen Taheri, Frouzandeh Mahjoubi.MRP1 but not MDR1 is associated with response to neoadjuvant chemotherapy in breast cancer patients. Journal of Disease Marker (2013) 34 : 387– 393 M Mirakhorli, Sabariah Abdulrahman * Syahrilnizam Abdullah, Masoud Vakili, Ahad Khoshzaban, Frouzandeh Mahjoubi. Multidrug resistance protein genetic polymorphism colorectal cancer recurrence in patients receiving adjuvant FOLFOX-4 chemotherapy. Molecular Medicine Reports (2013) 7: 613-617 Ramyar Molania, Frouzandeh Mahjoubi*,Rezvan Mirzaei, Saeed-Reza khatami, Bahar Mahjoubi. A panel of cancer testis antigens (CTA) and clinical risk factors to predict metastasis in colorectal cancer. Journal of Biomarkers (2014) 1 : 1- N Mokhberian N, F Mahjoubi, R Pourahmad . Investigation of G2677T/A polymorphism in MDR1 gene of childhood acute lymphoblastic leukemia Sci J Iran Blood Transfus Organ (2014) 11(2): 103-109 Samira Shabani, Frouzandeh Mahjoubi, Bahar Mahjoubi, Rezvan Mirzaee. Investigation of hTERT expression level and its relation with clinicopathological features and resistance to chemotherapy in colorectal cancer patients. Journal of Pharmaceutical Sciences (2014) Samira shabani, Sara Samanian, Rezvan Mirzaei, Bahar Mahjoubi, Frouzandeh Mahjoubi. Correlation among MDR1, MRP and hTERT Genes Expression Level and Clinical Response in Colorectal Cancer Patients. J Mol Biomark Diagn 2014, 3-:5 Personalized medicine 2016US budget: $215 million For NIH Thank You prognostic" and "predictive A prognostic biomarker is related with a patient's clinical outcome A predictive biomarker is related to the patient's response to a particular intervention. In other words, a predictive biomarker enables screening of a subset of patients that are responsive to a specific therapy Preventative BRCA1 (Breast Cancer 1) BRCA2 (Breast Cancer 2) TP53 gene ATM gene etc.. Predictive Genetically defined subgroups of patients Oncotype DX® who would benefit from a specific therapy Prognosis median survival: 4 yrs with conventional therapy (hydroxyurea, busulfan), 6 yrs with aIFN therapy; allogeneic bone marrow transplantation may cure the patient; otherwise, the best treatment to date associates interferon a, hydroxyurea and cytarabine prognostic" and "predictive A prognostic biomarker is related with a patient's clinical outcome . In other words, a predictive biomarker enables screening of a subset of patients that are responsive to a specific therapy A predictive biomarker is related to the patient's response to a particular intervention Adjuvant systemic treatment Nodal status [ Tumor size Tumor type/grade Lymphatic and vascular invasion Tumor hormone receptor (HER2)/neu status Age ethnicity [29-31]. Numerous proteins and genes exist that are specifically associated with breast cancer growth, proliferation, and metastasis. Preventative BRCA1 (Breast Cancer 1) BRCA2 (Breast Cancer 2) TP53 gene ATM gene Pte.. Predictive Genetically defined subgroups of patients Oncotype DX® who would benefit from a specific therapy Participatory patients will be more likely and willing to comply with their treatments. خودت این اسالید را درست کن و نشان بده که ما در مرحله 3هستیم “A surgeon who uses the wrong side of the scalpel cuts her own fingers and not the patient; if the same applied to drugs they would have been investigated very carefully a long time ago” Personalized Medicines Are Benefitting Patients Across Many Different Diseases Oncology is on the Leading Edge of Personalized Medicine Iran Age-standardized incidence rate of all cancers per 100 000 in male in Iran 2005–2006. S. M. Mousavi et al. Ann Oncol 2008;20:556-563 © The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected] Age-standardized incidence rate of all cancers per 100 000 in female in Iran 2005–2006. S. M. Mousavi et al. Ann Oncol 2008;20:556-563 © The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected] The age-standardized incidence rate of cancer per 100 000 population in female and male in 2003–2006. S. M. Mousavi et al. Ann Oncol 2008;20:556-563 © The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected] Pharmacogenomic examples-2011 • • • • • • • • • • • bcr/abl or 9:22 translocation—imatinib mesylate* HER2-neu—trastuzumab** C-kit mutations—imatinib mesylate** Epidermal growth factor receptor mutations—gefitinib Thiopurine S-methyltransferase—mercaptopurine and azathioprine* UGT1A1-irinotecan** CYP2D9/VKORC1-warfarin* HLA-B*5701-abacavir * HLA-B*1502-carbamazepine * CYP2C19-clopidogrel Cytochrome P-450 (CYP) 2D6—5-HT3 receptor antagonists, antidepressants, ADHD drugs, and codeine derivatives, tamoxifen*