Cancer Genomics and Personalized Oncology. Dirce M Carraro, PhD Scien0st, Head of Genomics and Biology Molecular Group

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1 Cancer Genomics and Personalized Oncology Dirce M Carraro, PhD Scien0st, Head of Genomics and Biology Molecular Group

2 Cancer in Brazil 600,000 new cases/year Popula0on: 210,867,959 Number of new cases: 555,371 Number of Deaths: 243,588

3 Pa*ent Centered Care Personalized and integrated patient journey Navigation Tumor Board Research Educa*on

4 Interna0onal Research Center / AC Camargo Cancer Genomics Hereditary tumors Tumor Biology Personalized Oncology Genomics Meta-genomics Liquid Biopsy Gastric tumors Immunology Tumor Immunology Immunology of infec0ous diseases Tumor biology Tumor markers Cellular signaling Liquid biopsy (exosomes) Cancer Epidemiology Sta0s0cs Bioinforma0cs Data Analysis in Molecular Oncology Muta0onal Signatures Sta0s0cal Learning Gene0cs and Genomics Immuno-oncology Tumor Biology Epidemiology Bioinforma0cs

5 From Genomics to Personalized Oncology New era of Cancer Treatment Xylella fas)diosa s Genome Project Simpson AJ et al, Nature, 2000 Cancer Human Genome De Souza SJ et al, PNAS, 2000 Camargo AA et al, PNAS, 2001 Sogayar MC et al, Genome Research, 2004 Personalized Oncology

6 Evolu0onary Process of accumula0ng soma0c muta0ons ü Ac*va*on of Oncogenes ü Inac*va*on of tumor suppressor genes Heterogeneous Gene*c Disease Clinical Heterogeneity Personalized Oncology Sequencing

7 LGBM Clinical Se]ng Genetic Testing for risk Newest applica0on of genomics Precision Oncology Oncology Genomic tes0ng Liquid Biopsy for monitoring treatment Personalized Treatment Research Se]ng

8 Scien0fic Projects FUNDING: INCT_FAPESP/CNPq / FAPESP -2013/ FAPESP / INCT_FAPESP/CNPq / FAPESP / FAPESP / CEPID_FAPESP 2001 to 2013

9 Hereditary Cancer Project

10 Hereditary Syndromes of Predisposi0on to Cancer (HSPC) Mendelian disorders higher risk for developing tumors Loss of func0on muta0ons in known genes (gene panels) 10% with VUS Mul0-ins0tu0onal efforts 60% nega0ve Whole exome sequencing Breast and Ovarian More than 1,000 pa0ents suspected of HSPC 30% Lynch and FAP Melanoma 10% Gastric Li-Fraumeni 60% Mutados MUTATED Variantes VUS Sig Nega0ve Nega0vos Incerto Improvement in pa0ent and family management Functional analysis and segregation analysis Fron0ers in Gene0cs, 2018 Candidate selec*on Nega*ve Pa*ents WES 2 family members Genetic Counseling Valida*on Variants selec*on

11 Contribu0ons in different cancer predisposing syndromes Hereditary Breast and Ovarian Cancer (HBOC) Hereditary colorectal Cancer (Lynch and FAP/ MAP) Hereditary Melanoma Li-Fraumeni BREAST Palmero et al, Sci Rep Torrezan GT et al, Front Genet Brianese RC et al, Breast Cancer Res Tr Silva FC, Torrezan GT et al, Mol Genet Geno Med Villacis RA et al, Tumour Biol Silva FC et al, BMC Med Genet Silva AG et al, BMC Cancer Krepischi AC et al, Breast Cancer Res Peixoto A et al, Breast Cancer Res Treat Carraro DM et al, PLoS One pa6ents (200Research Projects) pa6ents (Clinical se@ng/diagnos6c Laboratory) BRCA1, BRCA2 and TP53 75% nega6ve 180 Lynch and 30 FAP/ MAP MLH1, MSH2, MSH6, PMS1 and PMS2 APC and MUTYH 60% nega6ve 70 pa6ents CDKN2a and CDK4 80% nega6ve ü ü ü ü ü R337H screening New muta0ons in known genes Frequency of muta0on in recently associated genes Clinical impact of VUS Phenotype and genotype correla0ons New candidate genes associated to Cancer Syndromes COLORECTAL Silva FC, et al, Am J Surg Pathol Villacis RA et al, Int J Cancer Carneiro da Silva F, et al PLoS One Dominguez M et al, Her Cancer Clin Pract Valentin MD et al, Anticancer Res Monteiro Santos EM et al BMC Cancer.2012 Valentin MD et al, Fam Cancer Dominguez MV et al, Int J Colorectal Dis Torrezan GT et al, Orphanet J Rare Dis Torrezan GT et al, BMC Med Genet Torrezan GT et al, BMC Med Genet MELANOMA Fidalgo F et al, Future Oncol Puig S et al, Genet Med De Araújo ÉS et al, Melanoma Res de Araújo É et al, Exp Mol Pathol de Ávila AL et al, Fam Cancer Fidalgo F et al, Exp Mol Pathol Silva AG et al, Am J Gastroenterol Rezze GG et al, Acta Derm Venereol LI-FRAUMENI Silva AG et al, Orphanet J Rare Dis Silva AG et al, Orphanet J Rare Dis. 2012

12 Tumor Biology and Liquid Biopsy

13 Wilms tumor Renal pediatric tumor Molecular and Genetic alterations involved with WT arising and progression Krepischi AC et al. Mol Cytogenet Torrezan GT, Ferreira EN, at al. Nat Commun Maschie_o M, et al. Cell Death Dis Maschie_o M, et al., Eur J Cancer Maschie_o M, et al., Oncology.2008 Definition of the complete mutational repertoire Gene Panel with genes mutated in WT Liquid Biopsy (circulating tumor DNA in plasma and urine) Specific marker of tumor Monitoring of therapy response Diagnosis Pioneer on the discovery of DROSHA recurrent muta0on and the defini0on of its mechanis0c actua0on in microrna repertoire 18-Gene Panel No mutation Diagnosis Neoadjuvant chemo Surgery Adjuvant Chemo Incorpora0on in gene panel New mutated Gene WES (en0re human gene content) Urine sediment Urine supernadant Plasma Urine Plasma Good Response - Favorable outcome DROSHA (p.e1147k) mutated in 10% of TW microrna biogenesis genes in 30% Sensi*vity Cost Poor Response - Unfavorable outcome

14 Triple Nega0ve Breast Cancer (TNBC) and BRCA1 muta0on in Young Women ü Heterogeneous Group of breast cancer - young women ü Aggressive and poor prognosis tumor ü BRCA1 loss of func*on - inac*vity of DNA repair mechanisms (Homologous recombina*on repair) High sensi*vity to DNA Damage therapy Hereditary BRCA1-mutated pa*ent (26%) BRCA1 impaired BRCA1 proficient Sporadic BRCA1- hypermethylated TNBC (29%) Sporadic TNBC BRCA1 proficient (45%) + BRCA1 impaired in 55% of TN in young women Clinical impact - Better survival Perspective: Better response to DNA damage chemotherapy and PARP inhibitor (Target Therapy approved for TN with BRCA1/2 mutation) Brianese R, et al Breast Cancer Res and Treat, 2018

15 Study design for monitoring therapy response Mo0va0on ü Resistance for chemotherapy or target therapy ü High level of toxicity TNBC BRCA or other HR-associated gene Pa0ents Enrolled At least 100 pa0ents for each tumor type ü Renal tumors ü Colorectal cancer ü Lung Cancer ü Melanoma ü Head and Neck and rare tumors Germline Soma0c Leucocyte DNA FFPE Tumor DNA Plasma cfdna GERMLINE variants ü Hereditary cancer predisposing genes ü Pharmacogenomics SNV associated to drug metabolism ü Ancestry SOMATIC variants ü TUMOR-specific muta*ons (acquired) ü TUMOR muta*on burden SOMATIC variants ü TUMOR-specific altera*ons ü Deep-amplicon Sequencing ü Other tumor markers (CpG methyla*on) Sample collec*ons: 1 st 2 nd 3 rd 4 th 5 th 6 th Tissue Biopsy TNBC diagnosis Chemotherapy or target therapy Surgery 3 months aker surgery 6 months aker surgery

16 Triple Nega0ve Breast Cancer Project Adamant05 38 yo at diagnosis Sporadic BRCA1 proficient Sample collec*ons: 1 st 2 nd 3 rd 4 th 5 th 6 th Tissue Biopsy TNBC diagnosis Anthracycline / Cyclophosphamide Taxane ± carbopla*n Surgery 3 months aker surgery 6 months aker surgery Neoadjuvant chemotherapy 33,00% SYNE1_c.6632G>C_p.Gly2211Ala NUP98_c.2608G>C_p.Asp870His SAMD9_c.3010A>G_p.Lys1004Glu TP53_c.1018delA_p.Met340Cysfs Residual Invasive Disease 3 rd 17,74% Surgery 11,16% 9,26% 5,66% 0,22% 1,72% 0,93% 0% 0% 0% 0,20% 0% 0% Tissue Biopsy 1. Plasma 2. Plasma 3. Plasma

17 Genomics and Molecular Biology - CIPE Researchers: -Adriana Miti Nakahata -Giovana Tardin Torrezan -Carolina Berra Scientific Technicians -Claudia A. A de Paula -Karina M. Santiago PosDocs and Researchers: -Vanessa Karen de Sá -Eliana Vanina Elias -Mariana Rezende -Pablo Nicola PhD candidates: -Isabella Tanus Job e Meira -Paulo Henrique Baldan Pineda -Rafael Canfield Brianese -Kivvi Duarte de M. Nakamura -Sara Iolanda Oliveira da Silva Master candidates: -Ana Carolina K. Miguez -Nathália de Angelis de Carvalho Undergraduate students: -Bianca Naomi Niitsuma -Ana Carolina de Araújo

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