DirceMCarraro,PhDScien0st,HeadofGenomicsandBiologyMolecularGroup

CancerGenomicsandPersonalizedOncology

CancerinBrazil–600,000newcases/year

Popula0on: 210,867,959Numberofnewcases:555,371NumberofDeaths:243,588

Personalized and integrated patient journey

Navigation

Tumor Board

Research

Pa*entCenteredCare

Educa*on

Interna0onalResearchCenter/ACCamargo

CancerGenomics

Hereditarytumors

TumorBiology

PersonalizedOncology

Genomics

Meta-genomics

LiquidBiopsy

Gastrictumors

Immunology

TumorImmunology

Immunologyof

infec0ousdiseases

Tumorbiology

Tumormarkers

Cellularsignaling

Liquidbiopsy(exosomes)

CancerEpidemiology

Sta0s0cs

Bioinforma0cs

DataAnalysisinMolecularOncology

Muta0onalSignatures

Sta0s0calLearning

Gene0csandGenomics Immuno-oncologyTumorBiologyEpidemiologyBioinforma0cs

FromGenomicstoPersonalizedOncology

Xylellafas)diosa’sGenomeProject

SimpsonAJetal,Nature,2000

CancerHumanGenome

DeSouzaSJetal,PNAS,2000CamargoAAetal,PNAS,2001SogayarMCetal,Genome

Research,2004

PersonalizedOncology

NeweraofCancer

Treatment

HeterogeneousGene*cDisease

ClinicalHeterogeneity

PersonalizedOncology

Evolu0onaryProcessofaccumula0ngsoma0cmuta0ons

ü  Ac*va*onofOncogenesü  Inac*va*onoftumorsuppressorgenes

Sequencing

Newestapplica0onofgenomics

OncologyGenomictes0ng

PersonalizedTreatment

Genetic Testing for risk

Precision Oncology

Liquid Biopsy for monitoring treatment

ClinicalSe]ng

LGBM

ResearchSe]ng

Scien0ficProjects

FUNDING:

INCT_FAPESP/CNPq-2014/50943-1FAPESP-2013/23277-8FAPESP-2010/00223-1

INCT_FAPESP/CNPq - 2008/57887-9FAPESP-2006/00054-0FAPESP-2005/05155-6

CEPID_FAPESP – 2001 to 2013

Hereditary Cancer Project

30%10%

60%

Mutados VariantesSigIncerto

Nega0vos

HereditarySyndromesofPredisposi0ontoCancer(HSPC)Mendeliandisorders–higherriskfordevelopingtumors

Lossoffunc0onmuta0onsinknowngenes(genepanels)

Morethan1,000pa0entssuspectedofHSPC

60%nega0ve

Fron0ersinGene0cs,2018

MUTATEDVUSNega0ve

Mul0-ins0tu0onalefforts

BreastandOvarian

LynchandFAP Melanoma Gastric

Li-Fraumeni

Improvementinpa0entandfamilymanagement

Genetic Counseling

10%withVUS

Functional analysis and segregation analysis

Wholeexomesequencing

Nega*vePa*ents

WES2familymembers

Variantsselec*onValida*on

Candidateselec*on

Contribu0onsindifferentcancerpredisposingsyndromes

HereditaryBreastandOvarian

Cancer(HBOC)

900pa6ents(200ResearchProjects)+700pa6ents(Clinicalse@ng/Diagnos6c

Laboratory)

BRCA1,BRCA2andTP53

75%nega6ve

HereditarycolorectalCancer(LynchandFAP/

MAP)

180Lynchand30FAP/MAP

MLH1,MSH2,MSH6,PMS1andPMS2

APCandMUTYH

60%nega6ve

HereditaryMelanoma

70pa6ents

CDKN2aandCDK4

80%nega6ve

Li-Fraumeni

R337Hscreening

BREAST Palmero et al, Sci Rep. 2018

Torrezan GT et al, Front Genet. 2018 Brianese RC et al, Breast Cancer Res Tr. 2017

Silva FC, Torrezan GT et al, Mol Genet Geno Med. 2017 Villacis RA et al, Tumour Biol. 2016

Silva FC et al, BMC Med Genet. 2014 Silva AG et al, BMC Cancer. 2012

Krepischi AC et al, Breast Cancer Res. 2012 Peixoto A et al, Breast Cancer Res Treat. 2011

Carraro DM et al, PLoS One. 2013

COLORECTAL Silva FC, et al, Am J Surg Pathol. 2017

Villacis RA et al, Int J Cancer. 2016 Carneiro da Silva F, et al PLoS One. 2015

Dominguez M et al, Her Cancer Clin Pract. 2013 Valentin MD et al, Anticancer Res. 2012

Monteiro Santos EM et al BMC Cancer.2012 Valentin MD et al, Fam Cancer. 2011

Dominguez MV et al, Int J Colorectal Dis. 2008 Torrezan GT et al, Orphanet J Rare Dis. 2013

Torrezan GT et al, BMC Med Genet. 2012 Torrezan GT et al, BMC Med Genet. 2011

MELANOMA

Fidalgo F et al, Future Oncol. 2016 Puig S et al, Genet Med. 2016

De Araújo ÉS et al, Melanoma Res. 2015 de Araújo É et al, Exp Mol Pathol. 2014

de Ávila AL et al, Fam Cancer. 2014 Fidalgo F et al, Exp Mol Pathol. 2014

Silva AG et al, Am J Gastroenterol. 2013 Rezze GG et al, Acta Derm Venereol. 2012

LI-FRAUMENI

Silva AG et al, Orphanet J Rare Dis. 2014 Silva AG et al, Orphanet J Rare Dis. 2012

ü  Newmuta0onsinknowngenes

ü  Frequencyofmuta0oninrecentlyassociatedgenes

ü  ClinicalimpactofVUSü  Phenotypeandgenotype

correla0onsü  Newcandidategenes

associatedtoCancerSyndromes

Tumor Biology and Liquid Biopsy

Wilmstumor–RenalpediatrictumorMolecular and Genetic alterations

involved with WT arising and progression

DROSHA(p.E1147K)mutatedin10%ofTWmicroRNAbiogenesisgenesin30%

↑Sensi*vity

↓Cost

Definition of the complete mutational repertoire

•  GenePanelwithgenesmutatedinWT

18-GenePanel

WES(en0rehumangenecontent)

Incorpora0oningenepanel

Urine sediment Urine supernadant Plasma

UrinePlasma

Good Response - Favorable outcome

Liquid Biopsy (circulating tumor DNA in plasma and urine)

•  Specific marker of tumor

Diagnosis Neoadjuvantchemo Surgery AdjuvantChemo

No mutation

§  Monitoringoftherapyresponse§  Diagnosis

Poor Response - Unfavorable outcome

KrepischiACetal.MolCytogenet.2016TorrezanGT,FerreiraEN,atal.NatCommun.2014Maschie_oM,etal.CellDeathDis.2011Maschie_oM,etal.,EurJCancer.2011Maschie_oM,etal.,Oncology.2008

•  PioneeronthediscoveryofDROSHArecurrentmuta0onand the defini0on of its mechanis0c actua0on inmicroRNArepertoire

New mutated Gene

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)

TripleNega0veBreastCancer(TNBC)andBRCA1muta0oninYoungWomen

HereditaryBRCA1-mutatedpa*ent(26%)

SporadicBRCA1-hypermethylatedTNBC(29%)

SporadicTNBCBRCA1proficient(45%)

BrianeseR,etalBreastCancerResandTreat,2018

BRCA1impairedBRCA1proficient

+

ü  HeterogeneousGroupofbreastcancer-youngwomenü  Aggressiveandpoorprognosistumorü  BRCA1lossoffunc*on-inac*vityofDNArepairmechanisms(Homologousrecombina*onrepair)–Highsensi*vitytoDNADamagetherapy

Soma0cGermline

TNBCBRCAorotherHR-associatedgene

ü  Renaltumorsü  Colorectalcancerü  LungCancerü  Melanomaü  HeadandNeckandraretumors

LeucocyteDNA FFPETumorDNA PlasmacfDNA

GERMLINEvariantsü Hereditarycancerpredisposinggenesü Pharmacogenomics–SNVassociatedtodrugmetabolismü Ancestry

SOMATICvariants

ü  TUMOR-specificmuta*ons(acquired)ü  TUMORmuta*onburden

SOMATICvariants

ü  TUMOR-specificaltera*onsü  Deep-ampliconSequencingü  Othertumormarkers(CpGmethyla*on)

Pa0entsEnrolled

Atleast100pa0entsforeachtumor

type

Samplecollec*ons:

TissueBiopsyTNBCdiagnosis Chemotherapyortargettherapy Surgery 3monthsakersurgery 6monthsakersurgery

1st 2nd 3rd 5th 6th4th

StudydesignformonitoringtherapyresponseMo0va0onü  Resistancefor

chemotherapyortargettherapy

ü  Highleveloftoxicity

11,16%

0,20% 0% 0%

9,26%

0,93% 0% 0%

5,66% 0,22%0%

0%

33,00%

17,74%

0%1,72%

TissueBiopsy 1.Plasma 2.Plasma 3.Plasma

SYNE1_c.6632G>C_p.Gly2211Ala SAMD9_c.3010A>G_p.Lys1004Glu

NUP98_c.2608G>C_p.Asp870His TP53_c.1018delA_p.Met340Cysfs

Samplecollec*ons:

TissueBiopsyTNBCdiagnosis Taxane±carbopla*nAnthracycline/

Cyclophosphamide Surgery 3monthsakersurgery 6monthsakersurgery

1st

Neoadjuvantchemotherapy

2nd 3rd 5th 6th4th

TripleNega0veBreastCancerProjectAdamant05–38yoatdiagnosis–SporadicBRCA1proficient

Surgery

3rd

ResidualInvasiveDisease

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

GenomicsandMolecularBiology-CIPE

www.accamargo.org.br