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EPIDEMIOLOGY OF CHILDHOOD AML IN EPIDEMIOLOGY OF CHILDHOOD AML IN BRAZILBRAZIL
Maria S.Pombo de Oliveira M.D., PH.DMaria S.Pombo de Oliveira M.D., PH.DPEDIATRIC HEMATOLOGY-ONCOLOGY PEDIATRIC HEMATOLOGY-ONCOLOGY
PROGRAPROGRAM
[email protected]@inca.gov.br
Maria S.Pombo de Oliveira M.D., PH.DMaria S.Pombo de Oliveira M.D., PH.DPEDIATRIC HEMATOLOGY-ONCOLOGY PEDIATRIC HEMATOLOGY-ONCOLOGY
PROGRAPROGRAM
[email protected]@inca.gov.br
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ACUTE MYELOID LEUKEMIAACUTE MYELOID LEUKEMIA
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CHILDHOOD AMLCHILDHOOD AML
• AML are hetereogenous diseases with respect to phenotype, genetic and clinical outcome; Accounts for ~16% in ≤15yrs of age;
• Somatic mutation in genes involved in different aspects of their pathogenesis;
• Type-I and Type-II aberrations confer impact on prognosis and guide the stratification of pediatric AML;
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pro-B ALL, AMLMLL/AF4, ENL, AF9,AF6, ELL; GATA-1 mutHox11L2NUP98MYST3/CREBP
Bcp-ALLBcp-ALL
ETV6-RUNX1+ ETV6-RUNX1+ E2A/PBX1, E2A/PBX1, HYPERDIPLOID,HYPERDIPLOID,iAMP21iAMP21
T-ALL, AML
SIL/TAL1, NOTCH1, HOX11l2, BCR/ABL, AML1/ETO, others
AGE AGE AND AND LEUKEMIA BIOMARKERS LEUKEMIA BIOMARKERS
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AML-EPIDEMIOLOGYAML-EPIDEMIOLOGY
Average incidence rate of AML, adjusted by age* and sex Average incidence rate of AML, adjusted by age* and sex (in 1.000.000), PBCR, Brazil, 1998-2009.(in 1.000.000), PBCR, Brazil, 1998-2009.
1- Does the distribution of pediatric AML vary among “ethnic” groups?
2- Does the frequency of specific subtypes of AML vary in distinct geographical population?
3- The interaction between host susceptibility genetic factors and environmental carcinogenic factors should be unveiled?
Marceli Santos
In 9 out of 16 PBCRs demonstrated regional differences regarding the incidence of AML in Brazil (13.3-24.5 per million children); period 1995-2009
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ANALYSIS OF MOLECULAR ABERRATIONS OF PEDIATRIC AML, BRAZIL, 2001-10
Francianne AndradeHEMO2012Abstract#359
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LESSONS FROM BACKTRACKING LESSONS FROM BACKTRACKING dry blood spotdry blood spot
9-months-old Brazilian boy; WBC 318.730/µL and AML-M4 morphology; Cytogenetics: 46,XY t(2;11)(q31;p15)[26].
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AML OCCUR IN UTERO ?AML OCCUR IN UTERO ?
• Evidences from molecular studies that malignat clones arise in utero (MLL-r, RUNX-RUNT1; CBFb-MYH11);
• For some subtype of AML the time-frame latency for clinical onset is very short (e.g., congenital AML, infant AML with fusion-genes);
• It is possible to design epidemiological studies to test exposures to environmental agents that have a biological nature similar with some chemotherapeutics properties;
• Consistent results associations with benzene and pesticides exposures;• Foetus is vulnerable to toxic effects of maternal intakes and
environmental compounds throughout placental barriers.
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PESTICIDES ever EXPOSED PESTICIDES ever EXPOSED along pregnancyalong pregnancy
ALL ≤12 mo =adj. OR, 2.10, 95% CI, 1.14-3.86; ≥13-23 months, adj.OR= 1.88, 95% C.I, 1.05-5.23.
AML =adj. OR,5.01, 95% C.I, 1.97-12.7 (all ages ≤24 mo.);
MLL-r= OR, 2.91, 95% C.I. 1.40-6.07
PREGNANCY EXPOSURES AND EARLY AGE PREGNANCY EXPOSURES AND EARLY AGE CHILDHOOD LEUKEMIACHILDHOOD LEUKEMIA
Pyrethroids exposure revealed an OR, 2.18 , 95% CI, 1.44 -3.29;Other pesticides showed an OR,3.61, 95% CI, 1.69-7.73;Household pesticides showed an adjusted OR, 2.25, 95% CI 1.48-3.43;Agriculture pesticides exposure showed an adjusted OR, 9.26, 95% CI, 2.82 -30.4.
Jeniffer D. Ferreira, Arnaldo C. Couto, Maria S. Pombo de Oliveira, Sergio Koifman, Brazilian Collaborative Study Group of Infant Acute Leukemia, Env.Health Perspect, Oct 2012.
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* OR adjusted by use of oral contraceptives during pregnancy, mother’s educational level; birth weight and skin color ;** 3 months before pregnancy; *** 3 months after delivery
PESTICIDE EXP.CASES N(%)
CONT. N (%)
AML OR (IC95%)
OR AJD*
no 138 (54.8) 316 (74.7) 1.00 1.00
yes 114 (45.2) 107 (25.3) 3.50 (2.01-6.11) 3.23 (1.74-5.99)
Periconceptional**
no 159 (69.7) 345 (83.5) 1.00 1.00
yes 69 (30.3) 68 (16.5) 3.01 (1.61-5.62) 3.29 (1.65-6.56)Breastfeeding***
no 172 (75.4) 357 (86.7) 1.00 1.00
yes 56 (24.6) 55 (13.3) 2.98 (1.54-5.72) 2.88 (1.41-5.88)
PREGNANCY, EXPOSURE TO PESTICIDES, AND EAL IN PREGNANCY, EXPOSURE TO PESTICIDES, AND EAL IN BRAZIL, 1999-2007BRAZIL, 1999-2007. .
Jeniffer D. Ferreira, Arnaldo C. Couto, Maria S. Pombo de Oliveira, Sergio Koifman, Brazilian Collaborative Study Group of Infant Acute Leukemia, Env.Health Perspect, ocT 2012.
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HYPOTHESISHYPOTHESIS
PON1PON1
Genetic susceptibility-duos
Long lasting MeTABoLiTSLong lasting MeTABoLiTS
Known Maternal Exposures
NOQO1NOQO1
Variant Variant
Acq fusion genes
GST1
SULT1SULT1 NAT2NAT2
-Foetus is vulnerable to toxic effects of compounds food and environmental throughout maternal –placenta circulation;
Continous exposure and their interactions with biological molecules may responsible for some leukemogenesis patway steps.
-Foetus is vulnerable to toxic effects of compounds food and environmental throughout maternal –placenta circulation;
Continous exposure and their interactions with biological molecules may responsible for some leukemogenesis patway steps.
CYPsCYPsAdj. By protective factors*
Adj. By protective factors*
*Folate genes
*Folate genes
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Interação com inibidores da Topoisomerase II
NQ01 609 C>T provoca uma perda quase total da atividade enzimática
NQ01 desempenha um papel na ativação e desintoxicação de quinonas, incluindo metabolitos de benzeno e inhibidores de topo-II. Maior frequência do genótipo de baixa função foi associado a t-LMA ;freqüência elevada de 609T T aumenta o risco de LA MLL+?.
COMT Val 108 Met resulta na redução de 3-4 vezes na atividade
COMT metaboliza quercetina, um conhecido inibidor de topo- II . Quercetina é encontrado em frutas e vegetais. A baixa atividade na variante da mãe poderia aumentar o risco de IL- MLL+?
INTERAÇÃO COM LEUCEMOGENOS
GSTM1 GSTT1
Supressão GSTs estão envolvidas na desintoxicação de agentes cancerígenos como agentes óxidos e alquilantes. GSTM1 nulo está associado à LMA.
GSTP1 Iso 105 Val:Iso 105val: resulta na redução da atividade catalítica
GSTP1 está ativo para muitos policíclicos hidrocarbonetos aromáticos. Aumento de adutos deDNA foram relatados em crianças que possuem, no genótipo isoleucina (Ile / Ile, ile / Val) em comparação com val / Val; este polimorfismo ainda não foi estudado em IL
PON1 Variante L55M e G192A, reduzem a hidrólise de paraoxon
PON1 (paraoxanase) detoxifica organofosforados incluindo inseticidas e pesticidas; indivíduos com exposição crônica a pesticida e com genótipo PON192 variantes com atividade reduzida apresentaram mais doenças crônicas.
SULT1A1 Arg 213His; sresulta em redução de 70x atividade
Sulfotranferases são importantes no metabolismo de produtos químicos, e estrógenos; sulfation é uma das principais vias de desintoxicação na vida fetal, dado a inatividade do sistema de glucuronidação durante esse período. Muito relevante testar se as variantes pleomórficas de SULT1A estão associadas a IL.
MPO 493 G>A, Diminuí a atividade
A função da MPO é converter metabólitos genotóxicos benzeno fenólico para benzoquinones mielotoxicas. MPO está implicada na bioativação de outros procarcinogenos ambientais. Estudos que sugerem uma elevada assoc de 493G>A em adultos com LMA, mas não existem relatos em lactentes.
MECANISMOS DE PROTEÇÃO
MTHFR 677 C<T; 1298A<CResulta de baixa atividade redutase
Atividade reduzida de MTHFR está associada aos polimorfismos que reduzem o pool de methiltetrahidrofolate. Essas reduções aumenta a incorporação errônea de radical uracil, o que pode levar as quebras de DNA.
OUTROS
IGF-1 Ausência de 192 pb no alelo resultados mais baixos níveis circulantes de IGF-1
IGF1 é um polipeptídeo envolvido no controle de metagênese, célula de sobrevivência, e de regulamentação. Um polimorfismo microssatélite consistindo da variável CA seqüência repetida foi localizado a partir de 1 kb da transcrição, e acredita-se que o site tem significado funcional. Relatórios recentes sugerem que a ausência da repetição de 19 CA (192bp) está associada a um aumento do risco de baixo peso ao nascer, diabetes mellitus e de doenças cardiovasculares. Dada a forte associação positiva entre peso ao nascer e níveis de IGF-1, e o peso ao nascer e leucemia infantil, seria adequado para se avaliar se este polimorfismo podem ser importantes na etiologia.
GENETIC POLYMORPHISMSGENETIC POLYMORPHISMS
HLADRTNF
ERCC1ILs
• Immune Responses
CDKN1A/BCDKN2A/B
XRCC1XPD/ERCC2
• DNA repair
MPO1
SULT1A1
PON1
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Aguiar, BG, et al.
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PON1 POLYMORPHISM AND MATERNAL PON1 POLYMORPHISM AND MATERNAL
EXPOSURESEXPOSURES
Aguiar, BG, et al, Cancer Causes and Control, et al 2012
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DIRETORIO DE GRUPOS DE PESQUISAS: Grupo de Estudos de Leucemias de Lactentes Epidemiologia do Cancer- CNPqGrupo de Tumores Pediátricos do Instituto Nacional de Cancer-MS
Dra Marceli O. Santos, Luis C.ThulerDra Marceli O. Santos, Luis C.ThulerJuliana Ferreira, Júlio Fernando,Juliana Ferreira, Júlio Fernando,
Dr Sergio Koifman, Dr Sergio Koifman,
*Médicos da Rede de Atenção Oncologica Infanto-Juvenil, INCA
Dra Marceli O. Santos, Luis C.ThulerDra Marceli O. Santos, Luis C.ThulerJuliana Ferreira, Júlio Fernando,Juliana Ferreira, Júlio Fernando,
Dr Sergio Koifman, Dr Sergio Koifman,
*Médicos da Rede de Atenção Oncologica Infanto-Juvenil, INCA
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Brazilian Collaborative Study Group of Brazilian Collaborative Study Group of Infant LeukaemiaInfant Leukaemia
ACKNOWLEDGMENTSACKNOWLEDGMENTS
Isis Q. Magalhães , José Carlos Cordoba ;Silvia Brandalise , Vitória R. Pinheiro,Jane Dobbin , Fernada Azevedo-Silva, Maria D. Dorea, Jozina M. de Andrade Agareno Gilberto RamosEny G. Carvalho , Ana M.Marinho da SilvaMaria Lucia M. LeeRosania Baseggio , Marcelo S. de Souza Mara A. D. Pianovski , Leniza C.L.Lichtvan Thereza C. S. Lafayette, Virginia Cóser Imaruí Costa , Denise Bousfield Teresa Cristina CardosoNilma Pimentel de Brito Alejandro M. Arancibe, Claudia T. Oliveira Renato MelaragnoVirginia Coser