francine blumental de abreu - PHL © Elysio - FUNDAÇÃO ANTÔNIO ...

More documents

Recommendations

Info

SUMMARY Abreu FB. [Analysis of copy number alterations in patients with breast and colorectal cancer syndrome that are negative for BRCA1, BRCA2, TP53, CHEK2, MLH1 and MSH2 mutations]. São Paulo, 2012. [Tese de Doutorado-Fundação Antônio Prudente]. Lynch syndrome (LS) is a hereditary colorectal cancer syndrome associated to an increased risk to develop extracolonic tumors. In Brazil, breast cancer is the extracolonic tumor with more incidence among LS patients. On this study, 65 patients were dividided into three groups: 1 and 2, composed of 59 patients negative for BRCA1, BRCA2, TP53, CHEK2, MLH1 and MSH2 mutations and, 3, composed of six patients with a mutation in one of these genes. Group 1 had 26 patients with breast or colorectal cancer and group 2 had 33 patients with breast and colorectal cancer. Copy number variations (CNVs) were investigated by CGH array using 4x180K platform (Agilent Techonologies). Data were extracted by Feature Extraction Software and analyzed by Genomic Workbench 5.0 Software, using the ADM2 algorithm with a 6.7 threshold and absolute log ratio filter of -0,3≤log2≥0,3 to identify genomic losses and gains. The DNA copy number imbalances were compared to a Database of Genomics Variants (DGV) and to a Brazilian reference group. It was identified 451 CNVs, where 161, 257 and 33 were from group 1, 2 and 3, respectively. After the comparison with the reference group, the CNVs were dividided into commum, rare and new rare. It was considered for further analysis rares CNVs (identified in less than 1% of the reference group) and new rares (absent in the reference group and DGV). In cases with absence of gene mutations, new rare CNVs were both commonly and exclusively detected in groups 1 and 2. Gain at SLC38A6 gene was identified in two patients from group 1 and one patient from group 2. This gene is involved on glutamine transport, that is an amino acid with multiple functions, including ATP production. The GRM1 and TMPRSS3 genes
(exclusive from group 1) and FOXP1 and BLM genes (exclusive from group 2), all involved in genomic gains, may contribute to tumor development. The familial member analysis, specific rare and new rare CNVs mapped on specific genes as well as microRNAs were candidates to be associated breast and colorectal cancer predisposition. Loss at ROBO1 gene was observed in two patients (group 1 and 2) and in their affected relatives. This alteration was confirmed by qPCR. In addition, weak ROBO1 protein imunoexpression was associated with worse prognosis in hereditary breast and colorectal tumors. In overall, these results sugest the involvement of specific genomic alterations in hereditary breast and colorectal cancer predisposition.
Page 1 and 2: VARIAÇÃO NO NÚMERO DE CÓPIAS GE
Page 3 and 4: A minha família!!!! DEDICATÓRIA
Page 5 and 6: À minha orientadora... Dra Silvia
Page 7 and 8: As Instituições de Fomento... FAP
Page 9: Entre os pacientes sem mutação, f
Page 13 and 14: Figura 11 Representação esquemát
Page 15 and 16: LISTA DE TABELAS Tabela 1 Classific
Page 17 and 18: Tabela 25 Alterações identificada
Page 19 and 20: LISTA DE SIGLAS E ABREVIATURAS aCGH
Page 21 and 22: UTR* Untranslated region VNTR* Vari
Page 23 and 24: 4.2.3 Análise de CNVs entre os fam
Page 25 and 26: O câncer colorretal (CCR) é o ter
Page 27 and 28: vezes, está associado com a histó
Page 29 and 30: análise de MSI é realizada pela P
Page 31 and 32: (2010) relataram que o tumor extrac
Page 33 and 34: 1.2 SÍNDROME DE CÂNCER DE MAMA-C
Page 35 and 36: PMS2). Segundo os autores, é mais
Page 37 and 38: contribuir para a patogênese e pro
Page 39 and 40: contém um elemento upstream que re
Page 41 and 42: 2 OBJETIVOS 2.1 OBJETIVO PRINCIPAL
Page 43 and 44: Figura 1 - Fluxograma representando
Page 45 and 46: o SMCMH2: pelo menos um indivíduo
Page 47 and 48: Tabela 1 - Dados clínicos e histop
Page 53 and 54: (1100delC) e TP53. Neste estudo, fo
Page 55 and 56: Tabela 5 - Iniciadores utilizados n
Page 57 and 58: Tabela 6 - Condições da PCR para
Page 59 and 60: As sequências alteradas foram clas
Page 61 and 62:
por 2 horas e 65°C por 15 min. Foi
Page 63 and 64:
As regiões identificadas como alte
Page 65 and 66:
(http://www.ncbi.nlm.nih.gov, http:
Page 67 and 68:
Figura 2 - Representação gráfica
Page 69 and 70:
O gene de referência, GAPDH, é fr
Page 71 and 72:
(tissue microarray - TMA), contendo
Page 73 and 74:
citoplasmática moderada, porém em
Page 75 and 76:
4 RESULTADOS 4.1 SEQUENCIAMENTO 4.1
Page 77 and 78:
Tabela 10 - Mutações não patogê
Page 79 and 80:
Figura 5 - Representação gráfica
Page 81 and 82:
número maior de CNVs, quando compa
Page 83 and 84:
21 não apresentaram CNVs. Por outr
Page 85 and 86:
A. C. Figura 7 - Representação gr
Page 87 and 88:
envolvida em perda genômica, prese
Page 89 and 90:
Cont/ Tabela 11 Região Cromossômi
Page 91 and 92:
Page 93 and 94:
Page 95 and 96:
Page 97 and 98:
Page 99 and 100:
Page 101 and 102:
As CNVs raras e novas raras foram c
Page 103 and 104:
Page 105 and 106:
Page 107 and 108:
Cont/ Tabela 13 CNVs Raras Exclusiv
Page 109 and 110:
Page 111 and 112:
Page 113 and 114:
Page 115 and 116:
Cont/ Tabela 14 CNVs Novas Raras Ex
Page 117 and 118:
Tabela 15 - Alterações com genes
Page 119 and 120:
Tabela 16 - Funções dos genes map
Page 121 and 122:
Entre as CNVs novas raras comuns ao
Page 123 and 124:
100
Page 125 and 126:
102 Entre as CNVs novas raras exclu
Page 127 and 128:
14q32.11: gene FOXN3 End: 89.136.41
Page 129 and 130:
7p22.2: gene MAD1L1 Start: 2.106.88
Page 131 and 132:
108 Entre as CNVs novas raras exclu
Page 133 and 134:
Start: 71.124.097 3p14.1: gene FOXP
Page 135 and 136:
Start: 71.478.161 17q25.1: genes AC
Page 137 and 138:
7q36.3: gene PTPRN2E2 Start: 158.00
Page 139 and 140:
Start: 49.039.910 13q14.3: gene RCB
Page 141 and 142:
mutações no gene de reparo MLH1 (
Page 143 and 144:
Tabela 18 - Alterações identifica
Page 145 and 146:
Cont/ Tabela 18 Casos SL36 (G2) Reg
Page 147 and 148:
124 Na Tabela 20 estão representad
Page 149 and 150:
família foi identificada apenas um
Page 151 and 152:
Page 153 and 154:
Page 155 and 156:
Page 157 and 158:
Cont/ Tabela 23 Casos Região Cromo
Page 159 and 160:
Page 161 and 162:
Page 163 and 164:
Figura 17 - Heredograma do caso SM5
Page 165 and 166:
142 A plataforma de 4x180K (Agilent
Page 167 and 168:
Start: 78.990.568 3p12.3: gene ROBO
Page 169 and 170:
146 Após a identificação, por CG
Page 171 and 172:
Figura 21 - Representação gráfic
Page 173 and 174:
Tabela 29 - Cálculo do intervalo d
Page 175 and 176:
Figura 23 - Análise gráfica dos r
Page 177 and 178:
epresenta uma comparação em barra
Page 179 and 180:
156 Após a caracterização da ext
Page 181 and 182:
ROBO1. Em 61,12% das amostras foi d
Page 183 and 184:
160 Tabela 33 - Associação entre
Page 185 and 186:
162 Não houve associação signifi
Page 187 and 188:
164 Tabela 34 - Associação entre
Page 189 and 190:
4.3.2 Família SM89 166 Após a con
Page 191 and 192:
168 No exame clínico, a probanda e
Page 193 and 194:
170 A SM89.2 (III:3), negativa para
Page 195 and 196:
172 A SM89.5 (IV:5), positiva para
Page 197 and 198:
174 A presença de pequenos cromoss
Page 199 and 200:
176 BRCA1 apresentaram 12 CNVs (SM8
Page 201 and 202:
Page 203 and 204:
Page 205 and 206:
5 DISCUSSÃO 182 As variações gen
Page 207 and 208:
câncer de mama e cólon. Grande pa
Page 209 and 210:
para mutação nos genes de predisp
Page 211 and 212:
N (SLC38A3 e SLC38A5), porém todos
Page 213 and 214:
alterações, GRM1, MAD1L1 e NPAS1
Page 215 and 216:
192 Neste estudo, o ganho genômico
Page 217 and 218:
sugeriram que a nova variante do ge
Page 219 and 220:
como linfomas, além de uma associa
Page 221 and 222:
taxas de crescimento celular quando
Page 223 and 224:
200 Segundo dados da literatura, os
Page 225 and 226:
de CNVs também foi observado nas p
Page 227 and 228:
5.1.3 Análise de CNVs entre os fam
Page 229 and 230:
colorretal, quatro em linhagem celu
Page 231 and 232:
produzidos durante o catabolismo do
Page 233 and 234:
envolvendo essa região cromossômi
Page 235 and 236:
tem sua eficiência 10 vezes reduzi
Page 237 and 238:
214 As GTPases são responsáveis p
Page 239 and 240:
carcinomas primários de cabeça e
Page 241 and 242:
com história familial avaliadas no
Page 243 and 244:
também demonstraram que pacientes
Page 245 and 246:
cromossômicas foram observadas tan
Page 247 and 248:
A paciente SM87 (grupo 2) apresento
Page 249 and 250:
226 Banyard J, Barrows C, Zetter BR
Page 251 and 252:
228 Chung GT, Sundaresan V, Hasleto
Page 253 and 254:
230 Fre S, Huyghe M, Mourikis P, Ro
Page 255 and 256:
232 Höglund PJ, Nordström KJ, Sch
Page 257 and 258:
234 Kuiper RP, Ligtenberg MJ, Hooge
Page 259 and 260:
236 Mills RE, Walter K, Stewart C,
Page 261 and 262:
238 Peltomäki P, Vasen HF. Mutatio
Page 263 and 264:
240 Selamat SA, Galler JS, Joshi AD
Page 265 and 266:
242 Thélu J, Rossio P, Favier B. N
Page 267 and 268:
244 Wang J, Luo MH, Zhang ZX, et al
Page 269:
Anexo 1 - Heredogramas
Page 324:
Anexo 3 - Critérios de Bethesda pa
show all

francine blumental de abreu - PHL © Elysio - FUNDAÇÃO ANTÔNIO ...

Create successful ePaper yourself

Delete template?

Save as template?