Familial Breast and Ovarian Cancer: Genetics, Screening and Management

Half-title......Page 3
Title......Page 5
Copyright......Page 6
Dedication......Page 7
Contents......Page 9
Contributors......Page 11
Foreword......Page 15
Preface......Page 17
Acknowledgements......Page 18
Part 1 Molecular biology and natural history......Page 19
Services for cancer genetics......Page 21
Family history as an indicator of predisposition to breast cancer......Page 24
Studies of familial breast cancer......Page 25
Mutations......Page 26
Penetrance and prevalence......Page 27
BRCA2......Page 28
Mutations......Page 29
Founder effects involving BRCA1 and BRCA2......Page 30
Heterogeneity......Page 31
Li–Fraumeni syndrome......Page 32
Low penetrance/modifier genes......Page 33
Conclusions......Page 35
REFERENCES......Page 36
Epidemiology......Page 40
Cowden syndrome......Page 41
Genetics......Page 45
Bannayan–Riley–Ruvalcaba syndrome......Page 46
Cryptic PHTS......Page 47
Differential diagnosis......Page 48
Clinical cancer genetic management......Page 50
Somatic PTEN alterations in sporadic tumours......Page 51
PTEN function......Page 54
REFERENCES......Page 55
Introduction......Page 61
Population risk......Page 62
Familial ovarian cancer......Page 63
Hereditary breast/ovarian cancer......Page 67
Hereditary site-specific ovarian cancer syndrome......Page 71
Hereditary non-polyposis colorectal cancer syndrome......Page 73
Risk prediction models......Page 74
Histopathological type......Page 75
Genotype–phenotype associations......Page 76
Peritoneal cancer......Page 77
The natural history of BRCA1/2-related ovarian cancer......Page 78
Acknowledgements......Page 79
REFERENCES......Page 80
Introduction......Page 91
Clinical features......Page 92
Do ovarian and breast cancer belong to the tumour spectrum of HNPCC?......Page 93
Recent data from the Dutch HNPCC registry......Page 94
Peutz–Jeghers syndrome......Page 95
Surveillance recommendations......Page 96
REFERENCES......Page 97
Introduction......Page 99
Ipsi- and contralateral breast cancer recurrences......Page 101
Linkage-based studies and survival......Page 110
Mutation-based studies and survival......Page 112
Perspectives and conclusion......Page 118
REFERENCES......Page 119
Introduction......Page 126
BRCA1-associated tumours......Page 127
BRCA2-associated tumours......Page 129
Steroid hormone receptors......Page 130
TP53......Page 131
Cell cycle proteins......Page 132
Familial ovarian cancer......Page 133
BRCA1-associated tumours......Page 134
BRCA2-associated tumours......Page 135
Malignant germ-cell and stromal-cell neoplasms in BRCA1 and BRCA2 mutation carriers......Page 136
Borderline ovarian neoplasms and in situ lesions in women with and without BRCA germline mutations......Page 137
REFERENCES......Page 138
Introduction......Page 143
Pedigree analysis......Page 144
Genetic analysis (mutation screening)......Page 149
Is the calculated carrier probability valid for the prediction of mutations?......Page 152
Summary......Page 155
REFERENCES......Page 156
Part 2 Screening......Page 159
9 Developing a cancer genetics service: a Welsh model......Page 161
Cancer units......Page 162
Evaluation of services......Page 163
Primary care in the cancer genetics service for Wales......Page 164
Evaluation of the service......Page 165
Steering group......Page 167
Development of benchmarks for the regional cancer genetics service......Page 168
Service delivery and information technology......Page 170
Looking to the future......Page 171
REFERENCES......Page 174
Background......Page 175
Guidelines......Page 176
Ovarian cancer......Page 177
Methods......Page 178
Molecular genetic testing......Page 179
Summary......Page 180
REFERENCES......Page 181
11 Guidelines for the development of cancer genetics services......Page 184
Primary care......Page 185
Calculation of risk of breast cancer......Page 186
Computer-aided risk estimation......Page 187
Genetic counselling of ‘at risk’ individuals and families......Page 188
Management of patients in medium-and high-risk categories......Page 196
Costs and benefits......Page 197
The principle of informed consent......Page 202
Disclosure of test results......Page 204
Ethical issues......Page 205
Insurance issues......Page 206
Education and training......Page 207
Evaluation......Page 208
REFERENCES......Page 210
12 Cultural and educational aspects influencing the development of cancer genetics services in different European countries......Page 212
Standards......Page 213
Healthcare structure......Page 215
Cancer genetics services......Page 216
Education......Page 218
Public awareness......Page 219
REFERENCES......Page 220
Background......Page 222
Early diagnosis......Page 223
Prospective studies......Page 225
Population versus high-risk group screening......Page 226
Treatment......Page 228
Strategies for treatment......Page 229
Prophylaxis......Page 230
Associated cancers......Page 231
Summary......Page 232
Suggested guidelines......Page 233
Prophylactic surgery......Page 234
REFERENCES......Page 235
Why should we screen?......Page 238
Are there any reasons not to screen?......Page 239
What screening tests are in use?......Page 240
What data are available regarding screening in high-risk women?......Page 242
What are the current trials?......Page 243
Conclusions......Page 244
REFERENCES......Page 250
Part 3 Management......Page 253
Introduction......Page 255
Lifestyle modification......Page 256
Medical intervention (chemoprevention)......Page 259
Surgical intervention......Page 266
Medical intervention......Page 268
Surgical intervention......Page 269
Early detection......Page 271
Mammography......Page 273
Magnetic resonance imaging......Page 275
Prostate cancer......Page 276
Radiotherapy......Page 277
Chemotherapy......Page 278
REFERENCES......Page 279
Should the management of familial ovarian cancer differ from that of sporadic ovarian cancer?......Page 293
Presentation......Page 294
Surgery......Page 295
Chemotherapy......Page 296
Prevention......Page 297
Prophylaxis......Page 298
Counselling......Page 300
REFERENCES......Page 301
Genetic counselling and the family history clinic......Page 304
The prophylactic mastectomy protocol......Page 305
Surgical technique......Page 307
Operative sequence......Page 308
Outcomes......Page 309
Uptake......Page 310
REFERENCES......Page 311
Introduction......Page 313
Psychological distress associated with genetic counselling for breast/ovarian cancer......Page 314
Psychological distress amongst previously affected women......Page 315
Perceptions of risk......Page 316
Attitudes towards testing......Page 317
Inconclusive results......Page 318
Psychological impact of results......Page 319
REFERENCES......Page 320
Introduction......Page 324
The experience from other genetic tests......Page 325
Research into the potential uptake of BRCA1/2 testing......Page 326
Hereditary breast/ovarian cancer families......Page 327
What is the study population?......Page 330
Attendance for education and counselling......Page 331
Eligibility......Page 332
Research contexts......Page 333
Review of the literature to date......Page 337
Attendance......Page 349
‘Time since genetic diagnosis’ as a selection criterion......Page 350
Cancer and risk status......Page 351
Non-participants......Page 352
Summary......Page 353
REFERENCES......Page 354
Mammography and ovarian screening......Page 357
Gene testing......Page 358
Management options......Page 359
Education......Page 360
Exacerbating and alleviating anxiety......Page 361
Eligibility criteria......Page 362
Cost-effectiveness......Page 363
Confidentiality of family medical history......Page 365
Confidentiality of molecular genetic data......Page 366
Duty of care......Page 368
Gene patenting......Page 369
Paternity testing......Page 370
Definition of a genetic test......Page 371
The recent UK experience of insurance and genetic testing......Page 372
The situation in other European countries......Page 378
Benefits of genetic testing......Page 380
Evidence of discrimination......Page 381
REFERENCES......Page 383
Principles of gene therapy......Page 390
In vitro delivery......Page 392
Gene therapy treatment strategies......Page 393
Studies of gene therapy for breast and ovarian cancer......Page 394
Correction of genetic mutation in cancer cells......Page 395
Molecular chemotherapy......Page 396
Immunotherapy......Page 397
Gene therapy: the future......Page 398
REFERENCES......Page 400
22 Future directions......Page 402
REFERENCES......Page 406
Index......Page 411