Principles of Clinical Cancer Genetics (eBook)

Preface 5
Contributors 8
Chapter 1: Basic Principles of Cancer Genetics 11
Introduction 11
Germline Versus Somatic Genetic Alterations in Cancer 12
Driver and Passenger Genetic Abnormalities in Cancer Pathogenesis 12
Activation of Oncogenes and Proto-oncogenes 12
Point Mutations 14
Gene Amplifications and Chromosomal Translocations 14
Tumor Suppressor Genes 16
The Knudson Model for Loss of Tumor Suppressor Gene Function 17
Tumor Suppressors and Cell Cycle Dysregulation: The RB1 Pathway 18
The P53 Pathway and BRCA1 in Genome Stability and DNA Repair 20
DNA Mismatch Repair and Microsatellite Instability 21
Tumor Suppressors Involved in Cellular Signaling and Differentiation 22
Tumor Progression 24
The Accumulation of Genetic Lesions 24
Stepwise Accumulation of Genetic Abnormalities 24
Epigenetic Lesions and Gene Silencing 24
MicroRNAs and Cancer Progression 24
Evasion of Cell Death and Acquisition of Immortality 25
Metastasis and Angiogenesis 26
Genetic Mechanisms of Treatment Resistance 26
Techniques for Cancer Genetic and Genomic Analysis 28
References 30
Chapter 2: Principles of Cancer Genetic Counseling and Genetic Testing 33
Introduction 33
Identification of At-Risk Individuals 33
The Genetic Counseling Process 34
Contracting 34
Obtaining Medical Information 34
Obtaining the Family History 34
Information on All Individuals 35
Information on Affected Individuals 35
Accuracy of Information 35
Risk Assessment 35
Patient Reaction to High Risk Status 36
Patient Reaction to Low Risk Assessment 36
Principles of Genetic Testing 36
Ideal Testing Candidate 36
Timing of Genetic Testing 36
Implication for At-Risk Family Members 37
Choosing the Right Test 37
Choosing the Right Laboratory 38
Research Testing 38
DNA Banking 38
When Testing Is Declined 38
Disclosure of Test Results 38
The Process of Informed Consent 38
Education About Genetics and Cancer 39
Education About Genes, Tumorigenesis, and Inheritance Patterns 39
Education About the Disease and Risk Reduction Options 39
Education About Possible Test Results 40
Education About the Benefits, Risks, and Limitations of Testing 40
Benefits 40
Risks 41
Limitations 41
Psychosocial Assessment and Support 41
Pre-test Support 41
Patient Reaction to Test Results 42
Positive Test Result 42
Negative Test Result 42
Variant of Uncertain Significance 42
Post-test Support 42
The Informed Consent Document 42
Confidentiality 43
Costs and Billing Practices 45
Ethical Issues 45
Testing Minors 45
Preimplantation Genetic Diagnosis 46
Duty to Warn 47
Summary 47
References 48
Chapter 3: Genetics of Hereditary Breast Cancer 51
Introduction 51
Hereditary Breast Cancer Syndromes 51
Hereditary Breast and Ovarian Cancer Syndrome 51
Clinical Features and Genetics 51
Clinical Management 54
Li–Fraumeni Syndrome 56
Clinical Features and Genetics 56
Clinical Management 57
Cowden Syndrome 57
Clinical Features and Genetics 57
Clinical Management 58
Hereditary Diffuse Gastric Carcinoma 58
Summary 58
References 58
Chapter 4: Surgical Management of Hereditary Breast and Ovarian Cancer 62
Introduction 62
BRCA1 and BRCA2 Mutations 62
Efficacy of Bilateral Prophylactic Mastectomy in BRCA Gene Mutation Carriers 62
Decision-Making: High-Risk Screening Versus Prophylactic Mastectomy 63
Patient Satisfaction After Prophylactic Mastectomy 63
Prophylactic Mastectomy for Other Hereditary Breast Cancer Syndromes 64
p53 Mutation Carriers: Li Fraumeni Syndrome 64
PTEN Mutation Carriers: Cowden’s Syndrome 64
CDH1 Mutation Carriers: Hereditary Diffuse Gastric Carcinoma Syndrome 64
Technical Considerations in Prophylactic Mastectomy 64
Mastectomy Options 65
Skin-Sparing Mastectomy 65
Nipple-Sparing Mastectomy 65
Satisfaction with Reconstruction After Prophylactic Mastectomy 66
Sentinel Lymph Node Biopsy in the Setting of Risk-Reducing Mastectomy 66
Breast Cancer Screening After Prophylactic Mastectomy 67
Surgical Management of BRCA 1 or 2 Carriers with a New Cancer Diagnosis 67
Hereditary Ovarian Cancer 67
Bilateral Prophylactic Salpingo-Oophrectomy for BRCA Carriers 68
Efficacy of Risk-Reducing Bilateral Salpingo-Oophorectomy 68
Risk-Reducing Ovarian Cancer Surgery 68
Timing of Risk-Reducing BSO 69
Concurrent Hysterectomy 69
References 69
Chapter 5: Hereditary Colon Cancer: Colonic Polyposis Syndromes 72
Introduction 72
Adenomatous Polyposis Syndromes 72
FAP/Attenuated FAP 72
Clinical Features/Distinguishing Characteristics 72
Associated Extracolonic Manifestations 74
Genetics 74
Genotype/Phenotype Correlations 75
Genetic Testing 75
Management Implications 76
Strategies for Prevention of Cancer 76
MUTYH-Associated Polyposis Syndrome 76
Clinical Features/Distinguishing Characteristics 76
Genetics 77
Genetic Testing 77
Genotype/Phenotype Correlation 78
Genetic Testing 78
Management Implications 78
Strategies for Prevention of Cancer 78
Hamartomatous Polyposis Syndromes 78
Peutz–Jeghers Syndrome 78
Clinical Features/Distinguishing Characteristics 78
Genetics 79
Genetic Testing 79
Genotype/Phenotype Correlation 79
Management 79
Juvenile Polyposis Syndrome 79
Clinical Features/Distinguishing Characteristics 79
Genetics 80
Genetic Testing 80
Genotype/Phenotype Correlation 80
Management 80
PTEN Hamartoma Syndrome 80
Clinical Features/Distinguishing Characteristics 80
Genetics 81
Genetic Testing 81
Genotype/Phenotype Correlation 81
Management 81
Hyperplastic Polyposis Syndrome 81
Clinical Features/Distinguishing Characteristics 81
Genetics 82
Management 82
Summary 82
References 82
Chapter 6: Hereditary Colon Cancer: Lynch Syndrome 86
Introduction 86
Clinical Features of Lynch Syndrome 86
Clinical Criteria for Lynch Syndrome 87
Genetics of Lynch Syndrome and DNA Microsatellite Instability 87
Screening Tests for Lynch Syndrome 89
Hypermethylation and Sporadic Colon Cancers 90
Screening for Lynch Syndrome in Unselected Colorectal Cancer Populations 90
Genotype/Phenotype Correlations 92
Management of Patients with Lynch Syndrome 93
Genetic Counseling 94
Summary 94
References 95
Chapter 7: Hereditary Pancreatic Cancer 98
Introduction 98
Hereditary Pancreatic Endocrine Tumors 99
Exocrine Neoplasms of the Pancreas 99
Hereditary Tumor Syndromes Associated with Exocrine Pancreatic Neoplasms 99
Peutz–Jeghers 99
Hereditary Non-polyposis Colon Cancer: Lynch Syndrome 100
Familial Atypical Mole Melanoma Syndrome 100
Hereditary Breast/Ovarian Cancer Syndrome 100
Hereditary Pancreatitis and Pancreatic Neoplasms 100
Hereditary Pancreatitis 100
Familial Pancreatic Cancer 101
Screening and Surveillance Strategies in High-Risk Patients 102
Who Should Undergo Screening and Surveillance for Pancreatic Cancer? 102
When Should Screening and Surveillance Begin and How Frequently Should They Be Performed? 102
How to Screen for Pancreatic Cancer 103
MGH Screening Program for Pancreatic Cancer 103
References 104
Chapter 8: Hereditary Diffuse Gastric Cancer 106
Introduction 106
Hereditary Diffuse Gastric Cancer 106
CDH1 Gene 107
Genotype and Phenotype 108
Other Autosomal Dominant Gastric Cancer Susceptibility Syndromes 109
Genetic Counseling and Testing 109
Surveillance for Patients with Germline CDH1 Mutation 109
Prophylactic Total Gastrectomy 110
Associated Malignancies: Lobular Breast Cancer 114
Summary 114
References 115
Chapter 9: Familial Renal Cell Cancers and Pheochromocytomas 117
Introduction 117
Familial RCC with Clear Cell Histology 117
Von Hippel-Lindau (VHL) Disease (OMIM 193300) 117
Clinical Presentation 117
Central Nervous System Hemangioblastomas 118
RCC 118
Pheochromocytoma 118
Pancreatic Lesions 118
Papillary Cystadenomas 119
Treatment Considerations 119
Who Should Be Tested for Germline VHL Mutations? 119
When to Intervene 119
Antiangiogenic Agents in VHL Patients 120
Surveillance Considerations 120
Molecular Genetics of VHL Disease 121
Tuberous Sclerosis Complex (TSC1, OMIM 191100 and TSC2, OMIM 191092) 122
Clinical Presentations 122
Diagnostic Considerations 123
Molecular Genetics of TSC1/2 and Therapeutic Implications 124
Constitutive Translocations Involving Chromosome 3 124
Succinate Dehydrogenase-Related RCC 125
Supernumerary Nipple Syndrome 125
Familial RCC with Papillary Histology 125
Hereditary Papillary RCC Type 1 (HPRCC1) (OMIM 1447000) 125
Clinical Presentation 125
Molecular Genetics of HPRCC1 and Therapeutic Implications 125
Hereditary Leiomyomatosis with RCC (OMIM 150800) 126
Clinical Presentations 126
Molecular Genetics of HLRCC 126
Screening and Treatment Recommendations for HLRCC 126
HPRCC Associated with Papillary Thyroid Cancer (OMIM 605642) 126
Familial Chromophobe RCC and/or Oncocytoma 126
Birt-Hogg-Dube Syndrome (OMIM 135150) 126
Clinical Presentation 126
Molecular Genetics of BHD 127
Approach to the Patient with Familial RCC 127
Who Should Be Referred for Testing? 127
Referral Because of Positive Family History 128
Referral Because of Early Onset and/or Multifocal RCC 128
Referral Because of Extrarenal Lesions and Corresponding Symptoms 128
The Genetic Test Is Negative: Does the Patient Have the Disease? 128
Familial Pheochromocytoma and Paraganglioma 129
Clinical Presentation 129
Von Hippel-Lindau Disease 129
Neurofibromatosis Type 1 (See Chap. 13: Neurofibromatosis) 129
Multiple Endocrine Neoplasia Type 2 (See Chap. 11: MEN Syndromes) 129
Hereditary Paraganglioma-Pheochromocytoma Syndromes 129
Diagnostic Considerations and Recommendations for Genetic Testing 130
Surveillance Recommendations 130
Approach to the Patient with Hereditary Pheochromocytoma 131
Genetic Testing of At-Risk Family Members 131
The Genetic Test Is Negative: Does the Patient Have the Disease? 131
References 132
Chapter 10: Familial Atypical Mole Melanoma (FAMM) Syndrome 137
Introduction 137
Clinical Features 137
Distinguishing Sporadic From Hereditary Forms of the FAMM Syndrome 139
Genetics and Genotype/Phenotype Correlations 140
Associated Malignancies 142
Genetic Counseling and Testing 144
Management and Prevention 146
Summary 147
References 147
Chapter 11: Multiple Endocrine Neoplasia 153
Introduction 153
MEN 2 Overview 153
MEN 2 Molecular Genetics 153
Genotype–Phenotype Correlations in MEN 2 155
Clinical Features of Medullary Thyroid Carcinoma 156
Sporadic Medullary Thyroid Carcinoma 157
Familial Medullary Thyroid Carcinoma 157
MEN 2A 158
Pheochromocytoma in MEN 2A 158
Hyperparathyroidism in MEN 2A 159
Other Manifestations of MEN 2A 159
MEN 2B 159
Impact of Screening on Clinical Outcomes in MEN 2 160
Timing and Extent of Surgery 160
MEN 1 Overview 161
MEN 1 Molecular Genetics 161
Clinical Definition and Penetrance 162
Primary Hyperparathyroidism in MEN 1 162
Entero-Pancreatic Neuroendocrine Tumors 163
Gastrinomas 163
Insulinomas 164
Rare Functional Tumors in MEN 1: VIPomas, Glucagonomas, Somatostatinomas, GRH-omas [106] 164
Non-functional Tumors in MEN 1 164
Pituitary Adenomas in MEN 1 164
Carcinoid Tumors in MEN 1 165
Adrenal Abnormalities 165
Skin Changes in MEN 1 165
Miscellaneous Findings in MEN 1 165
Genetic Screening in MEN 1 165
Surveillance of MEN 1 Affected Individuals 166
Carney Complex and McCune Albright Syndrome 167
References 167
Chapter 12: Pediatric Malignancies: Retinoblastoma and Wilms’ Tumor 171
Introduction 171
Retinoblastoma 171
Clinical Features 171
Epidemiology 171
Clinical Presentation 171
Diagnosis 172
Evaluation for Extraocular Tumor 172
Management of Retinoblastoma 172
Molecular Biology, The RB1 Gene, Specific Mutations, and Tumor Penetrance 172
Molecular Biology 172
The RB1 Gene 173
The Protein Product pRB 173
Gene Mutations in Retinoblastoma 173
Penetrance and Mutation Detection Rates 174
The Role of p53 174
Genetic Diagnosis 175
Genetic Counseling 175
Summary of Retinoblastoma 176
Wilms’ Tumor 177
Introduction 177
Clinical Features 177
Epidemiology 177
Clinical Presentation 177
Diagnosis 177
Histology 178
Sporadic Versus Hereditary Wilms’ Tumor 178
Genetics, Genotype/Phenotype Correlations 179
The WT1 Gene 179
Chromosome 11p15 179
Chromosomes 1p and 16q 181
Chromosome 7p 181
The WTX Gene 181
Familial Wilms’ Tumor Loci 182
Other Syndromes Associated with Wilms’ Tumor 182
Management of Wilms’ Tumor 182
Management Implications 183
Role for Genetic Testing 183
Wilms’ Tumor Screening 183
Long-Term Side Effects 183
Summary of Wilms’ Tumor 184
References 184
Chapter 13: Neurofibromatosis and Schwannomatosis 189
Introduction 189
Neurofibromatosis 1 189
Clinical Features and Diagnostic Criteria 189
Tumor Manifestations 189
Non-tumor Manifestations 190
Genetics and Molecular Biology 191
Genetic Testing 192
Management of Patients with NF1 192
Relationship Between Sporadic and NF1-Related Tumors 192
Neurofibroma 192
Leukemia 193
Pheochromocytoma 193
Optic Pathway Glioma 193
Gastrointestinal Stromal Tumor 193
Malignant Peripheral Nerve Sheath Tumor 193
Neurofibromatosis 2 193
Clinical Features and Diagnostic Criteria 193
Tumor Manifestations 194
Nontumor Manifestations 194
Genetics and Molecular Biology 194
Genetic Testing 195
Management of Patients with NF2 195
Relationship Between Sporadic and NF2-Related Tumors 196
Schwannomatosis 197
Clinical Features and Diagnostic Criteria 197
Genetics and Molecular Biology 197
Genetic Testing 198
Management of Patients with Schwannomatosis 198
Relationship Between Sporadic, and Schwannomatosis-Related Tumors 198
Summary 198
References 199
Chapter 14: The HapMap Project and Low-Penetrance Cancer Susceptibility Alleles 202
Introduction 202
SNPs 203
HapMap 205
Genome-Wide Association Studies 207
Breast Cancer 207
Prostate Cancer 207
Colorectal Cancer 208
Summary of Results 208
Future Studies 208
Summary 210
References 210
Chapter 15: Somatic Genetic Alterations and Implications for Targeted Therapies in Cancer (GIST, CML, Lung Cancer) 212
Introduction 212
Chronic Myeloid Leukemia 212
Targeting BCR-ABL in CML 212
Molecular Monitoring of Disease 213
Mechanisms of Imatinib Resistance 214
Role of Dasatinib and Nilotinib in Imatinib-Resistant CML 214
Summary 215
Gastrointestinal Stromal Tumors 215
Molecular Targets in GIST 215
C-KIT 215
PDGFR-a 215
Targeting C-KIT and PDGFR-a in GIST 216
Genotype–Phenotype Correlations and Mechanisms of Resistance 217
Summary 217
Non-small Cell Lung Cancers Harboring Activating EGFR Mutations 217
EGFR Inhibitors in Unselected Patients with Advanced NSCLC 218
Somatic EGFR Mutations in Lung Cancer 219
The Biology of EGFR Oncogene Addiction 219
Acquired Resistance to Gefitinib/Erlotinib In EGFR Mutant Lung Cancer 219
Nonsmall Cell Lung Cancers Harboring Translocations of Anaplastic Lymphoma Kinase 221
Clinicopathologic Features of EML4-ALK-Positive NSCLC 221
Diagnostic Testing 222
Clinical Outcome with Standard Therapies 222
Clinical Outcome with Targeted Therapies 223
Summary and Future Directions 223
References 223
Index 228