The Role of Genetics in Breast and Reproductive Cancers (eBook)

Piri L. Welcsh, PhD is a Research Assistant Professor in the Department of Medicine, Division of Medical Genetics at the University of Washington.  She received her PhD in Molecular Genetics from The Ohio State University.  It was during this time that the seminal paper in which Dr. Mary-Claire King demonstrated that a single gene on chromosome 17, later known as BRCA1, was responsible for many breast and ovarian cancers was published.   During Postdoctoral studies at the University of Texas Southwestern Medical Center in Dallas, Dr. Welcsh worked under the guidance of Dr. Anne M. Bowcock and collaborated with Drs. Mary-Claire King and Francis Collins in an attempt to clone BRCA1.  Shortly after the gene encoding BRCA1 was identified, Dr. Welcsh joined the research group of Dr. King at the University of Washington where she conducted studies designed to elucidate the biological function of BRCA1.  She is currently an independent investigator  whose current research goals include the identification and characterization of both genetic and epigenetic mechanisms critical to the development of breast and ovarian cancer. 

Preface 5
Contents 8
Contributors 10
Part 1: Recognition of Hereditary Breast and Reproductive Cancer Syndromes 13
Cancer Genetics in the Clinic: The Challenges and Responsibilities of Counseling and Treating Women at Risk 14
Genetic Counseling Definition 14
Introduction 14
Distinguishing Aspects of Hereditary Cancer Syndromes 15
The Family as Client 15
Presymptomatic or Susceptibility Testing: The ‘‘Unpatient’’ and ‘‘Pre-vivors’’ 15
Alteration of Reproductive Plans 16
Labeling, Stigma, and Fears of Genetic Discrimination 16
Parental and Survivor Guilt 17
Genetic Counselors Are a Resource for Persons with Inherited Cancer Syndromes 17
The Process of Genetic Counseling for Inherited Cancer Syndromes 18
The Pedigree - a Graphical Family History 19
Constructing a Pedigree 22
Obtaining Medical Records and Death Certificates to Confirm Health Information 25
Noting Ancestry and Consanguinity 26
Pedigree Analysis and Risk Perception 27
Genetic Variants of Uncertain Significance 27
DNA Banking Is an Important Option 28
Summary 28
References 29
Management of Women with Inherited BRCA1 and BRCA2 Mutations 31
General Considerations 31
Breast Cancer Surveillance and Early Detection 31
Breast Cancer Chemoprevention 34
Lifestyle and Nutrition as Modifiers of Breast Cancer Risk 34
Prophylactic Mastectomy 35
Surgical Considerations in Women with BRCA1/2 Mutations Diagnosed with Breast Cancer 36
Prophylactic Mastectomy: Surgical Considerations 39
Breast Cancer Phenotypes in Women with BRCA1/2 Mutations 42
Treatment and Outcomes of Breast Cancer in Women with BRCA1/2 Mutations 42
Ovarian Cancer Surveillance and Early Detection 43
Risk-Reducing Salpingo-oophorectomy (RRSO) 44
Tubal Ligation 47
Chemoprevention 47
Ovarian Cancer in BRCA1 and BRCA2 Mutation Carriers 48
Targeted Therapies and Mechanisms of Resistance for BRCA1/2-Associated Breast and Ovarian Carcinomas 48
References 49
Part 2: Genetic Etiology of Breast and Reproductive Cancers 56
Unclassified Variants in the Breast Cancer Susceptibility Genes BRCA1 and BRCA2 57
What Is the Approximate Frequency Distribution of Unclassified Variants? 58
First Thought About Classification 59
First Effective Analysis 60
First General Solution: Splice Junction Variants 61
A More General Solution: The Integrated Analysis 61
Logical Bases of the Existing Component Analytic Methods 64
Co-segregation Analysis 64
Strengths 65
Weaknesses 65
Personal and Family History 65
Co-occurrence with Clearly Pathogenic Variants 66
In Silico Assessment of Sequence Conservation During Gene Evolution and Amino Acid Substitution Severity 67
Strength 68
Weakness 69
Tumor Pathology and Immunohistochemistry 69
Future Direction 70
Appendix 73
References 75
Recent Advances in Understanding the Cellular Functions of BRCA1 82
Structure of BRCA1 82
The BRCT Domain 83
BRCA1-BRCTs and the DNA Damage Response 84
The BRCA1-BRCT:Abraxas/CCDC98 Complex 85
The BRCA1-BRCT:CtIP Complex 85
The BRCA1-BRCT:FANCJ Complex 86
The BRCA1-BRCT:ACC1 Complex 87
BRCA1 RING Region 87
BRCA1 Generates Non-typical K6-Ub Linkages 88
BRCA1-E2 Interactions 88
BRCA1 E3 Ligase Targets 89
BRCA1 Targets CtIP 89
BRCA1 Targets Microtubule Stability 89
BRCA1 Targets RNA Polymerase II Subunits 90
BRCA1 Targets the Hormone Receptors 91
BRCA1 Binding Partners in Disease Susceptibility 92
References 93
Recent Advances in Understanding the Cellular Functions of BRCA2 100
Structure of the Human BRCA2 Protein 100
BRCA2 Homologues in Eukaryotes 101
BRCA2 Partners 102
BRCA2 Cellular Functions 103
Role of BRCA2 in Homologous Recombination 103
Control of Mitotic Exit 106
BRCA2 and the Fanconi Anaemia Pathway 107
Cellular Processes Requiring Homologous Recombination 107
Consequences of BRCA2 Deficiency 108
References 109
Genetic Modifiers of Risk of BRCA1- and BRCA2-Related Breast and Ovarian Cancers 113
The Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) 114
Candidate Genetic Modifiers 115
Androgen Receptor 116
Amplified in Breast Cancer 1 (AIB1) 117
TP53 118
RAD51 118
MTHFR 119
Other Genes 119
Cytogenetic Abnormalities in BRCA1 and BRCA2 Carriers 121
CIMBA Studies 122
AURKA 124
Breast Cancer Susceptibility Variants in FGFR2, TNCR9, and MAP3K1 Identified Through Genome-Wide Association Studies 125
Explained Variance in Genetic Modification of BRCA1 and BRCA2 126
Implications for Risk Predictions 127
Genome-Wide Association Studies for Modifiers of BRCA1 and BRCA2 127
Future Challenges 128
References 129
Other Hereditary Breast Cancer Syndromes and Genes 136
Rare Familial Cancer Syndromes with Breast Cancer as a Component 136
Li-Fraumeni Syndrome 136
Cowden Syndrome 138
Peutz-Jeghers Syndrome 139
Hereditary Diffuse Gastric Cancer (HDGC) 141
Deleterious Mutations in DNA Damage Response Genes Associated with an Increased Risk of Breast Cancer, Notably in Families with Multiple Breast Cancer Cases 142
Ataxia Telangiectasia, Mutated (ATM) 142
MRN Complex 145
Checkpoint Kinase 2 (CHEK2) 146
BRCA1-Associated Ring Domain (BARD1) 149
Fanconi Anemia Genes 150
DNA Damage Repair Genes and Breast Cancer Susceptibility 153
References 154
Ovarian and Endometrial Cancer in Patients with Hereditary Non-polyposis Colorectal Cancer Syndrome 168
Introduction 168
Amsterdam Criteria 169
Definition: Microsatellite Instability 170
Testing for Microsatellite Instability 172
Mutations in MMR Genes 174
MLH1 Methylation 176
Targets of MMR Genes 176
Endometrial Cancer and HNPCC 177
Ovarian Cancer 179
Clinical Screening Guidelines 181
Conclusion 182
References 183
Somatic Alterations and Implications in Breast Cancer 187
Introduction 187
Breast Cancer Initiation and Progression 188
Estrogen and Breast Cancer Development 189
Estrogen Simulates Cellular Proliferation 189
Estrogen Causes Direct Genotoxic Damage 190
Estrogen Receptor in Sporadic and Hereditary Breast Cancer 190
Other Alterations and Interactions that Promote Breast Tumorigenesis 191
Cell Cycle Alterations 191
Interactions Between Mammary Epithelial Cells and the Microenvironment 192
Normal Mammary Stem Cells and Breast Cancer Stem Cells 192
Genetic and Morphological Heterogeneity of Breast Cancer 196
Breast Cancer Subtypes 197
Molecular Profiling 197
Gene Expression Profiling 198
Genomic Alterations in Breast Cancer 199
Pathways Altered in Sporadic Breast Cancer 202
Growth Factor Receptor Signaling 202
PI3K-PTEN Alterations 202
DNA Repair in Non-Hereditary Breast Cancer 203
Future of Molecular Diagnostics in Breast Cancer 205
References 206
Somatic Genetic Development in Epithelial Ovarian Cancer 218
Summary 218
Molecular Alterations Identified in Ovarian Cancer Development 219
Genes Associated with Tumour Initiation and Early-Stage Ovarian Cancers 219
Chromosomes Aberrations in Ovarian Cancers 220
Genes Altered During Ovarian Cancer Development 224
Molecular Profiling in Epithelial Ovarian Cancers 225
Molecular Pathways Involved in Epithelial Ovarian Cancer 226
DNA Double-Stranded Break (DSB) Pathway 227
The Role of TP53 229
The DNA Mismatch Repair Pathway 229
Mitogen-Activated Protein Kinase Pathway 231
The Role of ERBB2 231
The Role of C-MYC 232
The Phosphatidylinositol 3-Kinase (PI3K) Signalling Pathway 232
Genetic and Phenotypic Heterogeneity in Ovarian Cancers 233
Type I Tumours 234
Low-Grade Serous Carcinoma/Serous Borderline Tumours 235
The Development of Mucinous Tumours 236
The Development of Endometrioid and Clear Cell Carcinomas 236
The Development of Malignant Brenner Tumours 237
Type II Tumours 238
The Development of High-Grade Serous Carcinoma 238
Undifferentiated Carcinoma and Malignant Mixed Mesodermal Tumours 238
Future Perspectives 239
References 240
Part 3: Genes and the Environment 250
High-Frequency Low-Penetrance Alleles 251
The Architecture of Genetic Susceptibility to Breast Cancer 251
Candidate Gene Studies 252
Genome-Wide Association Studies 253
Sub-group Effects 255
Function 256
Polygenic Susceptibility 257
Conclusion 262
References 262
Host and Viral Genetics and Risk of Cervical Cancer 265
Overview 265
Clinical Outcomes of HPV-Infected Women 266
Viral Genetics 267
Human Papillomavirus 267
HPV Types and Subtypes 269
Viral Epigenetic Modification 270
Host Genetics 271
Familial Associations in Cervical Cancer 271
HPV-Associated Genetic Diseases 271
Association Studies in CIN and ICC 272
Immune Response 272
HLA Class II 273
HLA Class I 274
Natural Killer (NK) Cells 274
Other Immune Response Genes 275
Other Host Genetic Modifications 275
Host Epigenetic Modifications 277
References 279
Estrogen-Metabolizing Gene Polymorphisms, Genetic Susceptibility, and Pharmacogenomics 287
Introduction 287
CYP1A1 290
Polymorphisms 290
Clinical Aspects of CYP1A1 Genotypes on Risk of Breast Cancer 291
Clinical Aspects of CYP1A1 Genotypes on Risk of Ovarian Cancer 293
Clinical Aspects of CYP1A1 Genotypes on Risk of Lung Cancer 294
Placenta Weight 294
CYP1A1 Polymorphisms and Biological Systems Outside of Breast and Lung 295
Pharmacogenomics 295
CYP1B1 296
Gene and Protein Structure of CYP1B1 296
Gene Regulation 296
Epigenetic Regulation 297
Polymorphisms 297
Breast Cancer 298
Endometrial Cancer 299
Pharmacogenomic Modulation 300
COMT 300
Polymorphism 301
COMT and Breast Cancer Risk 301
COMT and Endometrium 303
Cardiovascular System 303
COMT and Brain 304
Sulfotransferases (SULTs) UDP-Glucuronosyltransferase (UGT) 305
References 306
The Future of Discoveries in Breast and Reproductive Cancers: The Genome and Epigenetics 317
Introduction 317
DNA Methylation 319
DNA Methylation Changes in Cancer 320
DNA Methylation as a Breast Cancer Diagnostic 323
DNA Methylation in Breast and Ovarian Cancer Prognosis 324
Use of DNA Methylation to Predict Response to Treatment in Breast and Ovarian Cancer 325
Histone Modifications 326
Histone Acetylation is Deregulated in Cancer 327
Epigenetics in Cancer Treatment 329
DNA Methylation Inhibitors 329
HDAC Inhibitors 329
Conclusions 331
References 331
Index 335