Hereditary Tumors: From Genes to Clinical Consequences

Hereditary Tumors
	Foreword
	Preface
	Contents
	List of Contributors
	Part I Hereditary Tumors – General Aspects
		1 General Insights Into Tumor Invasion, Progression, and Metastasis
			Summary
			1.1 The Metastatic Cascade
			1.2 Key Molecules Promoting Metastasis
				1.2.1 Adhesion and Migration
				1.2.2 Tumor-Associated Proteolysis and Invasion
					1.2.2.1 u-PA
					1.2.2.2 u-PAR
					1.2.2.3 Plasminogen Activator Inhibitors
					1.2.2.4 Evidence for Diverse Functions of the u-PAR System Relevant for Cancers
				1.2.3 Factors for Tumor Growth and Angiogenesis
			1.3 Potential Hereditary Aspects of Molecules Promoting Metastasis
			References
		2 The Genetic Background of Hereditary Tumor Diseases
			Summary
			2.1 Introduction
			2.2 Sporadic Versus Hereditary Tumors
				2.2.1 Sporadic Malignancies Are More Common
				2.2.2 Red Flags for Hereditary Tumors
			2.3 Inheritance Patterns in Hereditary Tumor Predispositions
				2.3.1 Autosomal Dominant Inheritance
				2.3.2 Autosomal Recessive Inheritance
			2.4 Genotype–Phenotype Relations in Hereditary Tumor Predispositions
				2.4.1 Mechanisms Underlying Genotype–Phenotype Relations
			2.5 From Predisposition to Cancer – Is One Gene Enough?
				2.5.1 Experimental Evidence for the Two-Hit Hypothesis
				2.5.2 “Multi Hit” and Recruitment Hypotheses
			2.6 The Phenomena of Cell-Type Specificity
				2.6.1 Colocalization of Additional Mechanisms
				2.6.2 The Involvement of More Than One Cell Type
				2.6.3 Cell-Type Specificity in Recessive Inheritance
			2.7 Conclusions and Future Directions
			References
	Part II Syndromal Types of Hereditary Tumors
		3 Family Cancer Syndromes
			Summary
			3.1 Introduction
			3.2 Hereditary Non-Polyposis Colon Cancer Syndromes (HNPCC)
			3.3 APC-Associated Polyposis Syndromes
			3.4 Hamartomatous Tumor Syndromes
			3.5 Familial Endocrine Tumor Syndromes
			3.6 Familial Cancer Associated Genodermatoses
			3.7 Familial Renal Cancer Syndromes
			3.8 Sarcoma Family Syndrome
			References
		4 Genetic Dysmorphic Syndromes Leading to Tumorigenesis
			Summary
			4.1 Overgrowth Syndromes
				4.1.1 Beckwith–Wiedemann Syndrome (BWS)
				4.1.2 Isolated Hemihyperplasia (IHH)
				4.1.3 Proteus Syndrome (PS)
				4.1.4 Sotos Syndrome (SS)
				4.1.5 Weaver Syndrome (WS)
				4.1.6 Simpson–Golabi–Behmel Syndrome (SGBS)
				4.1.7 Bannayan–Riley–Ruvalcaba Syndrome (BRRS)
			4.2 Syndromes with Mutations in the Mitogen-Activated Protein Kinase (MAPK)-RAS Pathway
				4.2.1 Noonan Syndrome (NS)
				4.2.2 Cardio-Facio-Cutaneous Syndrome (CFC)
				4.2.3 Costello Syndrome (CS)
				4.2.4 Noonan-Neurofibromatosis Syndrome (NFNS)
			4.3 Miscellaneous Dysmorphic Syndromes Leading to Tumorigenesis
				4.3.1 Gorlin Syndrome (Nevoid Basal Cell Carcinoma Syndrome, NBCCS)
				4.3.2 Rubinstein-Taybi Syndrome (RSTS)
				4.3.3 Rothmund–Thomson Syndrome (RTS)
			References
	Part III Site-Specific Aspects of Hereditary Tumors
		5 Hereditary Brain Tumors
			Summary
			5.1 Introduction and General Concepts
			5.2 Cowden Syndrome
			5.3 Li–Fraumeni Syndrome
			5.4 Naevoid Basal Cell Carcinoma Syndrome (NBCCS)
			5.5 Neurofibromatosis I
			5.6 Neurofibromatosis Type 2
			5.7 Rhabdoid Tumour Predisposition Syndrome
			5.8 Tuberous Sclerosis (TSC)
			5.9 Turcot Syndrome
			5.10 von Hippel–Lindau syndrome
			References
		6 Neurofibromatosis
			Summary
			6.1 Clinical Diagnosis
				6.1.1 Neurofibromatosis Type 1
				6.1.2 Neurofibromatosis Type 2
				6.1.3 Schwannomatosis
			6.2 The Disease-Causing Genes
				6.2.1 The NF1 Gene and Its Gene Product Neurofibromin
				6.2.2 The NF2 Gene and Its Gene Product Merlin
				6.2.3 INI1: The Familial Schwannomatosis Gene?
			6.3 Genetic Testing
			6.4 Clinical Manifestations
				6.4.1 Tumors Arising in NF1 Patients
				6.4.2 Tumors Arising in NF2 Patients
			6.5 Future Perspective/Translational Medicine
			References
		7 Retinoblastoma: The Prototypic Hereditary Tumor
			Summary
			7.1 Introduction
			7.2 Clinical Features
			7.3 Clinical Retinoma
			7.4 Nature of Susceptible Retinal Cell
			7.5 Progression from Normal Retina to Retinoblastoma
				7.5.1 Tumor Initiation: Bi-Allelic Inactivation of RB1
					7.5.1.1 Types of RB1 Mutations
					7.5.1.2 Penetrance and Expressivity of RB1 Mutations
					7.5.1.3 RB1 Loss and Retinoma
				7.5.2 Tumor Progression: Post-RB1 Genomic Changes in Retinoblastoma
					7.5.2.1 Genomic Gain at Chromosome 1q
					7.5.2.2 Genomic Gain of 2p: NMYC
					7.5.2.3 Genomic Gain at Chromosome 6p
					7.5.2.4 Genomic Loss at Chromosome 16q
					7.5.2.5 Cell Death Regulator p53
					7.5.2.6 NGFR/p75(NTR)
			7.6 Conclusions
			References
		8 Hereditary Cancer in the Head and Neck
			Summary
			8.1 Familial Factors in Head and Neck Squamous Cell Cancer (HNSCC)
			8.2 Interactions of Genetic and Environmental Factors
				8.2.1 Metabolizing Enzyme Polymorphism
			8.3 Mutagenicity, Genetic Susceptibility and Tumor Suppressor Genes
				8.3.1 Mutagenicity in Bleomycin Assays
				8.3.2 Multiple Primary Cancers
				8.3.3 Relationship between the Genetic Susceptibility to HNSCC and the Presence of Common Fragile Sites
				8.3.4 Germline Mutations of Tumor Suppressor Gene p16INK4a (p16)
			8.4 Familial Nasopharyngeal Carcinoma
			References
		9 Hereditary Medullary and Familial Non-Medullary Thyroid Carcinoma
			Summary
			9.1 Introduction
			9.2 Hereditary Medullary Thyroid Carcinoma
				9.2.1 Genetic Testing for MEN 2A, MEN 2B and FMTC
				9.2.2 Genotype-Phenotype-Correlation
				9.2.3 Surgical Management for Hereditary MTC
				9.2.4 Postoperative Management and Prognosis of Medullary Thyroid Carcinoma
			9.3 Familial Nonmedullary Thyroid Carcinoma
			References
		10 Lung Tumors
			Summary
			10.1 Introduction
			10.2 Familial Aggregation Studies of Lung Cancer
			10.3 Polymorphisms
				10.3.1 Detoxification Genes
				10.3.2 DNA Repair Genes
				10.3.3 Others
			10.4 Genome Wide Association Studies
			10.5 Other Thoracic Tumors
			10.6 Future Directions
			10.7 Conclusions
			References
		11 Hereditary Breast Cancer
			Summary
			11.1 Introduction
			11.2 Genetic Background
				11.2.1 High Penetrance Genes
					11.2.1.1 BRCA1
					11.2.1.2 BRCA2
				11.2.2 Low Penetrance Genes
					11.2.2.1 CHEK2
					11.2.2.2 ATM
					11.2.2.3 PALP2
				11.2.3 Genome-Wide Association Studies
			11.3 Risk Calculation
			11.4 Clinical and Histopathological Characteristics
			11.5 Clinical Management
				11.5.1 Ovarectomy
				11.5.2 Mastectomy
				11.5.3 Prevention Using Drugs
				11.5.4 Structured Surveillance
			References
		12 Hereditary Ovarian and Endometrial Cancer
			Summary
			12.1 Epidemiology
			12.2 Genetic Background
			12.3 Phenotype
			12.4 Clinical Management
			12.5 Prevention Strategies
				12.5.1 Primary Prevention
					12.5.1.1 Prophylactic Salpingo-Oophorectomy (BPSO)
					12.5.1.2 Prevention Using Drugs
				12.5.2 Secondary Prevention (Structured Surveillance)
			References
		13 Prostate Cancer
			Summary
			13.1 Epidemiology
			13.2 Phenotypes of Prostate Cancer
			13.3 Genetics
				13.3.1 Hereditary Transmission
				13.3.2 PC Susceptibility Genes
			13.4 Prevention and Early Detection
			13.5 Therapy
			13.6 Future Aspects
			References
		14 Wilms and Rhabdoid Tumors of the Kidney
			Summary
			14.1 Wilms Tumor
			14.2 The WT1 Gene and Its Functions
			14.3 Function of the WT1 Gene in the Development of the Kidneys and the Formation of Tumors
			14.4 Wilms Tumor-Associated Syndromes
			14.5 WT1 Gene Associated Syndromes
				14.5.1 Aniridia and WAGR Syndrome
				14.5.2 Genitourinary Anomalies (GU) and Isolated Nephrotic Syndrome (NS)
				14.5.3 Denys–Drash Syndrome (DDS)
				14.5.4 Frasier-Syndrome (FS)
			14.6 Non-WT1 Gene Associated Syndromes
				14.6.1 Overgrowth Syndromes
				14.6.2 Familial Wilms Tumors
				14.6.3 Tumor Predisposition Syndromes
				14.6.4 Malignant Renal Rhabdoid Tumor (MRR)
			14.7 Micro-Deletion Syndromes and Tumor Risk
			14.8 Recommendations for Genetic Counseling and Therapy
			References
		15 Hereditary Renal Tumors of the Adult
			Summary
			15.1 General Introduction
			15.2 Renal Cell Carcinoma
				15.2.1 Introduction
				15.2.2 Familial Clear Cell RCC
					15.2.2.1 Von Hippel–Lindau (VHL) Disease
					15.2.2.2 Constitutional Chromosome 3 Translocations
					15.2.2.3 Familial Clear Cell Renal Cell Cancer (FCRC)
					15.2.2.4 SDHB-Associated Heritable Paraganglioma
					15.2.2.5 Tuberous Sclerosis Complex (TSC)
				15.2.3 Familial Papillary RCC
					15.2.3.1 Hereditary Papillary RCC (HPRC)
					15.2.3.2 Hereditary Leiomyomatosis Renal Cell Cancer (HLRCC)
					15.2.3.3 Hyperparathyroidism–Jaw Tumor (HPT-JT)
					15.2.3.4 Papillary Thyroid Carcinoma with Associated Renal Neoplasia (FPTC-PRN)
				15.2.4 Familial Chromophobe RCC and Oncocytomas
					15.2.4.1 Birt–Hogg–Dubé syndrome (BHD)
				15.2.5 Medullary Renal Carcinoma (MRC)
			15.3 Transition Cell Cancers of the Renal Pelvis
				15.3.1 Lynch Syndrome
				15.3.2 Diagnostic Recommendations
				15.3.3 Therapeutic Recommendations
			References
		16 Gastrointestinal Polyposis Syndromes
			Summary
			16.1 Introduction
			16.2 Adenomatous Polyposis Syndromes
				16.2.1 APC-Associated Familial Adenomatous Polyposis (FAP)
					16.2.1.1 Classic (Typical) FAP
					16.2.1.2 Attenuated FAP (AFAP, AAPC)
					16.2.1.3 Allelic Subtypes of Classic FAP
					16.2.1.4 Genetics
					16.2.1.5 Clinical Management
				16.2.2 MUTYH-Associated Polyposis (MAP)
					16.2.2.1 Clinical Features
					16.2.2.2 Genetics
					16.2.2.3 Clinical Management
			16.3 Hamartomatous Polyposis Syndromes
				16.3.1 Peutz–Jeghers Syndrome (PJS)
					16.3.1.1 Clinical Diagnosis
					16.3.1.2 Genetics
					16.3.1.3 Tumor Risk
					16.3.1.4 Clinical Management
				16.3.2 Juvenile Polyposis Syndrome (JPS)
					16.3.2.1 Clinical Diagnosis
					16.3.2.2 Genetics
					16.3.2.3 Tumor Risk
					16.3.2.4 Clinical Management
				16.3.3 PTEN Hamartoma Tumor Syndrome (PHTS)
					16.3.3.1 Clinical Diagnosis
					16.3.3.2 Genetics
					16.3.3.3 Cancer Risk and Clinical Management
			References
		17 Lynch Syndrome (HNPCC)
			Summary
			17.1 Introduction
			17.2 Characteristics of Lynch Syndrome
			17.3 Genetic Alteration
			17.4 Lynch Syndrome, HNPCC or Familial Cancer?
			17.5 Clinical Identification
			17.6 Surveillance Colorectum
			17.7 Familial Cancer
			17.8 Surveillance of the Endometrium/Ovary
			17.9 Surveillance for Other Related Cancers
			17.10 Surgical Management
			17.11 Chemotherapy
			References
		18 Gastrointestinal Stromal Tumors (GISTs)
			Summary
			18.1 Sporadic GISTs
				18.1.1 Epidemiology and Clinicopathologic Features of GISTs
				18.1.2 The KIT Gene
				18.1.3 Pathogenesis and Molecular Features of GISTs
				18.1.4 Imatinib Mesylate in the Treatment of Advanced GISTs
			18.2 Hereditary GISTs
				18.2.1 Familial GIST Syndrome
				18.2.2 GISTs Associated with Neurofibromatosis Type I
				18.2.3 Carney–Stratakis Syndrome
				18.2.4 Carney Triad
			References
		19 Hereditary Gastric Cancer
			Summary
			19.1 Introduction to Gastric Cancer
			19.2 Criteria of Potential Heredity
			19.3 Hereditary Gastric Cancer
			19.4 Hereditary Diffuse Type Gastric Cancer (HDGC)
				19.4.1 Clinical Presentation
				19.4.2 Molecular Genetics
				19.4.3 Histology
				19.4.4 Surveillance, Predictive Testing, and Therapy
			19.5 HNPCC Associated Gastric Cancer
				19.5.1 Clinical Presentation
				19.5.2 Molecular Genetics
				19.5.3 Histology
				19.5.4 Surveillance, Predictive Testing and Therapy
			19.6 Familial Gastric Cancer of Unknown Origin
				19.6.1 Clinical Presentation
				19.6.2 Molecular Genetics
				19.6.3 Histology
				19.6.4 Surveillance and Therapy
			19.7 Gastric Cancer as Part of Rare Hereditary Tumor Syndromes
			19.8 Impact of Polymorphisms on Gastric Cancer Risk
			19.9 Future Perspectives
			References
		20 Pancreatic Cancer
			Summary
			20.1 Introduction
			20.2 History and Epidemiology of Familial Pancreatic Cancer
			20.3 Inherited Tumor Syndromes Associated with Pancreatic Cancer
				20.3.1 Familial Atypical Multiple Mole Melanoma
				20.3.2 Peutz–Jeghers Syndrome
				20.3.3 Hereditary Breast and Ovarian Cancer
				20.3.4 Hereditary Nonpolyposis Colon Cancer and Familial Adenomatous Polyposis
				20.3.5 Ataxia Telangiectasia
				20.3.6 Pancreatic Cancer and Basal Cell Carcinoma
			20.4 Hereditary Pancreatitis and Cystic Fibrosis
			20.5 Familial Pancreatic Cancer
				20.5.1 Genetic Background of Familial Pancreatic Cancer
				20.5.2 Current Status of Surveillance and Treatment in FPC
			20.6 Conclusion
			References
		21 Liver Tumors
			Summary
			21.1 Introduction
			21.2 Hereditary Diseases Affecting Liver Function and Carcinogenesis
				21.2.1 Hemochromatosis
				21.2.2 Wilson’s Disease
				21.2.3 Alpha 1-Antitrypsin Deficiency
				21.2.4 Cystic Fibrosis
				21.2.5 Galactosemia
				21.2.6 Fructosemia
				21.2.7 Tyrosinemia
				21.2.8 Glycogen Storage Disease
				21.2.9 Beckwith–Wiedemann Syndrome
				21.2.10 FAP (Familial Adenomatous Polyposis)
				21.2.11 Alagille Syndrome
			21.3 Liver Carcinogens
			21.4 Cancer Genetics
			References
		22 DNA-Repair Deficiency and Cancer: Lessons from Lymphoma
			Summary
			22.1 Introduction
			22.2 DNA Repair
			22.3 Base Excision Repair (BER)
			22.4 Nucleotide Excision Repair (NER)
			22.5 Mismatch Repair (MMR)
			22.6 Reversion Repair (RER)
			22.7 Recombination Repair (RR)
			22.8 Genetic Diseases with a High Risk of Lymphoma: Ataxia-Telangiectasia and Nijmegen Breakage-Syndrome
			22.9 Lymphoma in Ataxia-Telangiectasia and Nijmegen Breakage Syndrome
			22.10 Treatment of Malignancies in Nijmegen Breakage Syndrome
			22.11 Somatic Mutations in Sporadic Lymphoma
			22.12 Outlook and Perspectives
			References
		23 Familial Leukemias
			Summary
			23.1 Introduction
			23.2 Leukemias Associated with Genetic Syndromes
				23.2.1 DNA Repair Deficiency Syndromes
				23.2.2 Bone Marrow Failure Syndromes
					23.2.2.1 Fanconi’s Anemia
					23.2.2.2 Dyskeratosis Congenita
					23.2.2.3 Shwachman-Diamond Syndrome
					23.2.2.4 Severe Congenital Neutropenia and Kostmann Syndrome
					23.2.2.5 Diamond-Blackfan Anemia
				23.2.3 Constitutional Chromosome Anomalies
					23.2.3.1 Down’s Syndrome (Trisomy 21)
					23.2.3.2 Trisomy 8
				23.2.4 Hereditary Tumor Predisposition Syndromes
					23.2.4.1 Li–Fraumeni Syndrome
					23.2.4.2 Neurofibromatosis Type 1
					23.2.4.3 Noonan Syndrome
				23.2.5 Hemochromatosis
			23.3 Hereditary Non-Syndromal Leukemia
				23.3.1 Familial Thrombocytopenia with Leukemia Predisposition and Mutation of the CBFA2/RUNX1/AML1 Gene
				23.3.2 CEBPA Mutations and Familial AML
				23.3.3 Familial Myelodysplasia of Childhood with Monosomy 7
				23.3.4 Familial Chronic Lymphocytic Leukemia
				23.3.5 Genetic Susceptibility Factors for CLL and Other Leukemias
			References
		24 Malignant Melanoma
			Summary
			24.1 Introduction
				24.1.1 Epidemiology
					24.1.1.1 High Penetrance Genes
					24.1.1.2 Low Penetrance Genes
			24.2 More Melanoma-Susceptibility Genes
			24.3 Sporadic Melanoma
			24.4 Conclusion
			Abbreviations
			References
		25 Xeroderma Pigmentosum, Cockayne Syndrome, Trichothiodystrophy – Defects in DNA Repair and Carcinogenesis
			Summary
			25.1 The Nucleotide Excision Repair (NER) – Defective Syndromes
				25.1.1 Xeroderma Pigmentosum (XP)
				25.1.2 XP Plus Neurologic Abnormalities
				25.1.3 Cockayne Syndrome (CS)
				25.1.4 XP/CS Complex
				25.1.5 Trichothiodystrophy (TTD)
				25.1.6 XP/TTD Complex
				25.1.7 COFS (Cerebro-Oculo-Facio-Skeletal Syndrome)
			25.2 The Nucleotide Excision Repair (NER) Pathway
				25.2.1 Damage Recognition (I)
				25.2.2 Damage Demarcation (II)
				25.2.3 Incision of the Damage Containing DNA Strand (III)
				25.2.4 Removal of the Damage Containing Oligonucleotide (IV)
				25.2.5 Gap Filling (V)
			References
		26 Hereditary Tumors in Children
			Summary
			26.1 Introduction
			26.2 Familial Neoplastic Syndromes Associated with Childhood Cancer
			26.3 Non-Neoplastic Genetic Syndromes Associated with Childhood Cancer
			26.4 Numerical Chromosome Abnormalities Associated with Childhood Cancer
			26.5 Inherited Immune Deficiency Syndromes Associated with Childhood Cancer
			26.6 Inherited Bone Marrow Failure Syndromes Associated with Childhood Cancer
			26.7 Conclusions
			References
		27 Sarcomas and Bone Tumors in Adulthood
			Summary
			27.1 Epidemiology
				27.1.1 Incidence of Soft Tissue and Bone Sarcomas in General
				27.1.2 Mortality
				27.1.3 Proportion of Hereditary Tumors
			27.2 Syndromes
				27.2.1 Prevention/Prediction
			References
	Part IV Genetic Counseling, Psycho-Oncology, and General Perspectives for Therapeutic Strategies
		28 Genetic Counseling for Hereditary Tumors
			Summary
			28.1 Introduction
			28.2 Counseling Process
				28.2.1 First Contact and Counseling Session
				28.2.2 Documentation of the Pedigree and the Medical History
				28.2.3 Risk Calculation
				28.2.4 Risk Communication Strategies
				28.2.5 Pre-Test Counseling
				28.2.6 Physical Examination
				28.2.7 Written Report
				28.2.8 Post-Test Counseling
				28.2.9 Psychosocial Aspects
				28.2.10 Communication of Genetic Test Results within the Family
				28.2.11 Problems Due to Failed Communication
				28.2.12 Testing Children for Cancer Susceptibility
			28.3 Outlook
			References
		29 Psycho-Oncologic Aspects of Hereditary Tumors and Predictive Testing
			Summary
			29.1 Introduction
			29.2 The Psychosomatics Concerning the Discrepancies Between Physician, Patient, and Diagnosis
			29.3 Expectations Concerning the Diagnostics
			29.4 Function of Psychosomatics in the Interdisciplinary Consultation Setting
			29.5 Psychosomatic Aspects of the Patient
			29.6 Variables on Notification of Diagnosis
			29.7 Psychosomatic–Psychotherapeutic Procedures
			29.8 Conclusion
			References
		30 Molecular Targeted Therapy
			Summary
			30.1 Introduction
			30.2 Example for Success: Targeting Tyrosine Kinase Receptors, for Example, EGF-R
			30.3 Example: Targeting Apoptosis Pathways for Cancer Therapy
				30.3.1 Apoptosis Signaling Pathways
				30.3.2 Exploiting the Apoptotic Machinery for Cancer Therapy
					30.3.2.1 Targeting Death Receptors for Cancer Therapy
					30.2.2.2 Targeting the Mitochondrial Pathway for Cancer Therapy
					30.3.2.3 Targeting “Inhibitor of Apoptosis Proteins” (IAPs) for Cancer Therapy
			30.4 The Challenge of Today: Defining the Right Patients for the Right Therapeutic Concept
			30.5 Conclusion
			References
	Index