This week, my latest book entitled
Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Academic Press, an imprint of Elsevier.
The book develops a set of biological principles that apply to rare diseases and which distinguish the rare diseases from the common diseases on something other than a numeric basis (i.e., not just by their rarity).
Chapter 8 discusses the rare cancers, and their relationships to the common cancers.
The chapter is sprinkled with general rules that are discussed in depth within the text.
Here, the term “rule” means observations that are generally
true. In many cases, counter-examples and constraints
are also provided in the chapter. The rules are intended to encourage readers
to think critically about the subject matter. Readers will find that the disease
descriptions in the chapters will have greater meaning if the disease can be
associated with a biological rule.
Here are the "rules" of rare cancers.
8.2.1 Rule—Most common cancers are caused by environmental agents.
Brief Rationale—The vast majority of cancers occur at body sites that are
directly exposed to chemical, physical, or biological agents delivered by food,
water, and air. The tissues that receive the highest levels of exposure are the
same tissues that yield the highest number of tumors. Tissues of the body that
are not directly exposed to outside agents (e.g., muscle, connective tissues) are
not sites at which common cancers develop.
8.2.2 Rule—In adults, diseases of cells derived from ectoderm or from endoderm
typically have an environmental cause.
Brief Rationale—Tissues deriving from ectoderm and endoderm are exposed
to toxins at higher levels than are the tissues that derive from mesoderm. When
a disease targets ectodermal- or endodermal-derived cells in adults, it is likely
to have a toxic etiology. Cells of mesodermal origin (i.e., the inside cells) are
typically spared, because they are less exposed to the environment.
8.2.3 Rule—Most of the metabolism of foreign compounds entering the
human body is handled by cells derived from endoderm or ectoderm.
Brief Rationale—It stands to reason that the cells that receive the brunt of
environmental toxins will be the cells that are adapted to detoxify exogenous
chemicals.
8.2.4 Rule—Most chemical carcinogens need to be metabolized before they
are converted to an active (i.e., mutagenic) molecular form.
Brief Rationale—Activated carcinogens are highly reactive molecules that
can bind to just about any kind of molecule. Naturally active carcinogens would
react with, and be neutralized by, non-genetic molecules before they could reach
DNA. Highly carcinogenic molecules exist as stable, inactive molecular species
that are metabolized within cells to active molecules that react with DNA.
8.3.1 Rule—Virtually all cancers of childhood have a germline genetic component
to their pathogenesis.
Brief Rationale—The common cancers have multi-step etiologies, requiring
many years to develop, and occurring in adults. Children simply do not have the
opportunity to express diseases that involve repeated exposures to commonly
occurring environmental agents. Hence, cancers in children develop from
inborn mutations. Cancer-causing germline mutations are rare; hence, childhood
cancers are rare.
8.3.2 Rule—Rare tumors are much more likely to have a single cause, a single
carcinogenic pathway, a single inherited gene, or a single acquired marker, than
are any of the common tumors.
Brief Rationale—Many different factors can lead to a common cancer; that
is why the cancer is common. Only very specific and highly unlikely factors
(e.g., genetic mutation) lead to rare cancers; that is why they are rare.
8.3.3 Rule—In a tumor that can occur as a rare, inherited form, or as a common,
sporadic form, we always learn the most by studying the rare, inherited
form and later extending our gained knowledge to the common, sporadic form.
Brief Rationale—Only the subset of cases arising from an inherited germline
mutation can be studied in affected and unaffected relatives.
8.3.4 Rule—If you look hard enough, you can usually find examples of syndromic
disorders accounting for what might otherwise be considered to be a
sporadic or non-syndromic childhood cancer.
Brief Rationale—A germline mutation having the biological power to cause
cancer might be expected to produce some additional phenotypic effects in the
organism.
8.3.5 Rule—There is no such thing as a mutation that is necessary and sufficient,
by itself, to cause cancer.
Brief Rationale—In the worst of the inherited cancer syndromes, tumors do
not occur in every organ, or even in every individual who carries the cancercausing
mutation. The empiric absence of a 100% penetrant cancer mutation
(i.e., one that always causes cancer) suggests that more than one event or condition
must prevail during carcinogenesis.
8.3.6 Rule—In contrast to rare cancers, common cancers are characterized
by many different mutations in many different genes, and the affected genes will
vary from patient to patient and from tumor sample to tumor sample within the
same patient.
Brief Rationale—Common cancers are genetically unstable.
8.4.1 Rule—Carcinogenesis, the pathogenesis of tumors, is a multi-step
process.
Brief Rationale—Interventions can stop the process of carcinogenesis at
various points in tumor development (e.g., the precancer stage), indicating the
presence of multiple biological steps, each with characteristic properties and
vulnerabilities.
8.4.2 Rule—Each step in carcinogenesis is a potential target of cancer
prevention.
Brief Rationale—The key thing to know about carcinogenesis is that it
occurs in steps. Because there are multiple steps in carcinogenesis, there are
multiple opportunities for blocking the progression of cancer [6,7].
8.4.3 Rule—Rare cancers and rare cancer syndromes have helped us to
dissect the various steps of carcinogenesis.
Brief Rationale—We see rare cancers and rare cancer syndromes that target
various cellular processes occurring throughout carcinogenesis. These would
include polymorphisms in genes that metabolize carcinogens at the time of
initiation, that repair DNA (e.g., xeroderma pigmentosum), that preserve the
integrity of DNA replication, that control microsatellite stability (e.g., hereditary
non-polyposis colon cancer syndrome), that control apoptosis, that activate
tumor suppressor genes (e.g., Li–Fraumeni syndrome) and tumor oncogenes
(BCR/ABL fusion gene in chronic myelogenous leukemia), that drive hyper-
plasia of particular cell types (e.g., c-KIT gastrointestinal stromal tumors), and
so on.
8.4.4 Rule—Rare cancers are easier to cure than common cancers.
Brief Rationale—The malignant phenotypes of rare cancers are often driven
by a single genetic alteration or a single cellular pathway. It is feasible to target
and inhibit a single pathway with a single drug. Common cancers are driven
by hundreds or thousands of aberrant pathways. We currently have no way of
inhibiting all of the possible pathways that drive the malignant phenotype in
common cancers.
TABLE OF CONTENTS for Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases
PART I. Understanding the Problem
1. What are the Rare Diseases, and Why Do We Care?
1.1 The Definition of Rare Disease
1.2 Remarkable Progress in the Rare Diseases
2. What are the Common Diseases?
2.1 The Common Diseases of Humans, a Short but Terrifying List
2.2 The Recent Decline in Progress against Common Diseases
2.3 Why Medical Scientists have Failed to Eradicate the Common Diseases
3. Six Observations to Ponder While Reading This Book
3.1 Rare Diseases are Biologically Different from Common Diseases
3.2 Common Diseases Typically Occur in Adults; Rare Diseases are Often Diseases of Childhood
3.3 Rare Diseases Usually Occur with a Mendelian Pattern of Inheritance. Common Diseases are Non-Mendelian
3.4 Rare Diseases Often Occur as Syndromes, Involving Several Organs or Physiologic Systems, Often in Surprising Ways. Common Diseases are Typically Non-Syndromic
3.5 Environmental Factors Play a Major Role in the Cause of Common Diseases; Less so in the Inherited Rare Diseases
3.6 The Difference in Rates of Occurrence of the Rare Diseases Compared with the Common Diseases is Profound, Often on the Order of a Thousand-Fold
3.7 There are Many More Rare Diseases than there are Common Diseases
PART II. Rare Lessons for Common Diseases
4. Aging
4.1 Normal Patterns of Aging
4.2 Aging and Immortality
4.3 Premature Aging Disorders
4.4 Aging as a Disease of Non-Renewable Cells
5. Diseases of the Heart and Vessels
5.1 Heart Attacks
5.2 Rare Desmosome-Based Cardiomyopathies
5.3 Sudden Death and Rare Diseases Hidden in Unexplained Clinical Events
5.4 Hypertension and Obesity: Quantitative Traits with Cardiovascular Co-Morbidities
6. Infectious Diseases And Immune Deficiencies
6.1 The Burden of Infectious Diseases in Humans
6.2 Biological Taxonomy: Where Rare Infectious Diseases Mingle with the Common Infectious Diseases
6.3 Biological Properties of the Rare Infectious Diseases
6.4 Rare Diseases of Unknown Etiology
6.5 Fungi as a Model Infectious Organism Causing Rare Diseases
7. Diseases of Immunity
7.1 Immune Status and the Clinical Expression of Infectious Diseases
7.2 Autoimmune Disorders
8. Cancer
8.1 Rare Cancers are Fundamentally Different from Common Cancers
8.2 The Dichotomous Development of Rare Cancers and Common Cancers
8.3 The Genetics of Rare Cancers and Common Cancers
8.4 Using Rare Diseases to Understand Carcinogenesis
PART III. Fundamental Relationships between Rare and Common Diseases
9. Causation And the Limits of Modern Genetics
9.1 The Inadequate Meaning of Biological Causation
9.2 The Complexity of the So-Called Monogenic Rare Diseases
9.3 One Monogenic Disorder, Many Genes
9.4 Gene Variation and the Limits of Pharmacogenetics
9.5 Environmental Phenocopies of Rare Diseases
10. Pathogenesis; Causation's Shadow
10.1 The Mystery of Tissue Specificity
10.2 Cell Regulation and Epigenomics
10.3 Disease Phenotype
10.4 Dissecting Pathways Using Rare Diseases
10.5 Precursor Lesions and Disease Progression
11. Rare Diseases and Common Diseases: Understanding Their Fundamental Differences
11.1 Review of the Fundamentals in Light of the Incidentals
11.2 A Trip to Monte Carlo: How Normal Variants Express a Disease Phenotype
11.3 Associating Genes with Common Diseases
11.4 Mutation Versus Variation
12. Rare Diseases and Common Diseases: Understanding Their Relationships
12.1 Shared Genes
12.2 Shared Phenotypes
13. Shared Benefits
13.1 Shared Prevention
13.2 Shared Diagnostics
13.3 Shared Cures
14. Conclusion
14.1 Progress in the Rare Diseases: Social and Political Issues
14.2 Smarter Clinical Trials
14.3 For the Common Diseases, Animals are Poor Substitutes for Humans
14.4 Hubris
Appendix I List of Genes Causing More Than One Disease
Appendix II Rules, Some of Which are Always True,
and All of Which are Sometimes True
Glossary
Index
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Jules J. Berman, Ph.D., M.D.
