Friday, June 6, 2014

Rare Cancers

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



-Jules J. Berman, Ph.D., M.D.