Rare Cancers Hiding Among Common Cancers

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

Here is an excerpt from Chapter 12:

It is easy to find cases wherein a rare disease accounts for a somewhat uncommon clinical presentation of a common disease.

12.1.2 Rule—Uncommon presentations of common diseases are sometimes rare diseases, camouflaged by a common clinical phenotype.
Brief Rationale—Common diseases tend to occur with a characteristic clinical phenotype and a characteristic history (e.g., risk factors, underlying causes). Deviations from the normal phenotype and history are occasionally significant.

Rare diseases may produce a disease that approximates the common disease; the differences being subtle findings revealed to the most astute observers. Here is some pithy wisdom that senior physicians love to impart to junior colleagues: “When you see hoof prints, look for horses, not zebras.” The message warns young doctors that most clinical findings can be accounted for by common diseases. Nonetheless, physicians must understand that zebras, unlike unicorns and griffins, actually exist. Occasionally, a rare disease will present with the clinical phenotype of a common disease.

For example, mutations of the JAK2 gene are involved in several myeloproliferative conditions, including myelofibrosis, polycythemia vera (see Glossary item, Polycythemia), and at least one form of hereditary thrombocythemia (i.e., increased blood platelets) [9–11]. Surprisingly, somatic blood cells with JAK2 mutations are found in 10% of apparently healthy individuals [12]. The high incidence of JAK2 mutations in the general population, and the known propensity for JAK2 mutations to cause thrombocythemia and thrombosis, should alert physicians to the possibility that some cases of idiopathic thrombosis may be caused by a platelet disorder caused by undiagnosed JAK2 mutation of blood cells. As it happens, it has been shown that a JAK2 mutation can be found in 41% of patients who present with idiopathic chronic portal, splenic and mesenteric venous thrombosis [13]. Such thrombotic events are uncommon in otherwise healthy patients. The search for a zebra, in this case a cryptic myeloproliferative disorder caused by a JAK2 mutation, pays off (see Glossary item, Myeloproliferative disorder).

Zebras can hide among the horses. Consider lung cancer, the number one cause of cancer deaths in the U.S. When lung cancer occurs in a young person, you might wonder if this is a rare disease cloaked as a common disease. Midline carcinoma of children and young adults is an extremely rare type of lung cancer. It is characterized by a NUT gene mutation, not typically found in commonly occurring lung cancers of adults [14]. Hence, midline carcinoma of children and young adults is an example of a rare disease hidden in a common disease. Secretory carcinoma, formerly known as juvenile breast cancer, is a rare form of breast cancer. It has a less aggressive clinical course than commonly occurring breast cancer, and occurs at a younger median age (i.e., about 25 years) than the median age of occurrence of common breast cancer (i.e., 61 years). In 2002, it was discovered that the expression of the ETV6-NTRK3 gene fusion is a primary event in the carcinogenesis of secretory breast carcinoma [15]. Once again, an uncommon presentation of a common tumor was found to hide a rare disease with its own characteristic genetic mutation.

Myelodysplastic syndrome, formerly known as preleukemia, is a rare blood disorder occurring almost exclusively in older individuals. The specific gene causing myelodysplastic syndrome is unknown, but recurrent cytogenetic alterations have been found in bone marrow cells, particularly losses of the long arm of chromosome 5 (i.e., 5q-) and of chromosome 7 (i.e., monosomy 7). Myelodysplastic syndrome occurs in very young children, with extreme rarity. Virtually all such childhood cases involve monosomy 7. An inherited predisposition to lose one copy of chromosome 7 in somatic cells has been reported in kindreds whose children have a high likelihood of developing myelodysplastic syndrome, or of acute leukemia. Hence, it seems that a somatic chromosomal abnormality associated with a rare disease occurring in adults is also associated with an even more rare childhood form of the disease. The childhood disease may occur when an inherited mutation predisposes children to the equivalent somatic chromosomal abnormality observed in the adult form of the disease [16,17].

As a final example, there are two recognized types of acute myelogenous leukemia (AML): AML following myelodysplasia, a preleukemia, and de novo AML, which develops in the absence of an observed preleukemic condition [18]. De novo AML can occur in children or in adults. The de novo AML cases in children have a different set of cytogenetic markers than those observed in adult de novo AML [19].

I urge you to read more about my book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D. tags: common disease, orphan disease, orphan drugs, rare disease, subsets of disease, disease genetics, genetics of complex disease, genetics of common diseases, cryptic disease

The 80/20 Rule

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

The book has an extensive glossary, that explains the meaning and relevance of medical terms appearing throughout the chapters. The glossary can be read as a stand-along document. Here is an example of one term, "Pareto's Principle", excerpted from the glossary.

Pareto’s principle - Also known as the 80/20 rule, Pareto’s principle holds that a small number of items account for the vast majority of observations. For example, a small number of rich people account for the majority of wealth. Just two countries, India plus China, account for 37% of the world population. Within most countries, a small number of provinces or geographic areas contain the majority of the population of a country (e.g., east and west coastlines of the U.S.). A small number of books, compared with the total number of published books, account for the majority of book sales.

Likewise, a small number of diseases account for the bulk of human morbidity and mortality. For example, two common types of cancer, basal cell carcinoma of skin and squamous cell carcinoma of skin, account for about 1 million new cases of cancer each year in the U.S. This is approximately the sum total for all other types of cancer combined. We see a similar phenomenon when we count causes of death. About 2.6 million people die each year in the U.S. [98]. The top two causes of death account for 1,171,652 deaths (596,339 deaths from heart disease and 575,313 deaths from cancer [99]), or about 45% of all U.S. deaths. All of the remaining deaths are accounted for by more than 7000 conditions.

Sets of data that follow Pareto’s principle are often said to follow a Zipf distribution, or a power law distribution. These types of distributions are not tractable by standard statistical descriptors because they do not produce a symmetric bell-shaped curve. Simple measurements such as average and standard deviation have virtually no practical meaning when applied to Zipf distributions. Furthermore, the Gaussian distribution does not apply, and none of the statistical inferences built upon an assumption of a Gaussian distribution will hold on data sets that observe Pareto’s principle.

I urge you to read more about my book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D. tags: 80/20 rule, common disease, data analysis, glossary, orphan disease, orphan drugs, rare disease, statistics

Hamartoma Syndromes

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

The book has an extensive glossary, that explains the meaning and relevance of medical terms appearing throughout the chapters. The glossary can be read as a stand-along document. Here is an example of one term, "hamartoma", excerpted from the glossary.

Hamartoma - Hamartomas are benign tumors that occupy a peculiar zone lying between neoplasia (i.e., a clonal expansion of an abnormal cell) and hyperplasia (i.e., the localized overgrowth of a tissue). Some hamartomas are composed of tissues derived from several embryonic lineages (e.g., ectodermal tissues mixed with mesenchymal tissue). This is almost never the case in cancers, which are clonally derived neoplasms wherein every cell is derived from a single embryonic lineage. Tuberous sclerosis is an inherited hamartoma syndrome. The pathognomonic lesion in tuberous sclerosis is the brain tuber, from which the syndrome takes its name. Tubers of the brain consist of localized but poorly demarcated malformations of neuronal and glial cells. Like other hamartoma syndromes, the germline mutation in tuberous sclerosis produces benign hamartomas as well as carcinomas, indicating that hamartomas and cancers are biologically related. Hamartomas and cancers associated with tuberous sclerosis include cortical tubers of brain, retinal astrocytoma, cardiac rhabdomyoma, lymphangiomyomatosis (very rarely), facial angiofibroma, white ash leaf-shaped macules, subcutaneous nodules, cafe-au-lait spots, subungual fibromata, myocardial rhabdomyoma, multiple bilateral renal angiomyolipoma, ependymoma, renal carcinoma, subependymal giant cell astrocytoma [62].

Another genetic condition associated with hamartomas is Cowden syndrome, also known as multiple hamartoma syndrome. Cowden syndrome is associated with a loss of function mutation in PTEN, a tumor suppressor gene. Features that may be encountered are macrocephaly, intestinal hamartomatous polyps, benign hamartomatous skin tumors (multiple trichilemmomas, papillomatous papules, and acral keratoses), dysplastic gangliocytoma of the cerebellum, and a predisposition to cancers of the breast, thyroid and endometrium.

I urge you to read more about my book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D. tags: rare disease, genetic disease, orphan disease, orphan drugs, types of cancer, tumor biology, rare cancers, hyperplasia, tissue overgrowth, carcinogenesis, glossary

Mosaic Variegated Aneuploidy Syndrome-1

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

The book has an extensive glossary, that explains the meaning and relevance of medical terms appearing throughout the chapters. The glossary can be read as a stand-along document. Here is an example of one term, "aneuploidy", excerpted from the glossary.

Aneuploidy - The presence of an abnormal number of chromosomes (for the species) in a cell. Most cancers contain aneuploid cells; an observation that holds true for virtually every poorly differentiated cancer. Aneuploidy is seen less often in benign tumors and well-differentiated tumors. Aneuploidy is also found in epithelial precancers and other growing lesions that can sometimes regress spontaneously (e.g., keratoacanthoma). These observations have prompted speculation that chromosomal instability and the acquisition of aneuploidy is an underlying cause of the cancer phenotype (i.e., tumor growth, invasion into surrounding tissues, and metastases).

Such causal associations invite skepticism, particularly in the realm of cancer biology, as virtually every cellular process and constituent of cancer cells has been shown to deviate from the norm. Nonetheless, there is good reason to suspect that aneuploidy is at least a factor in tumor development, as mutations that cause aneuploidy are associated with a heightened risk of cancer (e.g., Brca1 gene mutations [13] and mutations of mitotic checkpoint genes [14]). Cancer researchers have warned that aneuploidy, by itself, may not cause cancer [15]. Aneuploidy may need to be accompanied by other factors associated with genetic instability, such as the accumulation of DNA damage, specific cancer-causing mutations, epigenomic and cytogenetic abnormalities, and reduced cell death [15].

As usual, a rare disease helps to clarify the role of aneuploidy in carcinogenesis. Mosaic variegated aneuploidy syndrome-1 (MVA1) is caused by a homozygous or compound heterozygous mutation in the BUB1B gene, which encodes a key protein in the mitotic spindle check point. This disease is characterized by widespread aneuploidy in more than 25% of the cells of the body, and a heightened risk of developing childhood cancers (e.g., rhabdomyosarcoma, Wilms tumor, and leukemia). Because the underlying cause of mosaic variegated aneuploidy syndrome-1 is a gene that produces aneuploidy, and because such aneuploidy is an early event (i.e., congenital) that precedes the development of cancer and that is found in the developed cancer cells, then it is reasonable to infer that aneuploidy is closely associated with events that lead to cancer. See Mutator phenotype, Carcinogenesis, Cytogenetics, and Karyotype.

I urge you to read more about my book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D. tags: rare disease, common disease, orphan disease, orphan drugs, types of cancer, cancer types, tumor types, tumor biology, rare cancers, common cancers, aneuploidy, cytogenetics, euploidy, carcinogenesis, glossary

Virtually Every Type of Cancer is a Rare Cancer

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

Here is an excerpt from Chapter 8:

There are about 6000 types of cancer that have been assigned names by pathologists [4–6]. About a dozen of these cancers are common diseases. The remaining cancers (i.e., about 6000 entities) comfortably qualify as “rare” under U.S. Public Law 107-280, the Rare Diseases Act of 2002 [7]. Consequently, healthcare workers must somehow come to grips with 6000 types of rare cancers.

Moreover, the variety of rare cancers is increasing rapidly. As we learn more and more about the genetics of cancers, we find that the common cancers can be subtyped into genetically distinct groups. Furthermore, we are finding an increasing number of alternate alleles and heterogeneous genes that account for rare diseases.

Hence, the trend is leading us to divide the common cancers into genetically distinct subtypes that qualify as rare cancers, and to divide the known rare cancers into ultra-rare subtypes.

I urge you to read more about my book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D. tags: rare disease, common disease, orphan disease, orphan drugs, types of cancer, cancer types, tumor types, tumor biology, rare cancers, common cancers

Clinical Trials for Rare Diseases are More Effective than Clinical Trials for Common Diseases

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

For a variety of reasons, clinical trials for rare diseases tend to have much greater likelihood of success than clinical trials on common diseases. Moreover, treatments developed for the rare diseases will almost always find some value in the treatment of one or more common diseases [a major theme discussed developed in the book]. Here is a short excerpt from Chapter 14.

It can be difficult or impossible to enroll all the patients required for a clinical trial. In an analysis of 500 planned cancer trials, 40% of trials failed to accrue the minimum necessary number of patients. Of cancer trials that have passed through preclinical, phase I clinical, and phase II clinical trials, three out of five failed to achieve the necessary patient enrollment to move into the final phase III clinical trial [12]. Most clinical trials for cardiovascular disease, diabetes, or depression are designed to be even larger than cancer trials [12].

Overall, about 95% of drugs that move through the clinical trial gauntlet will fail [13]. Of the 5% of drugs that pass, their value may be minimal. To pass a clinical trial, a drug must have proven efficacy. It need not be curative; only effective. Of the drugs that pass clinical trials, some will have negligible or incremental benefits. After a drug has reached market, its value to the general population might be less than anyone had anticipated. Clinical trials, like any human endeavor, are subject to error [14–16]. Like any human endeavor, clinical trials need to be validated in clinical practice [10]. It may take years or decades to determine whether a treatment that demonstrated a small but statistically significant effect in a clinical trial will have equivalent value in everyday practice.

Funders of medical research are slowly learning that there simply is not enough money or time to conduct all of the clinical trials that are needed to advance medical science at a pace that is remotely comparable to the pace of medical progress in the first half of the twentieth century.

14.2.2 Rule—Clinical trials for common diseases have limited value if the test population is heterogeneous; as is often the case.
Brief Rationale—Abundant evidence suggests that most common diseases are heterogeneous, composed of genotypically and phenotypically distinct disease populations, with each population responding differently with the clinical trial.

The population affected by a common disease often consists of many distinct genetic and phenotypic subtypes of the disease; essentially many different diseases. A successful clinical trial for a common disease would require a drug that is effective against different diseases that happen to have a somewhat similar phenotype. One-size-fits-all therapies seldom work as well as anticipated, and more than 95% of the clinical trials for common diseases fail [13].

14.2.3 Rule—Clinical trials for the rare diseases are less expensive, can be performed with less money, and provide more definitive results than clinical trials on common diseases. Brief Rationale—Common diseases are heterogeneous and produce a mixed set of results on subpopulations. This in turn dilutes the effect of a treatment and enlarges the required number of trial participants. Rare diseases are homogeneous, thus producing a uniform effect in the trial population, and thus lowering the number of trial participants required to produce a statistically convincing result.

Rare diseases often have a single genetic aberration, driving a single metabolic pathway that results in the expression of a rather uniform clinical phenotype. This means that a drug that succeeds in one patient will likely succeed in every patient who has the same disease. Likewise, a drug that fails in one patient will fail in all the other patients. This phenomenon has enormous consequences for the design of clinical trials. When the effects of drugs are consistent, the number of patients enrolled in clinical trials can be reduced, compared with the size of clinical trials wherein the effects of drugs are highly variable among the treated population. In general, clinical trials targeted on rare diseases or on genotypically distinct subsets of common diseases require fewer enrolled participants than trials conducted on heterogeneous populations that have a common disease [13].

It is wrong to assume that because rare diseases affect fewer individuals than do the common diseases, it would be difficult to recruit a sufficient number of patients into an orphan drug trial. Due to the energetic and successful activities of rare disease organizations, registries of patients have been collected for hundreds of different conditions. For the most part, patients with rare diseases are eager to enroll in clinical trials. The rare disease registries, made available to clinical trialists, eliminate the hit-or-miss accrual activities that characterize clinical trials for common diseases.

I urge you to read more about my book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D. tags: rare disease, common disease, orphan disease, orphan drugs, clinical trials, complex disease, ancillary studies, trial design, statistical significance, reproducibility,

Disease Causality: Unexpected Complexity from Simple Gene Defects

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

One of the points discussed in the book is disease causation, and how we often fool ourselves into thinking that we understand how a disease develops, simply because we can name the gene or agent that precipitates the disease.

A gene may code for a single protein, but complex genetic and epigenetic conditions will effect the individual's response to a specific gene defect. Hence, different individuals, each with their own unique genome and epigenome, will respond differently to the same genetic aberration. Here is an excerpt from Chapter 9:

If a disease were truly caused by an aberration of a single gene, then all of the consequences of the genetic aberration would be identical in every person with the gene. In fact, some monogenic diseases have remarkably uniform clinical phenotypes in affected populations (e.g., sickle cell disease). What would happen if the same genetic aberration were recapitulated in a mouse? If the mouse homologue served the same purpose as the human gene, and if the gene were the sole cause of the disease, then you might expect the disease to be the same in man and mouse.

Lesch–Nyhan disease is a rare syndrome caused by a deficiency of HGPRT (hypoxanthine-guanine phosphoribosyl transferase), an enzyme involved in purine metabolism. In humans, HGPRT deficiency results in high levels of uric acid, with resultant renal disease and gout. A vast array of neurologic and psychologic signs accompanies the syndrome, including self-mutilation. Neurologic features tend to increase as the affected child ages. The same HGPRT deficiency of humans can be produced in mice. Mice with HGPRT deficiency do not have disease. As far as anyone can tell, mice with HGPRT deficiency are totally normal [18]. How can this be?

A single gene cannot cause a disease all by itself. Every monogenic disease is expressed in a complex system wherein the defective gene is a participant in various pathways that eventually lead to a disease. The mouse, evidently, has a set of pathways that compensates for the deficiency in HGPRT.

Diabetes is usually a common polygenic disease. There are rare subtypes of type 2 diabetes that have a monogenic origin. As you would expect, these rare subtypes arise in children, and have a Mendelian pattern of inheritance. One such monogenic form of diabetes is MODY-8 (maturity-onset diabetes of the young), caused by a mutation in the carboxyl-ester lipase gene. This same mutation was delivered to a transgenic mouse, intended as an animal model for MODY (see Glossary item, Transgenic). Mice carrying the same altered gene as the human failed to develop any signs of diabetes, or pancreatic damage, or any dysfunction caused by the mutated gene [19].

I urge you to read more about my book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D. tags: rare disease, common disease, orphan disease, orphan drugs, monogenic disease, complex disease, causality, disease causation, cause of disease, pathogenesis