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

Common Cancers Have Rare Cancer Subsets

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 key ideas developed in the book is that each common diseases is actually an aggregate of cellular processes that are present, individually, in rare diseases. In the case of the common cancers, we can find specific rare diseases that are subsets of the common diseases.

Here is an excerpt from Chapter 8:

8.3.3 Inherited syndromes that cause rare cancers are often associated with increased risk for developing common cancers; hence, the causes of rare cancers are related to the causes of common cancers. Many of the greatest advances in our understanding of common cancers have come through the study of rare familial cancer syndromes in which common types of cancer occur. Here are a few common cancers and the familial syndromes that account for a small percentage of cases.

Colon tumors (benign and malignant)

- Colorectal cancer hereditary non-polyposis
- Polyposis syndrome, mixed hereditary
- Turcot syndrome (central nervous system cancer and familial polyposis of the colon)
- Mismatch repair gene pmsl1 colorectal cancer hereditary, non-polyposis type 3 included
- Checkpoint kinase 2 S. pombe homologue of breast and colorectal cancer susceptibility
- Colorectal adenomatous polyposis autosomal recessive
- Oligodontia–colorectal cancer syndrome
- Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome
- Adenomatous polyposis of the colon (APC)
- Peutz–Jeghers syndrome
- Colorectal cancer hereditary non-polyposis type 2
- Colorectal cancer susceptibility on chromosome 9

Lung cancer

- Lung cancer 1
- Lung cancer, alveolar cell carcinoma included

Breast cancer

- Brca1 breast cancer type 1
- Breast cancer 11–22 translocation associated
- Brca2 breast cancer type 2
- Brca3 breast cancer type 3

Basal cell carcinoma of skin (see Glossary item, Basal cell carcinoma)

- Basal cell carcinomas with milia and coarse sparse hair
- Basal cell nevus syndrome
- Basal cell carcinoma, multiple
- Basaloid follicular hamartoma syndrome (see Glossary item, Hamartoma)
- Basal cell carcinoma with follicular differentiation
- Xeroderma pigmentosum complementation group b
- Xeroderma pigmentosum 1

Renal cell carcinoma

- Renal carcinoma, familial associated 1 included
- Renal cell carcinoma, papillary
- Non-papillary renal carcinoma 1
- Renal cell carcinoma, papillary 3
- Leiomyomatosis and renal cell cancer hereditary

Thyroid cancer

- Thyroid carcinoma, familial medullary
- Familial non-medullary thyroid cancer
- Papillary thyroid microcarcinoma
- Thyroid carcinoma, papillary with papillary renal neoplasia
- Thyroid carcinoma, non-medullary 1
- Thyroid carcinoma, Hürthle cell
- Thyroid carcinoma, follicular

Ovarian cancer

- Epithelial ovarian cancer
- Ovarian cancer, epithelial, susceptibility to

Melanoma

- Melanoma, cutaneous malignant 4
- Melanoma, cutaneous malignant 3
- Familial atypical multiple mole melanoma-pancreatic carcinoma syndrome
- Dysplastic nevus syndrome, hereditary b-k mole syndrome

Prostate cancer

- Prostate cancer, hereditary x-linked
- Prostate cancer, hereditary 1
- Prostate cancer, hereditary 20
- Prostate cancer, hereditary 7
- Prostate cancer, hereditary 3
- Prostate cancer/brain cancer, susceptibility

When we look at individual inherited cancer syndromes, we see that both rare and common cancers may result. Here is the list of different types of cancer associated with the Li–Fraumeni syndrome [15]. The syndrome-associated cancers are divided into common and rare cancers.

Common tumors associated with Li-Fraumeni syndrome

- Breast cancer
- Lung adenocarcinoma
- Colon cancer
- Pancreatic cancer
- Prostate cancer

Rare tumors associated with Li-Fraumeni syndrome

- Soft tissue sarcomas
- Osteosarcomas
- Brain tumors
- Acute leukemias
- Adrenocortical carcinomas
- Wilms tumor
- Phyllodes tumor of breast

It is worth noting that the common cancers associated with rare cancer syndromes have a similar morphologic appearance as their sporadic counterparts. This suggests that regardless of underlying genetic cause, the pathogenesis of each named common cancer tends to converge to its characteristic phenotype.

I urge you to read more about this 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, carcinogenesis, common cancers, rare cancers, cancer syndromes, familial cancer syndromes

Acquired Diseases that Replicate the Defect of Genetic 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.

Phenocopy diseases are medical conditions that closely mimic a genetic disease, but are caused or triggered by an environmental factor. In many cases, phenocopy diseases are non-hereditary and acute. In some cases, the phenocopy disease is reversible when the environmental trigger is removed or when an appropriate treatment is applied.

Here is just one example of phenocopy disease (from my book):

Acquired conduction defect [the phenocopy disease] and inherited conduction defect [the rare, genetic disease that is copied by the phenocopy disease]

Disorders of the electrical systems in humans that defects of ion flux across membranes are known as channelopathies. The inherited cardiac conduction channelopathies were discussed in Section 5.3.

Because the anti-arrhythmogenic and anti-epileptic drugs typically target ion channels, they are the drugs most likely to produce, as an adverse side effect, disorders of cardiac conduction. For example, rufinamide, an oral antiepileptic drug, has been reported to cause QT-interval shortening [44]. Quinidine, disopyramide, and procainamide have been reported to produce QT prolongation [45].

Several channelopathies can be acquired as autoimmune diseases, in which antibodies react with ion channels, or related cellular components upon which the ion channels depend (e.g., myasthenia gravis, Lambert–Eaton myasthenic syndrome, cerebellar ataxia associated with VGCC antibodies, acquired neuromyotonia, Morvan fibrillary chorea, limbic encephalitis) [46].

Progressive familial heart block type IA is a genetic disorder of the cardiac conduction system. Clinically similar conditions can be acquired when the tissues of the conduction systems are damaged, as in: myocardial infarct, conduction system ischemia (i.e., lack of blood flow to components of the conduction system, particularly the His–Purkinje conduction tissue), age-related degeneration of conduction system, and complications of procedures (i.e., insertion of wires or lines into the heart chambers) [47].

In a similar fashion, there are some types of cancer that can have a genetic cause or an environmental cause (or both). For example, most lung cancer occurring in humans has an an acquired, environmental cause (i.e., smoking). Some cases of lung cancers are genetic (i.e., inherited NUT gene mutation in midline lung carcinoma of the young). The importance of the phenocopy diseases (acquired near-equivalents of rare genetic diseases) to our general understanding of cancer, and to the successful treatment of rare cancers and common cancers, is discussed in my book.

I urge you to read more about this 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, phenocopy disease, complex disease, heart block, arrhythmia, disease biology, cancer, carcinogenesis, acquired cancer, environmental cancer, rare cancer, common cancer

Aging and Cancer: Two Diseases of Cellular Renewal

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.

Chapter 4 explains that much what we think we know about the aging process comes from studying rare diseases of premature aging, such as Hutchinson–Gilford progeria syndrome, Bloom syndrome, Werner syndrome, Cockayne syndrome, dyskeratosis congenita, Fanconi anemia, Wolfram syndrome, and xeroderma pigmentosum. Lessons learned from these rare diseases are summarized in Chapter 4.

From Chapter 4:

4.4.3 Rule—On a cellular basis, aging is a process confined to non-renewable cell populations. Brief Rationale—Long-lived cells that cannot replace themselves, such as fully differentiated neurons, muscle cells, and cartilage cells, have no biological destiny other than degeneration and death.

As non-dividing cells undergo wear and tear, or suffer damage that cannot be repaired, they will die. The tissues in which these damaged cells reside will function with diminished capacity. For example, osteoarthritis is a chronic disease that occurs from repeated episodes of bone crunching on its cartilage cushion within joints. Osteoarthritis occurs primarily in weight-bearing joints, such as knees and hips. Over a lifetime, the cartilage is frayed and eroded. Injured chondrocytes do not divide, or they divide with insufficient zest to restore a normal cartilaginous cushion. As erosion of the cartilaginous lining continues, an inflammatory reaction develops in the joint. The inflammatory reaction produces pain, swelling, and associated clinical symptoms.

Consider oocytes. All of the oocytes that a woman will produce are present in utero, reaching a peak of about 7 million cells at 5 months’ gestation. After the peak is reached, about 3 months before birth, the oocytes begin to die; they are not replaced. The number of live oocytes declines until the number falls below a threshold of 1000, triggering menopause [28]. In this instance, as in every other example of human tissues undergoing aging, the process involves cells that cannot regenerate.

Frailty is a universal feature of old age. After the age of about 50, muscle mass gradually declines. The frailty associated with extreme aging is due, in part, to progressive sarcopenia. Muscle cells atrophy (i.e., reduce their size), die, and are not renewed. Frailty occurs because muscle cells were not designed to renew themselves continuously and indefinitely.

It was once thought that the brain cells you were born with are the same cells that you will die with; that brain cells do not divide. It is now known that regeneration (i.e., the growth of new neurons) occurs throughout life. This may be so, but new growth comes from reserve cells, not from fully differentiated neurons. Cell division cannot occur in a cell that becomes very large, like a neuron, and has appendages (i.e., an axon and dendrites) extending to and from other cells, sometimes over great distances (up to several feet in the case of motor neurons innervating foot muscles). Axons are ensheathed by a dependent network of periaxonal cells (i.e., oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system). Neurons are transfixed anatomically, and cannot round up to divide. Hence, the fully mature neuron has little or no regenerative opportunity. Consequently, many of the cellular changes that we associate with aging take place in neurons. The dementia that accompanies aging is due to the inability of injured neurons to repair or replace

The tauopathies are disorders wherein tau protein accumulates within neurons. Tau proteins are involved in the stabilization of microtubules in every cell throughout the body, but they accumulate to the greatest extent in the neurons of the central nervous system. If a fully differentiated neuron cannot clear its tau proteins, it will suffer progressive damage, leading to cell death. Though tau proteins are ubiquitous, the tauopathies always develop as neurodegenerative disorders. Examples of diseases in which tau proteins are found include: Alzheimer’s disease, progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, dementia pugilistica, a form of Parkinsonism known as Lytico–Bodig disease or as Parkinson–dementia complex of Guam, a form of Parkinsonism linked to chromosome 17, frontotemporal dementia, frontotemporal lobar degeneration, Hallervorden–Spatz disease, lipofuscinosis, meningioangiomatosis, Pick’s disease, a rare tumor of neurons known as ganglioglioma [29], subacute sclerosing panencephalitis, lead encephalopathy, tangle-predominant dementia, and tuberous sclerosis.

Agin The prion diseases are another example of disorders that target non-dividing neurons. The term prion was introduced in 1982 by Stanley Prusiner [30]. Prions are the only infectious agent that contains neither DNA nor RNA. A prion is a misfolded protein that can serve as a template for proteins of the same type to misfold, producing globs of non-functioning protein, causing cells to degenerate. The site of greatest accumulation of prion protein is in brain cells. Though few scientists would consider prions to be organisms, living or otherwise, they are undoubtedly transmissible infectious agents. The most common mode of transmission of prion disease is through the consumption of brains of infected animals.

The cells of the body that are most vulnerable to prion disease are the neurons of the brain. The reason for the particular sensitivity of neurons to prion disease relates to the limited ability of neurons to replicate (i.e., to replace damaged neurons with new neurons), reconnect (to replace damaged connections between a neuron and other cells), and to remove degenerated cells and debris. There are five known prion diseases of humans, and all of them produce encephalopathies characterized by decreasing cognitive ability and impaired motor coordination. They are: Kuru, Creutzfeldt–Jakob disease, bovine spongiform encephalopathy (known in humans as new variant Creutzfeldt–Jakob disease), Gerstmann–Straussler–Scheinker syndrome, and fatal familial insomnia. At present, all of the prion diseases are progressive and fatal. Prions have been observed in fungi, where their accumulation does not seem to produce any deleterious effect, and may even be advantageous to the organism [31].

In Section 4.3, we listed the many causative mechanisms underlying the rare diseases of premature aging. Without exception, every disease of premature aging creates a defect in the normal process of cellular renewal. If we understood how to control and maintain stem cell renewal, a feat that nematodes seem to have mastered, then we might understand how to defeat the aging process. In Chapter 7, we will be discussing cancer, another disorder of cell renewal. Whereas aging is a disease of cells that cannot divide, cancer is a disease of cells that cannot stop dividing.

I urge you to read more about this 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: carcinogenesis, cancer and aging, rare disease, common disease, aging, ageing, cell renewal, cancer, cause of aging, biology of aging, orphan disease, orphan drugs

Between epigenomic extremes

This post continues yesterday's discussion of epigenomic cancer.

There seem to be only two tumors in humans that can be conceptualized as pure epigenomic tumors: malignant rhabdoid tumors and germ cell tumors. These two tumors occupy opposite extremes of epigenomic alteration. In rhabdoid tumors, something happens that wrecks epigenomic control (bi-allelic INI1 loss), and this results in a tumor that has no specifiable developmental lineage. In germ cell tumors, the epigenome "reset" button is pressed, and the resulting germ cell tumors either have a globally "erased" epigenome, as in the case of true germinomas (e.g., seminomas in males), or they take any of the differentiation paths open to them (e.g., embryonal carcinomas, teratocarcinomas, choriocarcinomas, etc.).

Between the malignant rhabdoid tumors and the germ cell tumors are all the remaining tumors of humans (several thousand kinds). These tumors tend to have varying amounts of epigenomic and genomic alterations. We know this to be true because we see both types of changes in almost every malignant tumor. We see the evidence of genetic changes when we look at the many chromosomal anomalies found in malignant cells. We see the epigenomic changes when we see cytologic atypia characterized by light and dark areas of the nuclei (corresponding to alterations in chromosomal proteins), variations of chromatin distribution on the nuclear borders, abnormally shaped and sized nucleoli, etc.

Of course, there is an interplay between epigenome and genome in cancers. A good example is seen in acute promyelocytic leukemia.

In acute promyelocytic leukemia, a gene translocation produces the PML/RAR(alpha) fusion protein.[1] Normally, promyelocytes differentiate to become non-dividing myelocytes (neutrophils). Neutrophils are the major circulating nucelated cell and play a crucial role in inflammation and the body's defenses against infections. This fusion protein causes the promyelocyte to divide, producing more promyelocytes and fewer neutrophils. Eventually, the population of clonal promyelocytes arising from the neoplastic progenitor cell will attain a sufficiently large number to be recognized clinically as a promyelocytic leukemia.

Acute promyelocytic leukemia is one of the few cancers that can achieve clinical remission without treatment with cytotoxic agents. Remission is achieved with all-trans retinoic acid, which somehow causes the neoplastic promyelocytes to differentiate and become non-dividing mature myelocytes.[2]

The mechanism by which the neoplastic fusion protein, PML/RAR(alpha), induces a neoplastic phenotype and the mechanism whereby all-trans retinoic acid reverses the neoplastic phenotype seems to be mediated through the epigenome. It is hypothesized that PML/RAR(alpha) modifies histone deacetylase complexes resulting in the inappropriate transcriptional repression of genes would normally inhibit promyelocyte proliferation. All-trans retinoic acid is though to reverse this effect.[1] If this turns out to be the case, promyelocytic leukemia would serve as an example of a genetic mutation (fusion gene) that employs epigenomic alterations to sustain a neoplastic phenotype.

In later posts, we'll discuss the pure (or nearly pure) genetic cancers.

1. Nouzova M, Holtan N, Oshiro MM, Isett RB, Munoz-Rodriguez JL, List AF, et al. Epigenomic changes during leukemia cell differentiation: analysis of histone acetylation and cytosine methylation using CpG island microarrays. J Pharmacol Exp Ther 311:968-981, 2004.
   
2. Flynn PJ, Miller WJ, Weisdorf DJ, Arthur DC, Brunning R, and Branda RF. Retinoic acid treatment of acute promyelocytic leukemia: in vitro and in vivo observations. Blood 62:1211-1217, 1983.
   

-© 2010 Jules J. Berman

key words: cancer, neoplasia, epigenome, epigenetics, cytogenetics, neoplasms, precancer, tumor biology, tumour biology, carcinogenesis, cancer development, epigenomics, acute promyelocytic leukaemia, differentiation

Rhabdoid tumors: the first clue

This post continues a discussion of rhabdoid tumors, begun in yesterday's blog.

One of the most important clues concerning the fundemantal nature of rhabdoid tumors is revealed when we compare its nuclear morphology with its genetic structure. When we make this comparison, we discover that much of what we thought we knew about cancer cells, in general, is simply incorrect.

Here is a photomicroscopic image of a rhabdoid tumor, available in the public domain, from wikipedia:


Look closely at all the nuclei in this very typical image of a rhabdoid tumor.
What can say about the nuclei?

1. They vary in shape and size from one cancer cell to another.
   
   
2. The nuclei are mottled, with areas of light and of dark, and the sizes and locations of these light and dark areas varies from nucleus to nucleus.
   
   
3. Some nuclei have large nucleoli; the number of nucleoli vary from nucleus to nucleus, ranging from 0 to 3; the nucleoli are not uniform in size or contour, or color.
   
   
4. The nuclei are outlined by a highly irregular membrane, with thick, dark borders in some areas, alternating with light borders elsewhere, with no constant pattern from nucleus to nucleus.
   
   
5. The nuclei are not consistently round, or oval or bean-shaped. Numerous sharp puckerings are seen on the nuclear boder; some nuclei seem to have tails and protrusions; others have focally straight edges.
   

Though you can't judge it from this image, which exclusively shows malignant cells, the nuclei of the rhabdoid tumor cells are larger than the nuclei of normal cells.

What do all of these nuclear observations indicate? The nuclear morphology of rhabdoid cells conforms to the classic cytologic features that characterize malignant cells.

Pathologists assume, when they see highly abnormal nuclei, that the observed abnormalities indicate genetic alterations in chromosome number (aneuploidy) and arrangements (cytogenetic abnormalities) resulting from genetic instability; all hallmarks of cancer.

But this is not the case with rhabdoid tumors.

Rhabdoid tumors are genetically stable, and have a normal karyotype (i.e., are diploid, not aneuploid).[1] The morphologic nuclear changes in malignant rhabdoid cells do not correlate with cytogenetic defects.

How is this remotely possible? Is everything we think we know about tumor cytology incorrect?

Yes and no. The nuclei of rhabdoid cells are highly abnormal, but the abnormalities are not the result of genetic alterations. The abnormalities are due to epigenetic alterations. Histologic stains do not bind to DNA. The routine nuclear stains used by pathologists will bind to chromosomal and nuclear proteins. Basically, routine nuclear stains provide pathologists with a view of the epigenome, not the genome. In most types of cancer, cells have profound changes in both the epigenome and the genome, so the kinds of nuclear abnormalities associated with malignant cells will almost always correlate with aneuploidy and genetic instability. But not so in the case of rhabdoid tumors.

When we look at the nuclei of a rhaboid tumor, using standard histologic stains, we are seeing the ravages of profound epigenomic alterations in a unique type of cancer.

In the next blog, we'll explain the biologic basis for rhabdoid tumors, and we will show that malignant rhabdoid tumor is the prototype for epigenomic (not genomic) carcinogenesis. In subsequent blogs, we will discuss the consequences of this finding for tumor classification and for cancer treatment, in general.

1. McKenna ES, Sansam CG, Cho YJ, Greulich H, Evans JA, Thom CS, Moreau LA, Biegel JA, Pomeroy SL, Roberts CW. Loss of the epigenetic tumor suppressor SNF5 leads to cancer without genomic instability. Mol Cell Biol 28:6223-6333, 2008.
   

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-© 2010 Jules J. Berman

key words: cancer, neoplasia, epigenome, epigenetics, cytogenetics, neoplasms, precancer, tumor biology, tumour biology, carcinogenesis, cancer development, pre-cancer, precancerous lesions, pre-malignant lesions, gene synonyms: Snf5 Ini1 Baf47 SmarcB1

Overview of neoplastic development

Modern tumor biology is pre-occupied with oncogenes and tumor suppressors. For the past several decades, cancer researchers have attemptedt o understand how specific genetic alterations contribute to the malignant phenotype. Certainly, research in tumor genetics has led to great advances in our understanding of cancer.

Still, tumor genetics has not really helped us understand tumor speciation. Tumor speciation is an area that gets very little attention from most cancer researchers, but if you don't have a grip on the general phenomenon of tumor speciation, you're not going to fully understand tumor classification, or carcinogenesis (the necessary biological steps leading to the development of cancer), or the biology of precancers (lesions that precede the development of cancer), or the class-based approach to precancer treatment.

Much of my book Neoplasms: Principles of Development and Diversity, is devoted to the subjects of tumor speciation and classification. I've also written about the phenomenon in prior blogs. Here's a discussion of tumor speciation, condensed to a few paragraphs.

Tumor genetics tells us that most of the common cancers occurring in adult humans are genetically complex, with thousands of mutations in tumor cells, and enormous genetic heterogeneity among the different cancer cells within the same tumor. Just as every human is genetically unique, so is every cancer that has ever occurred. If this is the case, why are the different types of cancers restricted to just a few hundred species of tumors (e.g., Wilms' tumor, chronic myelogenous leukemia, pheochromocytoma, hepatocellular carcinoma, malignant melanoma). The individual specimens within each tumor species look about the same under a microscope (that's how we diagnose them) and behave within somewhat predictable biologic paramaters. If cancers are genetically diverse, and if genetics is responsible for the behavior of cancers, wouldn't you expect to find a near-infinite number of tumor species?

The hypothesis developed in my book is that while cancer is caused by genes, tumors are speciated by epigenes, the non-sequence DNA changes that determine cellular differentiation in normal cells. Just as normal cells of the human body are restricted to a few hundred differentiated cell types [by the epigenome], cancer cells are restricted to a finite number of cell types [by the epigenome].

During carcinogeneis, cumulative genetic changes occur, but these changes must somehow fit into an epigenomic pattern that supports the continued growth of the tumor. In short, carcinogenesis is a genetic phenomenon, but tumor speciation is an epigenetic phenomenon.

Precancers are a late-stage epigenomic adjustment. If the adjustment is successful, from the perspective of the cancer cell, the precancer can develop into a cancer of a specific tumor species. Otherwise, the precancer regresses [spontaneously dies]. Precancers can be thought of as biological experiments conducted by cells undergoing carcinogenesis. Sometimes the experiment fails (and the precancer regresses). You're never sure of the result of the experiment (i.e., a precancer may develop into any one of several different tumor species, as in the case of bronchogenic precancers).

I admit that this all seems vague, but that's what happens when you try to cover a complex subject in a few paragraphs, without the aid of examples.

In the next blog, I'll introduce malignant rhabdoid tumors, and I'll try to explain how this unique tumor provides perspective to the whole problem of speciation.

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-© 2010 Jules J. Berman

key words: cancer, neoplasia, neoplasms, precancer, tumor biology, tumour biology, carcinogenesis, cancer development, pre-cancer, precancerous lesions, pre-malignant lesions, neoplastic development