Cancer results from a diseased genome. Each tumor contains a collection of genomic aberrations that activate oncogenes and inactivate tumor suppressor genes.
A recent survey of the scientific literature identified 229 oncogenes (or “dominant” cancer genes) and 62 tumor suppressors (“recessive” cancer genes), suggesting that more than 1% of the human genome may contribute directly to carcinogenesis and/or tumor progression (Futreal 2004).
Since many tumor mechanisms likely remain undiscovered, these numbers may underestimate the full spectrum of human cancer genes.
Moreover, the path to cancer may require at least 5–10 genetic mutations (Hahn and Weinberg 2002).
Theoretically, then, the total number of different genetic combinations possible across all human cancers exceeds ten trillion and may even reach 1018.
These estimates imply that a comprehensive genomic approach to cancer therapeutics may be exceedingly difficult to achieve.
Recent insights, however, suggest a more favorable conclusion:
The enormous complexity possible in theory may indeed prove both functionally reducible and therapeutically tractable in practice.
Among these is the recognition that most human cancers derive from perturbations within a finite number of fundamental physiological processes directing cellular proliferation, survival, angiogenesis, and invasion/metastasis (Hanahan and Weinberg 2000).
By itself, this conceptual framework does not completely resolve the challenge of tumor complexity, because many diverse genetic players and mutation chronologies may affect each of these properties.
Nonetheless, the notion that cancer involves definable biological hallmarks suggests that, ultimately, logic and order may be discerned from the immense genomic diversity characteristic of human cancer once the appropriate molecular contexts are more fully understood.
Consistent with this viewpoint is the recognition that cancer genomic aberrations, although complex, do not occur randomly. Instead, a relatively small number of cancer genes tend to undergo alterations at high frequencies.
The fact that cellular pathways involving RAS, p53, and pRb (among others) undergo genetic mutations so commonly (Vogelstein and Kinzler 2004) not only endorses the “hallmarks of cancer” model, but also suggests that cancers tend to employ the same genomic alterations to enact these processes. Thus, despite the inevitable complexity, an increased knowledge of cancer genomic alterations should contribute markedly to the elaboration of essential and broadly applicable tumor mechanisms.
ONCOGENE ADDICTION AND TUMOR DEPENDENCY
Another pivotal insight pertaining to deconvolution of cancer genomic complexity derives from the recent observation that some tumors require continued activity of a single activated oncogene for survival (Weinstein 2002).
Termed “oncogene addiction,” this phenomenon was first demonstrated in transgenic mouse models that enabled conditional overexpression of oncogenes such as myc, ras, and bcr-abl (Chin et al. 1999; Felsher and Bishop 1999; Huettner et al. 2000; Jain et al. 2002; Pelengaris et al. 2002). In these models, induction of the relevant oncogene triggered cancer formation; however, subsequent loss of oncogene expression resulted in regression and apoptosis of tumor cells. The presence of oncogene addiction in human malignancies was first demonstrated in chronic myelogenous leukemia (CML), which harbors the BCR-ABL translocation; and in gastrointestinal stromal tumors (GIST), which contain oncogenic mutations in the c-kit gene. Targeting the tyrosine kinase activity of these oncogenes with the small-molecule inhibitor imatinib was sufficient to induce complete remissions in the great majority of patients (Druker et al. 2001; Demetri et al. 2002; Kantarjian et al. 2002). More recently, oncogene addiction was also demonstrated in a subset of lung cancers that contain base mutations or small deletions in the epidermal growth factor receptor (EGFR) gene; these alterations confer sensitivity to EGFR inhibitors such as gefitinib or erlotinib (Lynch et al. 2004; Paez et al. 2004). Thus, a single oncogenic lesion may play a decisive role in tumor maintenance, even when many additional genetic alterations have also accrued (Kaelin 2004).
A synthesis of the oncogene addiction involves a massive apparent genetic complexity may be underpinned by a much smaller collection of critical “dependencies” operant in human tumors. By this view, the predicted tumor promoting effects of many genomic perturbations may converge onto a finite number of physiological processes, which in turn exhibit an even smaller set of limiting “nodes” or “bottlenecks” within key cellular pathways directing carcinogenesis.
MITF Gene
This gene encodes a transcription factor that contains both basic helix-loop-helix and leucine zipper structural features. It regulates the differentiation and development of melanocytes retinal pigment epithelium and is also responsible for pigment cell-specific transcription of the melanogenesis enzyme genes. Heterozygous mutations in the this gene cause auditory-pigmentary syndromes, such as Waardenburg syndrome type 2 and Tietz syndrome. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008])
Tumors arise from the pigment cells (melanocytes)
GeneCards Summary for MITF Gene
MITF (Microphthalmia-Associated Transcription Factor) is a Protein Coding gene. Diseases associated with MITF include tietz albinism-deafness syndrome and waardenburg syndrome, type 2a. Among its related pathways are IL6-mediated signaling events and Transport to the Golgi and subsequent modification. GO annotations related to this gene include transcription factor activity, sequence-specific DNA binding and RNA polymerase II core promoter proximal region sequence-specific DNA binding. An important paralog of this gene is TFE3.
UniProtKB/Swiss-Prot for MITF Gene
MITF_HUMAN,O75030
Transcription factor that regulates the expression of genes with essential roles in cell differentiation, proliferation and survival. Binds to symmetrical DNA sequences (E-boxes) (5-CACGTG-3) found in the promoters of target genes, such as BCL2 and tyrosinase (TYR). Plays an important role in melanocyte development by regulating the expression of tyrosinase (TYR) and tyrosinase-related protein 1 (TYRP1). Plays a critical role in the differentiation of various cell types, such as neural crest-derived melanocytes, mast cells, osteoclasts and optic cup-derived retinal pigment epithelium.
Source: Cold Spring Harbor Symposia on Quantitative Biology, Volume LXX. © 2005 Cold Spring Harbor Laboratory Press 0-87969-773-3.
On chemicals and cancer, an eminent German oncologist says that cancer is caused by environmental toxins. Others agree. While there are obviously other issues, fungus, viruses, genetics, etc., the major change in the world that could have lead to the explosion of cancer over the last 100 years has been the introduction of tens of thousands of chemicals into the environment. Chemicals that we had never been exposed to before. Ones that our bodies don’t know how to handle. The link between toxic Chemicals and Cancer becomes clearer the longer we are surrounded by them.
Dr Tuttle: Most of the time we don’t know what causes a specific patient’s thyroid cancer. The only well-accepted risk factor for the common types of thyroid cancer — papillary and follicular thyroid cancers — is exposure to ionizing radiation that occurs after exposure to fallout from nuclear reactors (like that following the Chernobyl accident), atomic bombs or therapeutic uses of radiation during young childhood. However, since the incidence of thyroid cancer has dramatically increased over the last 20 years, both in the United States and abroad, many investigators are re-examining the possibility that some environmental factor may be linked to the rise in thyroid cancer. But as of now, no specific chemical or environmental factor has been demonstrated to commonly cause thyroid cancer in humans.
