Pathology (neoplasia 5/molecular basis)

• This phenomenon has been ascribed to progressive shortening of telomeres at the ends of chromosomes.
• Indeed, short telomeres seem to be recognized by the DNA-repair machinery as double-stranded DNA breaks, and this leads to cell cycle arrest mediated by p53 and RB

• In cells in which the checkpoints are disabled by p53 or RB1 mutations, the nonhomologous end-joining pathway is activated as a last-ditch effort to save the cell, joining the shortened ends of two chromosomes.
• This inappropriately activated repair system results in dicentric chromosomes that are pulled apart at anaphase, resulting in new double-stranded DNA breaks.
• The resulting genomic instability from the repeated bridge-fusion-breakage cycles eventually produces mitotic catastrophe, characterized by massive cell death

• Loss of growth restraints is not enough.
• Tumor cells must also develop ways to avoid both cellular senescence and mitotic catastrophe

• If during crisis a cell manages to reactivate telomerase, the bridge-fusion-breakage cycles cease and the cell is able to avoid death.
• However, during the period of genomic instability that precedes telomerase activation, numerous mutations could accumulate, helping the cell march toward malignancy

Passage through a period of genomic instability

True

up-regulation of the enzyme telomerase

vascularized

• Cancer cells can stimulate neo-angiogenesis, during which new vessels sprout from previously existing capillaries, or, in some cases, vasculogenesis, in which endothelial cells are recruited from the bone marrow.
• Tumor vasculature is abnormal, however. The vessels are leaky and dilated, and have a haphazard pattern of connection.
• Neovascularization has a dual effect on tumor growth: perfusion supplies needed nutrients and oxygen, and newly formed endothelial cells stimulate the growth of adjacent tumor cells by secreting growth factors, such as insulin-like growth factors (IGFs), PDGF, and granulocyte-macrophage colony-stimulating factor.
• Angiogenesis is required not only for continued tumor growth but also for access to the vasculature and hence for metastasis. 
• Angiogenesis is thus a necessary biologic correlate of malignancy

the balance between angiogenesis promoters and inhibitors

True

increased production of angiogenic factors and/or loss of angiogenic inhibitors. These factors may be produced directly by the tumor cells themselves or by inflammatory cells (e.g., macrophages) or other stromal cells associated with the tumors

• Proteases, either elaborated by the tumor cells directly or from stromal cells in response to the tumor, are also involved in regulating the balance between angiogenic and anti-angiogenic factors.
• Many proteases can release the proangiogenic basic fibroblast growth factors (bFGF) stored in the ECM; conversely, three potent angiogenesis inhibitors—angiostatin, endostatin, and vasculostatin—are produced by proteolytic cleavage of plasminogen, collagen, and transthyretin

• Relative lack of oxygen stimulates HIF1α, an oxygen-sensitive transcription factor, which then activates transcription of a variety of pro-angiogenic cytokines, such as VEGF and bFGF.
• These factors create an angiogenic gradient that stimulates the proliferation of endothelial cells and guides the growth of new vessels toward the tumor.
• VEGF also increases the expression of ligands that activate the Notch signaling pathway, which plays a crucial role in regulating the branching and density of the new vessels

• For example, in normal cells, p53 can stimulate expression of anti-angiogenic molecules such as thrombospondin-1, and repress expression of pro-angiogenic molecules such as VEGF.
• Thus, loss of p53 in tumor cells not only removes the cell cycle checkpoints listed above but also provides a more permissive environment for angiogenesis.
• The transcription of VEGF is also influenced by signals from the RAS-MAP kinase pathway, and mutations of RAS or MYC up-regulate the production of VEGF

bFGF and VEGF

• anti-VEGF monoclonal antibody, bevacizumab,
• antibodies that inhibit Notch activation

• (1) invasion of the extracellular matrix (ECM);
• (2) vascular dissemination, homing of tumor cells, and colonization

underlying basement membrane

• Changes (“loosening up”) of tumor cell-cell interactions  
• Degradation of ECM  
• Attachment to novel ECM components  
• Migration of tumor cells

• Often the result of alterations in intercellular adhesion molecules.
• Cell-cell interactions are mediated by the cadherin family of transmembrane glycoproteins.
• E-cadherins mediate homotypic adhesions in epithelial tissue, thus serving to keep the epithelial cells together and to relay signals between the cells; intracellularly the E-cadherins are connected to β-catenin and the actin cytoskeleton. 
• In several epithelial tumors, including adenocarcinomas of the colon and breast, there is a down-regulation of E-cadherin expression. E-cadherins are linked to the cytoskeleton by the catenins, proteins that lie under the plasma membrane. The normal function of E-cadherin is dependent on its linkage to catenins. In some tumors E-cadherin is normal, but its expression is reduced because of mutations in the gene for α catenin

• Tumor cells may either secrete proteolytic enzymes themselves or induce stromal cells (e.g., fibroblasts and inflammatory cells) to elaborate proteases.
• Many different families of proteases, such as matrix metalloproteinases (MMPs), cathepsin D, and urokinase plasminogen activator, have been implicated in tumor cell invasion.
• MMPs regulate tumor invasion not only by remodeling insoluble components of the basement membrane and interstitial matrix but also by releasing ECM-sequestered growth factors.
• Indeed, cleavage products of collagen and proteoglycans also have chemotactic, angiogenic, and growth-promoting effects.
• For example, MMP9 is a gelatinase that cleaves type IV collagen of the epithelial and vascular basement membrane and also stimulates release of VEGF from ECM-sequestered pools
• Concurrently, the concentrations of metalloproteinase inhibitors are reduced so that the balance is tilted greatly toward tissue degradation.

type IV collagenase

• Recent in vivo imaging experiments have shown that tumor cells can adopt a second mode of invasion, termed ameboid migration.
• In this type of migration the cell squeezes through spaces in the matrix instead of cutting its way through it. This ameboid migration is much quicker, and tumor cells seem to be able to use collagen fibers as high-speed railways in their travels.

Tumor cells, in vitro at least, seem to be able to switch between the two forms of migration (degradation of ECM and ameboid migration)

local degradation of the basement membrane and interstitial connective tissue

changes in attachment of tumor cells to ECM proteins

• Normal epithelial cells have receptors, such as integrins, for basement membrane laminin and collagens that are polarized at their basal surface; these receptors help to maintain the cells in a resting, differentiated state.
• Loss of adhesion in normal cells leads to induction of apoptosis, while, not surprisingly, tumor cells are resistant to this form of cell death.
• Additionally, the matrix itself is modified in ways that promote invasion and metastasis.
• For example, cleavage of the basement membrane proteins collagen IV and laminin by MMP2 or MMP9 generates novel sites that bind to receptors on tumor cells and stimulate migration.

Locomotion

• Locomotion is the final step of invasion, propelling tumor cells through the degraded basement membranes and zones of matrix proteolysis.
• Migration is a complex, multistep process that involves many families of receptors and signaling proteins that eventually impinge on the actin cytoskeleton.
• Cells must attach to the matrix at the leading edge, detach from the matrix at the trailing edge, and contract the actin cytoskeleton to ratchet forward.
• Such movement seems to be potentiated and directed by tumor cell–derived cytokines, such as autocrine motility factors
• In addition, cleavage products of matrix components (e.g., collagen, laminin) and some growth factors (e.g., IGFs I and II) have chemotactic activity for tumor cells. Furthermore, proteolytic cleavage liberates growth factors bound to matrix molecules.
• Stromal cells also produce paracrine effectors of cell motility, such as hepatocyte growth factor–scatter factor, which bind to receptors on tumor cells. Concentrations of hepatocyte growth factor–scatter factor are elevated at the advancing edges of the highly invasive brain tumor glioblastoma multiforme, supporting their role in motility.

hepatocyte growth factor–scatter factor

• Dissociation of cells from one another-->E-Cadherin and catenin
• Local degradation of the basement membrane and interstitial connective tissue--> MMPs, cathepsin D, and urokinase plasminogen activator /ameboid migration
• Changes in attachment of tumor cells to ECM proteins-->cleavage of collagen IV and laminin by MMP2 or MMP9 generates novel binding site
• Locomotion --> tumor cell–derived cytokines, such as autocrine motility factors, cleavage products of matrix components (e.g., collagen, laminin) and some growth factors (e.g., IGFs I and II) , hepatocyte growth factor–scatter factor (by stromal cell)

True

• Mechanical shear stress,
• Apoptosis stimulated by loss of adhesion, (which has been termed anoikis),
• Innate and adaptive immune defenses

aggregating of tumor cells in clumps

Platelets

• Within the circulation, tumor cells tend to aggregate in clumps. This is favored by homotypic adhesions among tumor cells as well as heterotypic adhesion between tumor cells and blood cells, particularly platelets.
• Formation of platelet-tumor aggregates may enhance tumor cell survival and implantability.
• Tumor cells may also bind and activate coagulation factors, resulting in the formation of emboli. Arrest and extravasation of tumor emboli at distant sites involves adhesion to the endothelium, followed by egress through the basement membrane. Involved in these processes are adhesion molecules (integrins, laminin receptors) and proteolytic enzymes. 
• Of particular interest is the CD44 adhesion molecule, which is expressed on normal T lymphocytes and is used by these cells to migrate to selective sites in the lymphoid tissue. Such migration is accomplished by the binding of CD44 to hyaluronate on high endothelial venules, and overexpression of CD44 may favor metastatic spread.
• At the new site, tumor cells must proliferate, develop a vascular supply, and evade the host defenses

• CD44 adhesion molecule is expressed on normal T lymphocytes and is used by these cells to migrate to selective sites in the lymphoid tissue.
• Such migration is accomplished by the binding of CD44 to hyaluronate on high endothelial venules, and overexpression of CD44 may favor metastatic spread.

anatomic location of the primary tumor, with most metastases occurring in the first capillary bed available to the tumor

• prostatic carcinoma preferentially spreads to bone
• bronchogenic carcinomas tend to involve the adrenals and the brain
• neuroblastomas spread to the liver and bones

• Because the first step in extravasation is adhesion to the endothelium, tumor cells may have adhesion molecules whose ligands are expressed preferentially on the endothelial cells of the target organ.
• Chemokines have an important role in determining the target tissues for metastasis. For instance, some breast cancer cells express the chemokine receptors CXCR4 and CCR7. The chemokines that bind to these receptors are highly expressed in tissues to which breast cancers commonly metastasize. Blockage of the interaction between CXCR4 and its receptor decreases breast cancer metastasis to lymph nodes and lungs. Some target organs may liberate chemoattractants that recruit tumor cells to the site. Examples include IGFs I and II.
• In some cases, the target tissue may be a nonpermissive environment—unfavorable soil, so to speak, for the growth of tumor seedlings. For example, though well vascularized, skeletal muscles are rarely the site of metastases.

True

True

• prolonged survival of micrometastases without progression
• is well described in melanoma and in breast and prostate cancer

• Tumor cells secrete cytokines, growth factors, and ECM molecules that act on the resident stromal cells, which in turn make the metastatic site habitable for the cancer cell.  
• For example, breast cancer metastases to bone are osteolytic because of the activation of osteoclasts in the metastatic site. Breast cancer cells secrete parathyroid hormone–related protein (PTHRP), which stimulates osteoblasts to make RANK ligand (RANKL).
• RANKL then activates osteoclasts, which degrade the bone matrix and release growth factors embedded within it, like IGF and TGF-β.

The clonal evolution model suggest that, as mutations accumulate in genetically unstable cancer cells and the tumor become heterogeneous  a subset of tumor cell subclones develop the right combination of gene products to complete all the steps involved in metastasis. Thus, metastatic subclones result from clonal evolution, and it is only the rare cell that acquires all the necessary genetic alterations and can complete all the steps

• For example, a subset of breast cancers has a gene expression signature similar to that found in metastases, although no clinical evidence for metastasis is apparent.
• In these tumors it seems that most if not all cells develop a predilection for metastatic spread during early stages of carcinogenesis. Metastases, according to this view, are not dependent on the stochastic generation of metastatic subclones.
• The alternative hypothesis suggested by these data is that metastasis is the result of multiple abnormalities that occur in many, perhaps most, cells of a primary tumor, and perhaps early in the development of the tumor
• Such abnormalities give most cells within the tumor a general predisposition for metastasis, often called the “metastasis signature.”  This signature may involve not only properties intrinsic to the cancer cells but also the characteristics of their microenvironment, such as the components of the stroma, the presence of infiltrating immune cells, and angiogenesis

• A third hypothesis suggests that background genetic variation, and the resulting variation in gene expression, in the human population contributes to the generation of metastases. In mouse models, cancers induced with the same oncogenic mutations can have very different metastatic outcomes depending on the strain (i.e., background genetics) of the mouse used. Even very strong oncogenes can be significantly affected by background genetics.
• The fourth hypothesis is a corollary of the tumor stem cell hypothesis, which suggests that if tumors derive from rare tumor stem cells, metastases require the spread of the tumor stem cells themselves.

•  A, Metastasis is caused by rare variant clones that develop in the primary tumor; B, Metastasis is caused by the gene expression pattern of most cells of the primary tumor, referred to as a metastatic signature; C, A combination of A and B, in which metastatic variants appear in a tumor with a metastatic gene signature; D, Metastasis development is greatly influenced by the tumor stroma, which may regulate angiogenesis, local invasiveness, and resistance to immune elimination, allowing cells of the primary tumor, as in C, to become metastatic
• Also SC hypothesis and background genetic variation

True

• MiRNA --> suppressor or oncogene
• SNAIL and TWIST, which encode transcription factors whose primary function is to promote a process called epithelial-to mesenchymal transition (EMT)--> oncogene

• Among candidates for metastasis oncogenes are SNAIL and TWIST, which encode transcription factors whose primary function is to promote a process called epithelial-to mesenchymal transition (EMT).
• In EMT, carcinoma cells down-regulate certain epithelial markers (e.g., E-cadherin) and up-regulate certain mesenchymal markers (e.g., vimentin and smooth muscle actin). These changes are believed to favor the development of a promigratory phenotype that is essential for metastasis. Loss of E-cadherin expression seems to be a key event in EMT, and SNAIL and TWIST are transcriptional repressors that down-regulate E-cadherin expression. EMT has been documented mainly in breast cancers

Loss of E-cadherin

• True 
• (With some exceptions that haploinsufficiency occur)

• mismatch repair
• nucleotide excision repair
• recombination repair

DNA mismatch repair

• When a strand of DNA is being replicated, these genes act as “spell checkers.”
• For example, if there is an erroneous pairing of G with T rather than the normal A with T, the mismatch-repair genes correct the defect.
• Without these “proofreaders,” errors gradually accumulate randomly in the genome, and some of these errors may involve proto-oncogenes and tumor suppressor genes.
• One of the hallmarks of patients with mismatch-repair defects is microsatellite instability

mismatch-repair defects

• Microsatellites are tandem repeats of one to six nucleotides found throughout the genome.
• In normal people the length of these microsatellites remains constant.
• However, in people with HNPCC, these satellites are unstable and increase or decrease in length in tumor cells, creating alleles not found in normal cells of the same patient

germline mutations in the MSH2 (2p16) and MLH1 (3p21) genes each account for approximately 30% of cases

• Each affected individual inherits one defective copy of a DNA mismatch-repair gene and acquires the second hit in colonic epithelial cells.
• Thus, DNA-repair genes behave like tumor suppressor genes in their mode of inheritance, but in contrast to tumor suppressor genes (and oncogenes), they affect cell growth only indirectly—by allowing mutations in other genes during the process of normal cell division. 

• Increased risk for the development of cancers of the skin particularly following exposure to the UV light contained in sun rays.
• UV radiation causes cross-linking of pyrimidine residues, preventing normal DNA replication. Such DNA damage is repaired by the nucleotide excision repair system.
• Several proteins are involved in nucleotide excision repair, and an inherited loss of any one can give rise to xeroderma pigmentosum.

• A group of AR disorders comprising Bloom syndrome, ataxia-telangiectasia, and Fanconi anemia is characterized by hypersensitivity to other DNA-damaging agents, such as ionizing radiation (Bloom syndrome and ataxia-telangiectasia), or DNA cross-linking agents, such as many chemotherapeutic agents (Fanconi anemia).
• Their phenotype is complex and includes, in addition to predisposition to cancer, features such as neural symptoms (ataxia-telangiectasia), bone marrow aplasia (Fanconi anemia), and developmental defects (Bloom syndrome)

• AT
• Bloom

Fanconi anemia

Persons with Bloom syndrome have a predisposition to a very broad spectrum of tumors. The defective gene is located on chromosome 15 and encodes a helicase that participates in DNA repair by homologous recombination

BRCA2

• Mutations in two genes, BRCA1 (chromosome 17q) and BRCA2 (chromosome 13q), account for 25% of cases of familial breast cancer.
• In addition to breast cancer, women with BRCA1 mutations have a substantially higher risk of epithelial ovarian cancers, and men have a slightly higher risk of prostate cancer.
• Likewise, mutations in the BRCA2 gene increase the risk of breast cancer in both men and women as well as cancer of the ovary, prostate, pancreas, bile ducts, stomach, and melanocytes

• Cells that lack these genes develop chromosomal breaks and severe aneuploidy.
• Indeed, both BRCA1and BRCA2 have been shown to associate with a variety of proteins involved in the homologous recombination repair pathway.
• The Fanconi anemia proteins and the BRCA proteins form a DNA-damage response network whose purpose is to resolve and repair intrastrand and interstrand DNA cross-links induced by chemical cross-linking agents.
• Failure to resolve these cross-links before separation of the two strands would lead to chromosome breakage and exposed chromosome ends.
• Generation of such ends would, as with short telomeres, lead to the activation of the salvage nonhomologous end joining pathway, formation of dicentric chromosomes, bridge-fusion-breakage cycles, and massive aneuploidy.
• Similar to other tumor suppressor genes, both copies of BRCA1 and BRCA2 must be inactivated for cancer to develop.

True

• cleavage of matrix components such as type IV collagen releases angiogenic factors (VEGF), and enzymatic degradation of laminin-5 by MMP2 reveals a cryptic proteolytic fragment that favors cancer cell motility.
• The ECM also stores growth factors in inactive forms, which are released by active matrix proteases. Such factors include PDGF, TGF-β, and bFGF, which in turn affect the growth of tumor cells in a paracrine manner.

• Expression of pro-survival and pro-proliferation cytokines by immune cells, not only promote the development of cancer, but also promote survival and progression of tumor cells.
• Macrophages infiltrating the tumor can be induced by the tumor cells to secrete factors that promote metastasis.

• Fibroblasts secrete the matrix that results in the desmoplastic response to tumors.
• Interestingly, in vitro experiments that altered the stiffness of the matrix alone could change the aggressiveness of a cancer cell line. Thus, the desmoplastic response to cancer may be stimulated by the cancer cells and may promote their growth.
• Stroma can drive genetic changes that promote carcinogenesis.

Even in the presence of ample oxygen, cancer cells shift their glucose metabolism away from the oxygen hungry, but efficient, mitochondria to glycolysis

PET

• Altered metabolism confers a growth advantage in the hypoxic tumor microenvironment. Although angiogenesis generates increased vasculature, the vessels are poorly formed, and tumors are still relatively hypoxic compared to normal tissues. Indeed, the activation of HIF1α by hypoxia not only stimulates angiogenesis, but also increases the expression of numerous metabolic enzymes in the glycolytic pathway as well as downregulates genes involved in oxidative phosphorylation. Decreased demand by individual tumor cells increases the oxygen supply, thus increasing the number of tumor cells that can be supported by the vasculature and increasing the size of the tumor
• Warburg effect refers to aerobic glycolysis; glycolysis that occurs in the face of adequate oxygen for oxidative phosphorylation. Thus, the changes that promote the switch in metabolism during hypoxia must become fixed in the tumor cell. It may be that continuous rounds of hypoxia followed by normoxia, as is frequently seen in tumors, select for tumor cells that constitutively upregulate glycolysis. 
• Mutations in oncogenes and tumor suppressors that favor growth, such as RAS, p53 and PTEN, also stimulate metabolic changes in the cell.
• In addition to doubling its DNA content prior to division, an actively dividing cell (whether normal or transformed) must also double all of its other components, including membranes, proteins, and organelles. This task requires increased uptake of nutrients, particularly glucose (which produces the energy needed for biosynthesis of these components) and amino acids (which provide the building blocks used for protein synthesis) as well as increased synthesis of the necessary building blocks. Halting the breakdown of glucose at pyruvate allows these carbons to be shunted to anabolic pathways, such as lipid and nucleotide production; additionally, tumor cells are able to shunt glutamine into both the glycolytic as well as anabolic pathways.  Thus, the metabolic changes that tumor cells undergo increase their ability to synthesize the building blocks they need for cell division. Indeed, alterations in signaling pathways involved in cancer also stimulate the uptake of glucose and other nutrients, favor glycolysis over oxidative phosphorylation, and increase anabolic pathways in the cell.
• Normally, growth factors stimulate glucose and amino acid uptake through the PI3K/AKT/mTOR pathway, which is downstream of receptor tyrosine kinases and other growth factor receptors; in tumors, these signals are cell autonomous. Thus, mutation of tumor suppressors and oncogenes not only leads to constitutive activation of pathways that favor survival and proliferation, but they also make glycolysis and anabolic biosynthesis a permanent fixture of the tumor cell.

• uptake of glucose and other nutrients
• favor glycolysis over oxidative phosphorylation,
• increase anabolic pathways in the cell

• LKB1, a tumor suppressor gene encoding a threonine kinase that is mutated in Peutz-Jegher syndrome , which is associated with benign and malignant epithelial proliferations of the gastrointestinal tract.
• At least one aspect of LKB1's tumor suppressive activity is mediated through its ability to activate AMP-dependent protein kinase (AMPK), a conserved sensor of cellular energy status that is an important negative regulator of mTOR.
• Thus LKB1 suppresses tumor formation, at least in part, by putting the brakes on anabolic metabolism

negatively

• One adaptive response of normal cells to oxygen and glucose deprivation isautophagy, a state in which cells arrest their growth and cannibalize their own organelles, proteins, and membranes as carbon sources for energy production. If this adaptation fails, the cells die.
• Tumor cells often seem to be able to grow under marginal environmental conditions without triggering autophagy, suggesting that the pathways that induce autophagy are deranged. In keeping with this, several genes that promote autophagy are tumor suppressors, most notable PTEN (a negative regulator of the PI3K/AKT pathway), which is mutated or epigenetically silenced in a wide variety of human cancers
• Under conditions of severe nutrient deprivation tumor cells may use autophagy to become “dormant,” a state of metabolic hibernation that allows cells to survive hard times for long periods. Such cells are believed to be resistant to therapies that kill actively dividing cells, and could therefore be responsible for therapeutic failures.

PTEN

True

aneuploidy and chromosomal instability

translocations and inversions

• In lymphoid tumors specific translocations result in overexpression of proto-oncogenes by swapping their regulatory elements with those of another gene.  
• In many hematopoietic tumors, sarcomas, and certain carcinomas, the translocations allow normally unrelated sequences from two different chromosomes to recombine and form hybrid fusion genes that encode chimeric proteins that variously promote growth and survival, or enhance self-renewal and block differentiation

• Overexpression of a proto-oncogene caused by translocation.
• All such tumors carry one of three translocations, each involving chromosome 8q24 (MYC gene), as well as one of the three immunoglobulin gene–carrying chromosomes.
• At its normal locus, MYC is tightly controlled, and is most highly expressed in actively dividing cells.
• In Burkitt lymphoma the most common form of translocation results in the movement of the MYC-containing segment of chromosome 8 to chromosome 14q32, placing it close to the IGH gene.
• In most cases the translocation causes mutation or loss of the regulatory sequences of the MYC gene, replacing them with the control regions of the IGH locus, which is highly expressed in B-cell precursors. As the coding sequences remain intact, the gene is constitutively expressed at high levels. The invariable presence of the translocated MYC gene in Burkitt lymphomas attests to the importance of MYC overactivity in the pathogenesis of this tumor

MYC overactivity

Transcription factors

• Mantle cell lymphoma the cyclin D1 gene (CCND1) on chromosome 11q13 is overexpressed by juxtaposition to the IGH locus on 14q32.
• In follicular lymphomas, a t(14;18)(q32;q21) translocation, the most common translocation in lymphoid malignancies, causes activation of the BCL2 gene

• The Philadelphia chromosome, characteristic of CML and a subset of acute lymphoblastic leukemias, provides the prototypic example of an oncogene formed by fusion of two separate genes.
• In these cases, a reciprocal translocation between chromosomes 9 and 22 relocates a truncated portion of the proto-oncogene c-ABL (from chromosome 9) to the BCR (breakpoint cluster region) on chromosome 22.
• The hybrid fusion gene BCR-ABL encodes a chimeric protein that has constitutive tyrosine kinase activity.
• Although the translocations are cytogenetically identical in CML and acute lymphoblastic leukemias, they usually differ at the molecular level.
• In most cases of CML the chimeric protein has a molecular weight of 210 kD, whereas in the more aggressive acute leukemias a 190-kD BCR-ABL fusion protein is typically formed

• ABL (9q)–BCR (22) (9;22): CML
• ATF1 (12)–EWS (22) (12;22): Malignant melanoma of soft parts
• BCL1 (11)–IgH (14) (11;14): Mantle cell lymphoma
• BCL2 (18)–IgH (14) (14;18): Follicular lymphoma
• FLI1 (11)–EWS (22) (11;22): Ewing's sarcoma
• LCK (1)–TCRB (7) (1;7): T cell ALL
• MYC (8q)–IgH (14q) (8;14): Burkitt's lymphoma, B cell acute lymphocytic leukemia
• PAX3 (2)–FKHR/ALV (13) (2;13): Alveolar rhabdomyosarcoma
• PAX7 (1)–KHR/ALV(13) (1;13): Alveolar rhabdomyosarcoma
• RET (10)–PKAR1A (17) (10;17): Thyroid carcinoma
• TAL1(1)–TCTA (3) (1;3): Acute T cell leukemia
• TRK (1) TPM3 (1) Inv1(q23;q31): Colon carcinoma
• WT1 (11)–EWS (22) (11;22): Desmoplastic small round cell tumor
• HOX (11)-TCRA(14) (10;14): T cell ALL
• TMPRSS2 (21q) with other genes (ERG or ETV1) -->(21:21)(21:17)(21:7) Prostatic adenocarcinoma
• PML(15q) RARA(17q) t(15q:17q) AML M3

• The MLL gene on 11q23, a component of a chromatin-remodeling complex (many)
• Ewing sarcoma (EWSR1) gene at 22q12. In Ewing sarcoma/PNET, the EWSR1 gene fuses with the FLI1 gene (a member of the ETS TF family)
• Translocation involving an androgen-regulated gene, TMPRSS2(21q22), and one of three ETS family transcription factors (ERG [21q22], ETV1 [7p22.2], or ETV4 [17q21]) in 50% prostate adenocarcinomas.

• a translocation involving an androgen-regulated gene, TMPRSS2(21q22), and one of three ETS family transcription factors (ERG [21q22], ETV1 [7p22.2], or ETV4 [17q21]) was found to be present in 50% or more prostate adenocarcinomas.
• Development of this translocation seems to occur early in carcinogenesis, in that it is also present in high-grade prostatic intraepithelial neoplasia, a precursor lesion.
• It removes the ETS family gene from its normal control region and fuses it to the androgen-regulated TMPRSS2. Thus, the ETS family transcription factor is inappropriately expressed in prostate cells

Translocation

Deletions

nonhematopoietic solid tumors

RB gene/retinoblastoma

17p, 5q, and 18q

small cell lung cancer