Malignancy Translocation Affected Genes

Chronic myeloid leukemia (9;22)(q34;q11) Ab1 9q34

bcr 22q11

Acute leukemias (AML and ALL) (4;11)(q21;q23) AF4 4q21

MLL 11q23

(6;11)(q27;q23) AF6 6q27

MLL 11q23

Burkitt lymphoma (8;14)(q24;q32) c-myc 8q24

IgH 14q32

Mantle cell lymphoma (11;14)(q13;q32) Cyclin D 11q13

IgH 14q32

Follicular lymphoma (14;18)(q32;q21) IgH 14q32

bcl-2 18q21

T-cell acute lymphoblastic leukemia (8;14)(q24;q11) c-myc 8q24

TCR-14q11

(10;14)(q24;q11) Hox 11 10q24

TCR-14q11

Ewing sarcoma (11;22)(q24;q12) Fl-1 11q24

EWS 22q12

Underlined genes are involved in multiple translocations.

AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia.

course. The translocations associated with the ABL oncogene in chronic myeloid leukemia and with c-MYC in Burkitt lymphoma have been mentioned earlier, in conjunction with the discussion of molecular defects in cancer cells (see Fig. 7-32 ). Several other karyotype alterations in cancer cells are presented in the discussion of specific forms of neoplasia.

Two types of chromosomal rearrangements can activate protooncogenes—translocations and inversions. Chromosomal translocations are much more common ( Table 7-10 ) and are discussed here. Translocations can activate protooncogenes in two ways:

• In lymphoid tumors, specific translocations result in overexpression of protooncogenes by removing them from their regulatory elements.

• In many hematopoietic tumors, the translocations allow normally unrelated sequences from two different chromosomes to recombine and form hybrid genes that encode growthpromoting chimeric proteins.

Overexpression of a protooncogene caused by translocation is best exemplified by Burkitt lymphoma. All such tumors carry one of three translocations, each involving chromosome 8q24, where the MYC gene has been mapped, as well as one of the three immunoglobulin gene-carrying chromosomes. At its normal locus, the expression of the MYC gene is tightly controlled;

it is expressed only during certain stages of the cell cycle. In Burkitt lymphoma, the most common form of translocation results in the movement of the MYC-containing segment of chromosome 8 to chromosome 14q band 32 ( Fig. 7-33 ), placing it close to the immunoglobulin heavy-chain (IgH) gene. The genetic notation for the translocation is t(8:14)(q24;q32). The molecular mechanisms of the translocation-associated activation of MYC are variable, as are the precise breakpoints within the gene. In most cases, the translocation causes mutations or loss of the regulatory sequences of the MYC gene. As the coding sequences remain intact, the gene is constitutively expressed at high levels. The gene may be translocated to the antigen receptor loci simply because these loci are accessible (i.e. in "open" chromatin) and active in developing lymphocytes. The invariable presence of the translocated MYC gene in Burkitt lymphomas attests to the importance of MYC overexpression in the pathogenesis of this tumor.

There are other examples of oncogenes translocated to antigen receptor loci in lymphoid tumors. As mentioned earlier, in mantle cell lymphoma, the CYCLIN D1 gene 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 BCL-2 gene. Not unexpectedly, all these tumors in which the immunoglobulin gene is involved are of B-cell origin. In an analogous situation, overexpression of several protooncogenes in T-cell tumors results from translocations of oncogenes into the T-cell antigen receptor locus. The affected oncogenes are diverse, but in most cases, as with MYC, they encode nuclear transcription factors.

The Philadelphia chromosome, characteristic of chronic myeloid leukemia 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 protooncogene c-ABL (from chromosome 9) to the BCR (break point cluster region) on chromosome 22 ( Fig. 7-33 ). The hybrid fusion gene BCR-ABL encodes a chimeric protein that has constitutive tyrosine kinase activity. As mentioned, BCR-ABL tyrosine kinase has served as a target for leukemia therapy, with remarkable success so far.

Although the translocations are cytogenetically identical in chronic myeloid leukemia and acute lymphoblastic leukemias, they differ at the molecular level. In chronic myeloid leukemia, 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 formed.[62] [63] The molecular pathways activated by the BCR-ABL protein are complex and not completely understood. It inhibits apoptosis, decreases the requirement for growth factors, binds to cytoskeleton components, decreases cell adhesion, and activates multiple pathways, including those of RAS, PI-3 kinase, and STATs ( Chapter 3 ). BCR-ABL also acts on DNA repair and may cause genomic instability that contributes to the progression of the disease.

Transcription factors are often the partners in gene fusions occurring in cancer cells. For instance, the MLL (myeloid, lymphoid leukemia) gene on 11q23 is known to be involved in 25 different translocations with several different partner genes, some of which encode transcription factors (see Table 7-10 ). The Ewing Sarcoma (EWS) gene at 22q12 was first described in the t(11;22)(q24;12) reciprocal translocation present in Ewing sarcoma (a highly malignant tumor of children; Chapter 26 ) but may be translocated in other types of sarcomas. EWS is itself a transcription factor, and all of its partner genes analyzed so far also encode a transcription factor. In Ewing tumor, for example, the EWS gene fuses with the FLI 1 gene; the resultant chimeric EWS-FLI 1 protein is a member of the ETS transcription factor family, which has transforming ability.

Gene Amplification

Activation of protooncogenes associated with overexpression of their products may result from reduplication and amplification of their DNA sequences. Such amplification may produce several hundred copies of the protooncogene in the tumor cell.[137] The amplified genes can be readily detected by molecular hybridization with appropriate DNA probes. In some cases, the amplified genes produce chromosomal changes that can be identified microscopically. Two mutually exclusive patterns are seen: multiple small, chromosome-like structures called double minutes (dms), and homogeneous staining regions (HSRs). The latter derive from the assembly of amplified genes into new chromosomes; because the regions containing amplified genes lack a normal banding pattern, they appear homogeneous in a G-banded karyotype (see Fig. 7-34 ). The most interesting cases of amplification involve N-MYC in neuroblastoma and ERB B2 in breast cancers. N-MYC is amplified in 25% to 30% of neuroblastomas, and the amplification is associated with poor prognosis. In neuroblastomas with N-MYC amplification, the gene is present both in dms and HSRs. ERB B2 amplification occurs in about 20% of breast cancers and may represent a distinct tumor phenotype. Amplification of C-MYC, L-MYC, and N-MYC correlates with disease progression in small cell cancer of the lung. Another gene frequently amplified is CYCLIN D1 (breast carcinomas, head and neck carcinomas, and other squamous cell carcinomas).

Epigenetic Changes

It has become evident during the past few years that certain tumor suppressor genes may be inactivated not because of structural changes but because the gene is silenced by hypermethylation of promoter sequences without a change in DNA base sequence.[138] Such changes appear to be stably maintained through multiple rounds of cell division. Methylation takes place in CpG islands in DNA, but de novo methylation rarely occurs in normal tissues. However, methylation has been detected in various tumor suppressor genes in human cancers.

They include p14ARF in colon and stomach cancers, p16INK4a in various types of cancers, BRCA1 in breast cancer, VHL in renal cell carcinomas, and the MLH1 mismatch repair gene in colorectal cancer.[139] Methylation also participates in the phenomenon called genomic imprinting, in which the maternal or paternal allele of a gene or chromosome is modified by methylation and is inactivated. The reverse phenomenon, that is, demethylation of an imprinted gene leading to its biallelic expression (loss of imprinting) can also occur in tumor cells.

[140] Although the discussion of whether methylation of tumor suppressor genes has a causal role in cancer development continues, there has been great interest in developing potential therapeutic agents that act to demethylate DNA sequences in tumor suppressor genes. Recent data demonstrating that genomic hypomethylation causes chromosomal instability and induces tumors in mice greatly strengthens the notion that epigenetic changes may directly contribute to tumor development.[141]

Date: 2016-04-22; view: 683