Chromosomal Alterations in Cancer

Chromosomal alterations have been widely documented in the various forms of cancer, and some of these chromosomal aberrations are recognized to be causally related to cancer induction and/or progression. In some cases, these alterations represent loss of individual chromosomes, chromosome arms, or specific chromosomal segments, consistent with deletion of a tumor suppressor locus. In other cases, these alterations represent gain of individual chromosomes or specific chromosomal segments, consistent with activation of a positive mediator of cell proliferation. In addition, numerous complex chromosomal rearrangements (such as translocation) have been characterized in certain forms of cancer. In each of these cases, the result is alteration of gene dose (either as gene loss or gene amplification) and function (altered product or altered expression). Cytogenetic methods to characterize chromosomal alterations have been applied for many years, but recent developments have automated this process and opened the analysis to difficult samples (solid tumors). For instance, array-based comparative genomic hybridization (CGH) is a technique4 that analyzes global genomic changes by documenting gains and losses of chromosomal regions in diseases such as cancer.5-7 Recent studies have shown the potential of array CGH in detecting copy number alterations in gastric cancer,4 •9 chronic lymphocytic leukemia,10 fallopian tube carcinomas,11 oral squamous carcinoma,12 bladder cancer, 1 3 and pancreatic cancer. 1 4 A few well-characterized examples from major human cancers are given in the sections that follow.

Gene Amplifications in Cancer

Several chromosomal regions have been characterized to be overrepresented in lung cancer, 1516 suggestive of amplification of chromosomal regions. One such frequently overrepresented region is chromosome 8q, which harbors the c-myc proto-oncogene.17 The c-myc proto-oncogene is a member of the basic helix-loop-helix superfamily of nuclear transcription factors. 1 8 The myc protein heterodimerizes with max, and the resulting myc-max protein complex binds to and transcriptionally activates genes that contain a CAGCTG consensus binding sequence.19-22 Increased expression of c-myc has been reported for both small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC).23-27 Similarly, amplification of the c-myc locus has been observed in both SCLC and NSCLC,28 but it may be more prevalent in SCLC.29 Thus, overexpression of c-myc in lung cancer is the frequent consequence of gene amplification at 8q24.30-32 Gene amplification and overexpression of c-myc occur more frequently in advanced neoplasms and metastatic lesions, suggesting a role for this event in tumor progression, and partially explaining the significant correlation between c-myc amplification and poor prognosis.3 1 In contrast to other cancers (such as lymphoma), point mutation of c-myc and c-myc gene translocation related to specific chromosomal alterations have not been reported in lung cancer.

Several studies have examined chromosomal alterations in breast cancer using comparative genomic hybridization approaches.33-35 These studies (as well as those using cytogenetic techniques) have identified a number of gene amplifications in breast cancer. For instance, the TM4SF1 gene is located at 3q25.1 and is amplified frequently in BRCAl-related breast cancers.36 Similarly, the CYP24 gene that is located at 20q13.2 is subject to recurrent amplification in breast cancer.6 Amplification of the Her2/neu gene on 17q was first detected using Southern blotting37,38 and is thought to occur in approximately 20-25% of breast cancer patients.39,40 This gene amplification event results in multiple copies of the Her2/neu gene (>5 copies per cell, but perhaps as many as 50-100 copies per cell), and the increase in gene dose correlates with increased mRNA expression and overexpression of the p185/erbB2 protein. Her2/neu is a member of the epidermal growth factor receptor family that also includes Her1, Her3, and Her4. Breast cancers that are positive for Her2/neu amplification and overexpression of p185/erbB2 protein have a poor prognosis and are inherently resistant to common chemotherapeutic regimens.41 However, the p185/erbB2 protein product of the Her2/neu gene is the target for the monoclonal antibody trastuzumab (Herceptin), and breast cancer patients who have Her2/neu amplification significantly benefit from combination therapies that include trasuzumab, resulting in improved survival.42,43

Common Chromosomal Deletions in Cancer

Allelotype studies of lung cancer have identified several recurring chromosomal deletions. In SCLC, frequent loss of heterozygosity (LOH) occurs at 3p (91%), 5q (71%), 13q (96%), 17p (88%), and 22q (73%).44 NSCLCs display frequent LOH at 2q (68%), 3p (82%), 5q (60%), 9p (79%), 12q (63%), 13q (67%), 17p (89%), 18q (86%), and 22q (75%).45 However, distinct differences in the patterns of chromosomal deletion have been noted for the histological subtypes of NSCLC. Among squamous cell carcinomas, frequent LOH was noted for 3p (82%), 9q (67%), 13q (60%), and 17p (88%).46 In contrast, fewer chromosomal losses were noted among adenocarcinomas, with 51% LOH at 17p representing the most frequent alteration.4 6 In other studies, similar findings have been reported.47-49 Deletions affecting a specific chromosomal region (as measured by LOH) may be indicative of the presence of a tumor suppressor gene (or other negative mediator of cell proliferation) at that chromosomal location. Among lung cancers, frequent LOH affecting 3p, 5q, 13q, 17p, and 22q occur in both SCLC and NSCLC. Several regions of chromosome 3p have been implicated in lung cancer, including 3p12-p14, 3p21, and 3p25.50-52 These observations suggest that there may be three (or more) tumor suppressor genes on human chromosome 3p.5 2 Candidate tumor suppressor genes from chromosome 3p include FHIT at 3p12-p1453 and RASSF1 at 3p21.54 LOH at chromosome 5q typically corresponds to loss at 5q13-q21.35 A number of genes map to this chromosomal region, including MCC (for mutated in colorectal cancer) and APC (for adenoma-tous polyposis coli).56-59 Although neither of these genes has been shown to be mutated in lung cancer,6 0 frequent LOH at this chromosomal region suggests the involvement of one of these or other candidate genes localized to this region in the molecular pathogenesis of lung cancer. The tumor suppressor gene Rb1 localizes to chromosome 13q14.1.61,62 The expression of Rb1 is altered in a significant percentage of primary lung cancer.6 3,64 The p53 tumor suppressor gene is located at 17p13.135 and is lost as a result of chromosomal deletion of this region in all lung cancer types.66 The precise nature of the putative lung cancer tumor suppressor locus at chromosome 22q is not yet defined. However, a candidate gene, termed SEZ6L, has been localized to 22q12.1 and shown to be mutated in a SCLC cell line.67

A number of chromosomal regions demonstrate LOH in breast cancer, most commonly affecting 1p, 3p, 6q, 7q, 9p, 11p, 13q, 16q, 17p, 17q, 18q, and 22q.3 8-75 Many of these chromosomal locations harbor known or candidate tumor suppressor genes. BRCA1 localizes to 17q2176 and BRCA2 localizes to 13q12-q13.77 Other regions of 17p may also contain tumor suppressor loci that are important in breast can-cer.78 For instance, the p53 tumor suppressor gene is located at 17p13.165 and has been implicated in the genesis of some breast cancers. Similarly, genes located in other regions of 13q (including the Rb1 locus at 13q14.161,62) may be important in breast carcinogenesis. Chromosome 16q harbors the CDH1 gene, which encodes E-cadherin™ Loss of E-cad-herin has been implicated in breast cancer metastasis.80 Other known tumor suppressor genes that localize to chromosomal regions which demonstrate LOH in breast cancer include the DCC gene at 18q.81 Multiple regions of chromosome 1 and 11 are affected by LOH in breast cancers, suggesting the possibility of multiple distinct tumor suppressor loci on each chromosome.82-84 Several studies have examined chromosomal alterations in ductal carcinoma in situ (DCIS) in an attempt to identify genetic changes occurring in the preneoplastic breast that may contribute to malignant conversion. These studies found frequent LOH affecting various chromosomal regions including 8p, 13q, 16q, 17p, and 17q in DCIS.35,86 These results are consistent with the idea that known tumor suppressor genes (such as BRCA1, BRCA2, and p53) may be involved in the early stages of breast carcinogenesis.

Complex Chromosomal Rearrangements in Cancer

Chromosomal translocations have been studied from many years in hematopoietic malignancy. In fact, the first consistent chromosomal aberration observed in human cancer was the so-called Philadelphia chromosome, which was described in chronic myelogenous leukemia.87,88 This chromosomal aberration was later found to represent a balanced translocation between chromosomes 9 and 22 [t(9;22)(q34.1;q11.2)].89 Since then, numerous chromosomal translocations have been described in leukemia and lymphoma.

A major chromosomal translocation in acute myelogenous leukemia (AML) involves chromosomes 15 and 17. The resulting chromosomal abnormality [t(15;17) (q21;q21)], which occurs exclusively in acute promyelocyte leukemia (APL), is a balanced and reciprocal translocation in which the PML (for promyelocytic leukemia) gene on chromosome 15 and the RARa gene on chromosome 17 are disrupted and fused to form a hybrid gene.90,91 The PML-RARa fusion gene (located on chromosome 15) encodes a chimeric mRNA and a novel protein. On the derivative chromosome 15, both the PML and RARa genes are oriented in a head-to-tail orientation. There are three major forms of the PML-RARa fusion gene, corresponding to different breakpoints in the PML gene.92-94 The breakpoint in the RARa gene occurs in the same general location in all cases, involving the sequences within intron 2. Approximately 40-50% of cases have a PML breakpoint in exon 6 (the long form, termed bcr1), 40-50% of cases have the PML breakpoint in exon 3 (the short form, termed bcr3), and 5-10% of cases have a breakpoint in PML exon 6 that is variable (the variable form, termed bcr2). In each form of the translocation, the PML-RARa fusion protein retains the 5' -DNA-binding and dimerization domains of PML and the 3'-DNA-binding, heterodimerization, and ligand (retinoic acid)-binding domains of RARa. Recent studies indicate that the different forms of PML-RARa fusion mRNA correlate with clinical presentation or prognosis. In particular, the bcr3 type of PML-RARa correlates with higher leukocyte counts at time of presentation.'3,94 Both higher leukocyte counts and variant morphology are adverse prognostic findings, and the bcr3 type of PML-RARa does not independently predict poorer disease-free survival.94 The presence of the t(15;17) translocation consistently predicts responsiveness to a specific treatment utilizing all-trans-retinoic acid (ATRA). Retinoic acid is a ligand for the retinoic acid receptor (RAR). The gene encoding the RAR is involved in the t(15;17) chromosomal abnormality. ATRA has been suggested to function by overcoming the blockade of myeloid cell maturation, allowing the neoplas-tic cells to mature (differentiate).95,96

Progress toward characterization of complex chromosomal rearrangements in solid tumors was hindered by technical limitations until recently, when spectral karyotyping became available. A number of studies using spectral karyotyping of various human cancers, including lung cancer, have now appeared.48,97,98 These studies identified a number of unbalanced chromosomal translocations, in many cases involving some of the same chromosomal regions that are frequently deleted in lung cancer. These complex chromosomal rearrangements may alter the structure or expression of genes localized to the affected chromosomal regions. However, additional investigation will be required to characterize the molecular consequences associated with specific chromosomal rearrangements cancers of solid tissues, such as breast, prostate, colon, and lung.

The Smoker's Sanctuary

The Smoker's Sanctuary

Save Your Lungs And Never Have To Spend A Single Cent Of Ciggies Ever Again. According to a recent report from the U.S. government. Centers for Disease Control and Prevention, more than twenty percent of male and female adults in the U.S. smoke cigarettes, while more than eighty percent of them light up a cigarette daily.

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