Advances in Understanding Genetic Changes in Cancer Impact on Diagnosis and Treatment Decisions in the 1990s (1992) / Chapter Skim
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4. Solid Tumors
4. Solid Tumors
Pages 45-64
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From page 45... ...
Most solid tumors have acquired, nonrandom chromosomal abnormalities (Table 4-1) , which in some cases are sufficiently specific to be diagnostic.
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From page 46... ...
ADULT CANCERS Breast Colon Small cell lung carcinoma Non-small cell lung cancer Renal carcinoma Bladder cancer Prostate Liposarcoma Extraskeletal myxoid chondrosarcoma Synovial sarcoma Rhabdomyosarcoma (alveolar) Malignant melanoma Testicular tumors Glioma C
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From page 47... ...
in neuroblastoma, which can be detected by Southern blotting ~ 1571. Spindle cell tumors include synovial sarcoma, myxoid liposarcoma, extraskeletal myxoid chondrosarcoma, peripheral neural sheath tumors, and malignant fibrous histiocytoma.
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From page 48... ...
Eight of fourteen round cell tumors in children contained diagnostic abnormalities. These findings strongly support a role for cytogenetic analysis in diagnosis of these types of tumors.
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From page 49... ...
One method of staging the tumors is the Evans staging system, which was the basis for staging the tumors in Figures 4-l and 4-2, utilizing the following criteria: Stage I, tumor localized to the structure or organ of origin; Stage II, tumor that extends in continuity beyond the structure or organ of origin but does not cross the midline (may include lymph node involvement) ; Stage III, as in II but does cross the midline; Stage IV, primary tumor metastasized to distant sites, including bone, bone marrow, organs, soft tissues, and lymph nodes; and Stage IV-S, small primary tumor (such as Stage I or II)
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From page 50... ...
To improve this situation, many investigators have attempted to find markers in node-negative tumors that predict relapse. Some of the newer markers being studied include molecular alterations in proto-oncogenes, growth factors, growth factor receptors, tumor suppressor genes, and genes believed to be associated with the metastatic phenotype.
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From page 51... ...
In some of these studies, ERBB2 amplification was the second best predictor, after number of involved lymph nodes, of disease-free survival and overall survival in women with metastases to axillary lymph nodes (173,174~. One of these studies systematically compared the results obtained with Southern blotting, Northern blotting, Western blotting, and immunohistochemistry (the various methods used for assessing alterations of the gene in human tissue)
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From page 52... ...
The areas of LOH on 13q and 17p correspond respectively to the localizations of the RB1 and TP53 tumor suppressor genes. Almost all cases of SCLC and many cases of NSCLC show inactivating point mutations in the RB1 gene (197~.
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From page 53... ...
More than 50 different tumors have shown a propensity to aggregate in certain families. In some families, specific tumor types tend to occur, whereas other "cancer (~;~;A^~~ ~ ^-41_ ^~ ~ ._A~_ ~~ ^ ~ ~~~ In a growing number of instances, susceptibility to familial forms of cancer has been linked to inheritance of constitutional chromosomal abnormalities or to mutations in specific genes.
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From page 54... ...
A molecular search eventually identified a gene called RB1 (208) , which is always mutated on both alleles in tumors and typically mutated in one allele in the normal tissue of patients with familial retinoblastoma a actual tumor development (Figure 4-4~.
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From page 55... ...
Mapping of Other Cancer Predisposition Loci Elucidation of the genetic basis of familial retinoblastoma demonstrated the utility of RFLP analysis and, in some cases, cytogenetic analysis, in mapping the location of genes that cause familial tumor syndromes.
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From page 56... ...
I I Rb —15.0 —10.5 FIGURE 4-5 Use of restriction fragment length polymorphisms (RFLPs) to track an abnormal chromosome.
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From page 57... ...
Like RB1, it appears to function as a tumor suppressor gene by regulating the progression of cells through the cell cycle. It is also inactivated by proteins encoded by several tumorigenic viruses, including human papilloma virus (224~.
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From page 58... ...
Loss of Heterozygosity in Sporadic Solid Tumors Comparative RFLP analysis performed on DNA isolated from tumors and normal tissues of individual patients has also been used to look for evidence of LOH in sporadic forms of cancer. Numerous sporadic tumors have now been shown to be associated with LOH within specific chromosomes or portions of chromosomes (225,226~.
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From page 59... ...
This results in waves of clonal expansion and replacement as tumor progression occurs, with cancer resulting only when mutational events have occurred in a set of critical genes. On the basis of mutation rates and the association of cancer with increasing age, it was predicted more than 30 years ago that roughly four to six distinct mutations would be needed to produce a malignancy.
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From page 60... ...
Candidate tumor suppressor genes on Sq named MCC and ARC have also been identified (230,231~. These genes encode coiled-coil proteins with potential homologies to proteins known to interact with GTPbinding proteins.
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From page 61... ...
Finally, discovery of new suppressor genes has produced additional targets for possible therapeutic intervention. Glial Tumors Like colorectal tumors, glial tumors also demonstrate histologic and clinical evidence of tumor progression.
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From page 62... ...
The linkage of aflatoxin to a specific type of TP53 mutation raises the possibility that some mutagens may produce genetic changes that are so specific as to constitute a "smoking gun," thereby raising the possibility of a new field in "oncologic forensics." Viral Markers in Cancer Diagnosis Four different viruses have been associated with human cancers: EpsteinBarr virus (EBV) , human T cell lymphoma/leukemia virus I (HTLV I)
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From page 63... ...
Both genes produce proteins that appear to interact with and inactivate the products of tumor suppressor genes. The E6 gene product seems to inactivate the TP53 protein, and the E7 gene product seems to inactivate the RB1 protein (259-2611.
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From page 64... ...
In those viruses that integrate their genomes into host DNA (HTLV I and HBV) , the site of integration represents a clonal marker and can be assessed by Southern blotting with viral DNA probes and restriction enzymes that cut host DNA flanking the site of integration.
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