Identification of pathogenic gene rearrangements in carcinomas has lagged because karyotypically evident trans-locations and inversions (which point to the location of important oncogenes) are rare in carcinomas. However, advances in DNA sequencing have revealed recurrent cryptic pathogenic gene rearrangements in carcinomas as well. As with hematologic malignancies and sarcomas, gene rearrangements in solid tumors can contribute to carcinogenesis either by increasing expression of an oncogene or by generation of a novel fusion gene. Examples will be discussed along with specific cancers in other chapters. As with a fusion gene such as BCR-ABL, some of the fusion genes in solid tumors also provide drug targets (e.g., EML-ALK in lung cancer; Chapter 13).
Deletions are another prevalent abnormality in tumor cells. Deletion of specific regions of chromosomes may result in the loss of particular tumor suppressor genes.
Tumor suppressors generally require inactivation of both alleles in order for them to contribute to carcinogenesis. A common mechanism for this is an inactivating point mutation in one allele, followed by deletion of the other, non-mutated allele. As discussed later, deletions involving 13q14, the site of the RB gene, are associated with retinoblastoma, and deletion of 17p is associated with loss of TP53, arguably the most important tumor suppressor gene.
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Proto-oncogenes may be converted to oncogenes by gene amplification, with consequent overexpression and hyperactivity of otherwise normal proteins. Such amplification may produce several hundred copies of the gene, a change in copy number that 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, extrachromosomal structures called double minutes; and homogeneously staining regions. The latter derive from the insertion of the amplified genes into new chromosomal locations, which may be distant from the normal location of the involved genes; because regions containing amplified genes lack a normal banding pattern, they appear homogeneous in a G-banded karyotype. Two clinically important examples of amplification involve the NMYC gene in neuroblastoma and the HER2 gene in breast cancers. NMYC is amplified in 25% to 30% of neuroblastomas, and the amplification is associated with poor prognosis (
Fig. 6.15 ). HER2 (also known as ERBB2) amplification occurs in about 20% of breast cancers, and antibody therapy directed against the receptor encoded by the HER2 gene has proved effective in this subset of tumors.
Aneuploidy is defined as a number of chromosomes that is not a multiple of the haploid state; for humans, that is a chromosome number that is not a multiple of 23. Aneuploidy is remarkably common in cancers, particularly carcinomas, and was proposed as a cause of carcinogenesis over 100 years ago. Aneuploidy frequently results from errors of the mitotic checkpoint, the major cell cycle control mechanism that acts to prevent mistakes in chromosome segregation. The mitotic checkpoint prevents aneuploidy by inhibiting the irreversible transition to anaphase until all of the replicated chromosomes have made productive attachments to spindle microtubules. Complete absence of the mitotic checkpoint leads to rapid cell death as a consequence of abnormal chromosome segregation.