A Genetic Model for Colorectal Tumorigenesis Review
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Cell, Vol. 61, 759-767, June 1, 1990, Copyright 0 1990 by Cell Press A Genetic Model Review for Colorectal Tumorigenesis Eric Ft. Fearon and Bert Vogelstein having arisen from numerous stem cells. Thus, adenomas The Oncology Center arise from a single pocket of epithelial stem cells (Ponder Program in Human Genetics and Wilkinson, 1988) consistent with the idea that one or The Johns Hopkins University School of Medicine a small number of cells from within this pocket initiate the Baltimore, Maryland 21231 process of neoplasia by clonal expansion. In an attempt to gain an understanding of the molecular basis for this clonal expansion, investigators have sought Tumorigenesis has long been thought to be a multistep to identify somatic alterations present at various stages of process (Foulds, 1958); however, only recently has it be- colorectal tumor formation. Of particular interest are alter- come possible to identify the molecular events that under- ations present in all or virtually all of the neoplastic cells lie the initiation and progression of human tumors (Wein- studied. The presence of such an alteration suggests that berg, 1989; Bishop, 1987). Colorectal tumors provide an the genetic alteration itself provided the cell with a growth excellent system in which to search for and study the advantage, allowing it to outgrow other neoplastic cells genetic alterations involved in the development of a com- within the tumor to become the predominant cell type con- mon human neoplasm. Abundant clinical and histopatho- stituting the neoplasm (clonal expansion). Alternatively, logical data suggest that most, if not all, malignant colo- the genetic alteration, even if present in every neoplastic rectal tumors (carcinomas) arise from preexisting benign cell of an individual tumor, could have arisen coinciden- tumors (adenomas) (Sugarbaker et al., 1985). Tumors of tally with another change that actually provided the selec- various stages of development, from very small adeno- tive growth advantage. When the same genetic alteration mas to large metastatic carcinomas, can be obtained for is observed in many different tumors, the former explana- study, unlike the situation in most other common human tion is more likely. tumor types. Furthermore, both hereditary and environ- mental factors contribute to the development of colorectal Genetic Alterations in Oncogenes neoplasia, allowing for the study of both inherited and so- One important type of somatic alteration identified in matic genetic alterations. colorectal tumors is ras gene mutation. When transfected In this review we present a model for the genetic basis into appropriate recipient cells, mutated ras genes confer of colorectal neoplasia that includes the following salient neoplastic properties (reviewed in Barbacid, 1987; Wein- features. First, colorectal tumors appear to arise as a re- berg, 1989). Approximately 50% of colorectal carcinomas sult of the mutational activation of oncogenes coupled (Bos et al., 1987; Forrester et al., 1987) and a similar per- with the mutational inactivation of tumor suppressor genes; centage of adenomas greater than 1 cm in size have been the latter changes predominate. Second, mutations in at found to have ras gene mutations (Vogelstein et al., 1988). least four to five genes are required for the formation of In contrast, such mutations have been identified in fewer a malignant tumor. Fewer changes suffice for benign than 10% of adenomas less than 1 cm in size (Figure l), tumorigenesis. Third, although the genetic alterations of- regardless of whether the adenomas arose sporadically ten occur according to a preferred sequence, the total ac- or in patients with an inherited predisposition for their for- cumulation of changes, rather than their order with re- mation (Vogelstein et al., 1988; Farr et al., 1988). ras gene spect to one another, is responsible for determining the mutations may be the initiating event in a subset of co- tumor’s biologic properties. Fourth, in some cases, mutant lorectal tumors, and adenomas with ras gene mutations tumor suppressor genes appear to exert a phenotypic ef- may be more likely to progress than adenomas without fas fect even when present in the heterozygous state; thus, gene mutations. Alternatively, fas gene mutations may not some tumor suppressor genes may not be “recessive” at be the initiating event in most tumors, usually occurring the cellular level. The general features of this model may only in one cell of a preexisting adenoma. Such mutations be applicable to other common epithelial neoplasms, in would then be responsible for the conversion of a small which tumors of varying stage are more difficult to study. adenoma to a larger and more dysplastic one, through clonal expansion of the cell with the mutation. The Clonal Nature of Colonic Neoplasia In addition to somatic activation by point mutation, on- Various hypotheses for the development of cancer have cogenes may be activated by amplification or rearrange- been proposed. Mutational theories predict that neo- ment. Although the existence of amplified genes in a sig- plasms will have a monoclonal composition, whereas nificant percentage of colorectal tumors was suggested by aberrant differentiation processes or field effects might be the presence of double-minute chromosomes or homo- predicted to give rise to neoplasms with a polycolonal geneously stained regions in karyotypic analyses (Reich- composition. Although the earliest events in human co- mann et al., 1981) few cases of specific gene amplifica- lorectal tumor formation are not yet defined, study of the tion have been reported. These cases include examples clonal composition of human colorectal tumors has dem- of neu, c-myc, or c-myb amplification in primary colorectal onstrated that all tumors examined, including very small tumors or their derived cell lines (D’Emilia et al., 1989; adenomas, have a monoclonal composition (Fearon et al., Alitalo et al., 1983, 1984; Finley et al., 1989). In addition, 1987). In contrast, normal colonic epithelium is polyclonal, oncogene rearrangements, other than a single case of Cell 760 1987; Leppert et al., 1987). In patients without polyposis, allelic losses of chromosome 5q have been observed in 20%~50% of colorectal carcinomas and in about 30% of colorectal adenomas (Vogelstein et al., 1988; Sasaki et al., 1989). However, in adenomas from patients with familial adenomatous polyposis, allelic losses of chromosome 5q are rare (Solomon et al., 1987; Vogelstein et al., 1988; Sasaki et al., 1989). Thus, although each adenoma in a patient with polyposis appears to arise by clonal expan- sion (Fearon et al., 1987) this expansion is not associated EMILY INTERMEDIATE LATE CARCINOMA with allelic losses of the loci flanking the region linked to ADENOMA ADENOMA ADENOMA the disease. This finding contrasts with the pattern of al- TYPE OF TUMOR lelic loss seen in other inherited tumor predisposition syn- Figure 1. Frequency of ras Gene Mutations and Chromosome 17~ De- dromes; the implications of this finding will be discussed letions in Colorectal Tumors below. Early-stage adenomas were defined as adenomas that were 1.0 cm in The loss of a large portion of chromosome 17p, through size or less. Intermediate stage adenomas were greater than 1.0 cm chromosome loss or mitotic recombination, has been in size and did not contain foci of carcinoma. Late-stage adenomas seen in more than 75% of colorectal carcinomas (Vogel- were greater than 1.0 cm in size and contained foci of carcinoma (the stein et al., 1988; Delattre et al., 1989) but such loss is rel- adenomatous elements were separated from the nonadenomatous elements before analysis). DNA was prepared from all specimens by atively infrequent in adenomas of any stage (Figure 1). a cyrostat sectioning technique to enrich for areas of tumor that com- Moreover, in several patients the 17p allelic losses were prised 70% or greater neoplastic cells. ras gene mutations were identi- found to be associated with the progression of individual fied by oligonucleotide hybridization to DNA samples in which ras tumors from adenoma to carcinoma (Fearon et al., 1987; gene-specific sequences had been amplified by the polymerase chain reaction. Chromosome 17p losses were detected by study of DNA from Vogelstein et al., 1988). Other common adult tumors, in- normal colorectal mucosa and tumor tissue with probes detecting DNA cluding those of the breast (Mackay et al., 1988; Devilee polymorphisms on chromosome 17 (Vogelstein et al., 1966). et al., 1989) lung (Yokotaet al., 1987; Weston et al., 1989), bladder (Tsai et al., 1990) and brain (James et al., 1989), also have been found to have frequent losses of chromo- rearrangement of the frk oncogene (Martin-Zanca et al., some 17p alleles. The common region of loss on chromo- 1986) have not been observed in colorectal tumors. Thus, some 17p in colorectal tumors has been identified and the evidence to date does not support a major role for am- contains the ~53 gene (Baker et al., 1989). Furthermore, plification or rearrangement of oncogenes in the genesis mutations resulting in amino acid substitutions in the ~53 of colorectal neoplasms. gene product have been observed in the remaining ~53 alleles of several colorectal cancers that had concomitant Allelic Losses and Tumor Suppressor Genes allelic losses of chromosome 17p (Baker et al., 1989; Nigro A loss of specific chromosomal regions occurs frequently et al., 1989). Thus, point mutation of one allele of the ~53 in colorectal neoplasia. Usually the losses involve only gene coupled with loss of the remaining wild-type allele one of the two parental chromosomes present in normal appears to occur frequently in colorectal tumors. Similar cells. These allelic losses have been interpreted as evi- mutations have been observed in the remaining ~53 al- dence that the regions affected contain tumor suppressor leles of lung, breast, and brain tumors with chromosome genes, whose products normally regulate growth and dif- 17p losses (Nigro et al., 1989; Takahashi et al., 1989; lggo ferentiation in a negative fashion and thus indirectly sup- et al., 1990).