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Tumorigenesis is thought to be a multistep process in which genetic alterations accumulate, ultimately producing the neoplastic phenotype. A model was proposed to explain the genetic basis of colorectal neoplasia that included several salient features. First, colorectal tumors appear to occur as a result of the mutational activation of oncogenes coupled with the inactivation of tumor-suppressor genes. Second, mutations in at least four or five genes are required to produce a malignant tumor. Third, although the genetic alterations often occur in a preferred sequence, the total accumulation of changes, rather than their chronologic order of appearance, is responsible for determining the tumor's biologic properties. Several different genetic alterations were identified that occur during colorectal tumorigenesis. Activational mutation of the ras oncogene was found in approximately 50% of colonic carcinomas and in a similar percentage of intermediate-stage and late-stage adenomas. Allelic deletions were discovered of specific portions of chromosomes 5, 17, and 18, which presumably harbor tumor-suppressor genes. The target of allelic loss events on chromosome 17 has been shown to be the p53 gene, which is mutated, not only in colonic cancer, but also in a large percentage of other human solid tumors. The gene dcc recently was identified; this candidate tumor-suppressor gene on chromosome 18 appears to be altered in colorectal carcinomas. The protein encoded by the dcc gene has significant sequence similarity to neural cell adhesion molecules and other related cell-surface glycoproteins. By mediating cell-cell and cell-substrate interactions, this class of molecules may have important functions in mediating cell growth and differentiation. Alterations of the dcc gene may interfere with maintenance of these controls and thus may play a role in the pathogenesis of colorectal neoplasia. Another candidate tumor-suppressor gene also was identified on chromosome 5, mcc (for mutated in colorectal cancers). The mcc genetic alterations include one tumor with somatic rearrangement of one mcc allele and several tumors with somatically acquired point mutations in the coding region. Studies currently are ongoing to (1) identify additional tumor-suppressor gene candidates, (2) increase our understanding of normal tumor-suppressor gene function, and (3) demonstrate the functional tumor-suppressor ability of these genes both in vivo and in vitro.

Totally embedded radical prostatectomy specimens and their transurethral resections (TUR) from 32 Stage A (incidental) carcinomas were studied for severe dysplasia. These cases were selected to be representative of the majority of Stage A cancers and hence consisted of cases with predominantly low-grade centrally located tumor. In 43.75% of the cases, severe dysplasia was minimal in amount, 43.75% intermediate, and 12.5% extensive. Severe dysplasia was spatially associated with the main tumor in only 31.25% of cases. In 43.75% of the cases all of the severe dysplasia was isolated (i.e., not adjacent or intermingled with any carcinoma). Whereas this study confirms one general association between severe dysplasia and the presence of carcinoma within the gland, the data do not strongly support the concept that the dysplasia is a direct precursor to centrally located low-grade Stage A carcinomas. From a practical viewpoint, severe dysplasia in the TUR was seen in 15.6% of cases and was not predictive of the amount of tumor within the gland.

Severe dysplasia was studied in totally embedded radical prostatectomy specimens from 40 Stage B, intermediate-grade prostate cancers. All 40 cases had severe dysplasia which varied in amount (extensive in 35% of cases; intermediate in 55%; minimal in 10%). Severe dysplasia was predominantly concentrated in peripheral and posterior regions of the gland. Those cases with extensive severe dysplasia had more multifocal small cancers (14.6/case) compared with cases with intermediate (7.5/case) or minimal severe dysplasia (5.5/case). Most dominant tumor nodules had some intermingled severe dysplasia, and in 30% of the dominant tumor nodules, intermingled severe dysplasia occupied between 10% and 25% of the tumor nodule. Severe dysplasia was located next to the dominant tumor nodule in all cases. Nineteen percent of dominant tumor nodules had extensive adjacent severe dysplasia ranging from 5 to 14 mm in maximum diameter, showing that the potential exists for needle biopsy of prostate cancers to obtain only severe dysplasia. These data show a close relationship between severe dysplasia and Stage B cancers. In contrast, centrally located low-grade multifocal cancers, as seen in Stage A (incidental) carcinoma, had a significantly weaker association with severe dysplasia as compared with central, intermediate-grade, multifocal tumors or peripheral multifocal tumors of any grade.