The clinical and genetic manifestations of hereditary nonpolyposis colorectal carcinoma.

BACKGROUND: Hereditary nonpolyposis colorectal cancer (HNPCC) is a syndrome that affects a significant percentage of the total cancer population but is not easily recognized because of a lack of a distinctive clinical marker such as multiple polyps. DATA SOURCES: The present review discusses the clinical characteristics, pathology, genetics, management, and surveillance of HNPCC. The diagnosis of HNPCC is dependent upon family history. It is defined by the Amsterdam criteria consisting of: (1) 3 or more relatives with histologically verified colorectal carcinoma, 1 of whom is a first-degree relative of the other 2; (2) colorectal carcinoma involving at least two generations; and (3) one or more colorectal carcinoma cases diagnosed at less than 50 years of age. CONCLUSIONS: The diagnosis of HNPCC requires the demonstration of vertical transmission of the syndrome in the family pedigree. Attention should be focused on reports of cancer of all anatomic sites and the determination of site, histology, and age at diagnosis.

Expression of colorectal carcinoma-associated antigens in colonic polyps.

Immunohistologic techniques were used to study the expression of colorectal carcinoma-associated antigens in colonic polyps and to compare this with expression in the normal colonic epithelium. Forty-nine polyps were studied using monoclonal antibodies to 16 different blood group and differentiation antigens and carcinoembryonic antigen epitopes. With the Lewis(a) antigen and the two epitopes of CEA recognized by 3D6 and COL-4 expression in polyp tissue was the same as that in the normal colon. Five types of alteration of antigen expression in polyps were seen. The blood group antigens A, B, and Lewis(b), which are expressed only on the right side of the normal adult colon, were detected in both neoplastic and nonneoplastic polyps from the distal colon. The Lewis(x) antigen and the antigen epitopes detected by the antibodies COL-12, CA19-9, ME491, and GA73.3 showed an increased frequency of expression in all types of polyps in comparison with the normal colonic epithelium, while H-type 2, ND4, and the antigen epitope detected by CO29.11 showed a slightly decreased frequency of expression in polyp tissue. The X-like antigen which was expressed in only 7% of normal colon specimens showed increased frequency of expression in polyp tissue with significantly greater expression in neoplastic than hyperplastic lesions (P = 0.003). The TAG-72 antigen was detected only in adenomas with severe dysplasia (P = 0.01), correlating well with premalignant histology. These findings have helped us clarify the variation of antigen expression in colonic polyps and allowed us to define which antigens are worthy of further investigation as markers of possible malignant transformation.

Preneoplastic lesions induced by myc and src oncogenes in a heterotopic rat colon.

With the use of viral vectors harboring myc and src oncogenes, we have assessed the potential contribution of these different elements to colonic neoplasia using a transplantation technique resulting in the formation of a heterotopic colon in Wistar Furth rats. While myc alone induced atypia and some dysplasia, src induced focal dysplastic lesions throughout the colon mucosa with evidence of metaplasia. In contrast, lesions induced by myc and src acting cooperatively, were highly dysplastic with evidence of tumor formation after protracted periods. These results indicated the formation of histologically distinct preneoplastic lesions elicited by the action of a single oncogene in colon implants with the production of adenocarcinomas when such oncogenic elements act cooperatively. This model provides an opportunity for studies of the action of different oncogenes, acting singly or in combination, in the multi-step progression to colon tumor formation.

c-Ha-ras-I oncogene-induced differentiation and natural killer cell resistance in a human colorectal carcinoma cell line.

Natural killer (NK) activity is primarily a peripheral blood function of a lymphocyte population capable of spontaneous lysis of many transformed and metastatic targets. However, NK-susceptible targets tend to be relatively poorly differentiated. We have previously shown that poorly differentiated human colorectal carcinoma are lysed by NK cells. Well-differentiated and chemically differentiated colorectal carcinomas are insensitive to NK lysis. The present study demonstrates that transfection of the c-Ha-ras-I oncogene into a poorly differentiated colorectal carcinoma cell line also renders it NK resistant. This resistance is accompanied by a more differentiated colorectal carcinoma phenotype. Two ras-transfected lines (Clone-A-5 and Clone-A-4) showed a 30-66% decrease in susceptibility to NK lysis as compared to the parental line in standard cytotoxicity assays. The resistance of these transfectants was strictly dependent on expression of the activated p21, the H-ras protein product. Studies to assess the integrity of the initial binding step in NK lysis showed a significant decrease in the ability of these transfectants to form conjugates with fresh NK cells. It is likely that transfection with c-Ha-ras-I has selectively modulated critical NK target recognition structures.

Detection of the tumor-associated glycoprotein antigen (TAG-72) in premalignant lesions of the colon.

We used monoclonal antibody B72.3 to study the expression of the colorectal carcinoma-associated antigen TAG-72 in premalignant colonic lesions with the immunoperoxidase technique. This antigen, which is rarely detectable in the normal colonic epithelium, was expressed in 13 of 19 adenomas with moderate to severe dysplasia and nine of nine cases of inflammatory bowel disease. The antibody reacted with the normal-appearing mucosa adjacent to a carcinoma in 10 of 12 cases, although only eight of the tumors expressed the antigen. The expression of the TAG-72 antigen in the colonic epithelium may be an early marker of malignant transformation.

Detection of altered H-ras proteins in human tumors using western blot analysis.

H-ras p21 protein expression was investigated in bladder and colonic tumor tissues using an H-ras specific antibody in Western blot analysis. The specificity of this antibody to H-ras proteins was established using NIH/3T3 transfectants expressing oncogenic counterparts of the different ras gene family members. Use of this antibody to detect altered H-ras proteins was demonstrated using a panel of transfectants bearing different mutated H-ras genes and established cell lines previously characterized in transfection assays. Extension of this technique to direct analysis of human tumor material confirmed previous observations of H-ras activation within a group of bladder tumors and identified three more urothelial tumors expressing altered H-ras proteins. The altered migrational properties of these three were suggestive of point mutational events in 12 (1 case) and 61 (2 cases) codon hot spots. This study extends previous observations on the preferential activation of H-ras in urinary tract tumors and provides a rapid technique for evaluating the status of H-ras proteins in human tumor tissue.