Clinico-genetical studies of colonic cancer. II. Genetic analysis of predisposition to colonic cancer

The structure of subjection to different clinical forms of colon cancer and to the morbidity as a whole approximates better the quasi-continued phenotypical model within which the contribution of genetic factors reaches 68-84%, that of incidental medium factors being 16-32%. Genetic study of heterogeneity of colon cancer clinical forms revealed that their pathogenetic community was quite high. However, the origin of colon cancer depends strongly on genetic factors (83.7 +/- 7.3%), in comparison with rectal cancer (67.9 +/- 7.1%). The analysis of colon cancer interrelation with other malignant neoplasms (including specific ones for women--breast and uterus cancer) revealed that the development of another malignant neoplasms was the result of the influence of partially common genes (20-50%) which predetermined the development of colon cancer and other malignant neoplasms. According to the data obtained in this study, the tables of repeated risk have been worked out which may be used for medico-genetic consultation.     

Clinico-genetical analysis of colonic cancer. I. Occurrence, frequency in families and segregation analysis

The data on clinico-genealogic studies of colon cancer are presented. 694 families were examined with 432 probands having rectal and 262 colonic carcinoma among them. Clear family accumulation of colon cancer (2.4 +/- 0.35%) as well as other malignant tumors (6.8 +/- 0.6%) (p less than 0.01) was shown among the relatives of the first degree of relation. The values of segregation rates obtained for clinical forms of colon cancer were lower than theoretically expected for simple monogenic types of inheritance. The analysis of incomplete penetration of genotypes showed that, though formally the inheritance of colon cancer and its clinico-anatomical forms may be described by quasi-dominant types of inheritance, the penetration values are very low: from 4.3 to 13.3% for homozygotes and from 2.1 to 6.6% for heterozygotes. It shows that the supposition about the monogenic types of the colon cancer inheritance is doubtful and suggests that the colon cancer is to be regarded on the basis of the multifactorial model.     

Analysis of the genetic predisposition to cancer in families of patients with multiple primary malignant neoplasms]

Clinical-genetic examination of 305 patients with multiple primary tumors aimed at determining the rate of genetic burden to their development and community of joint accumulation of tumors in families of these patients has revealed a significant genetic community of inheritance of breast cancer, carcinomas of colon, endometrium, ovaries and stomach in the families of patients with multiple primary tumors. Comparative analysis of genetic correlations has shown the greatest genetic burden in families of patients with multiple primary tumours as against the families of patients with solitary cancer.     

Transcatheter therapy for malignant neoplasms.

Interventional radiology has developed into a subspecialty with application in the treatment and palliation of patients with advanced malignant diseases. A directed catheter delivers high concentrations of chemotherapy directly into the tumor bed. Embolic particles may be injected to stop hemorrhage or to occlude the blood supply of a cancer, resulting in pain relief or tumor shrinkage. These techniques can be incorporated into a multidisciplinary approach to cancer.     

Primary malignant lymphoma cutis.

Between 1934 and 1975, 16 patients with primary malignant lymphoma cutis were seen at the Ottawa clinic of the Ontario Cancer Foundation. The lesions were purplish, firm, dermal or hypodermal (or both) nodules, tumours and plaques. In all 16 the histopathologic diagnosis was diffuse non-Hodgkin''s lymphoma; 12 were considered to have prognostically bad lymphomas. However, the prognosis of primary malignant lymphoma cutis is significantly more favourable than is implied by the stage IV designation that such localized extranodal involvement would have required under the Rye clinical staging classification.     

Cell population kinetics of 1,2-dimethylhydrazine-induced colonic neoplasms and their adjacent colonic mucosa in the mouse.

The parameters of cell population kinetics of symmetrical 1,2-dimethylhydrazine-induced colonic neoplasms and their adjacent colonic mucosa in the mouse were analyzed using the fraction labeled-mitoses curve method and compared with those of three groups of epithelial cells in the crypt of the descending colon of normal mouse. The analysis of three groups of epithelial cells in the crypt of normal mouse indicates that differentiation of epithelial cells was associated not only with a smaller proliferative pool of cells but also with a shortening of the duration of G2 phase and a prolongation of mitotic time. Other parameters of cell cycle did not change significantly. The mean cell cycle time of neoplastic cells in chemically induced colonic neoplasms was similar to that of epithelial cells in normal colon, but the variance was much greater in neoplastic cells. In neoplastic cells, the proliferative pool was greater, the G1 phase prlonged, and the S phase and the mitotic time became shorter as compared to epithelial cells in normal colon. The duration of G2 phase of neoplastic cells fell between the values of presumptive stem cells and differentiating cells in normal colon, compatible with the hypothesis that neoplastic cells are transformed stem cells defective in cellular differentiation. In the colonic mucosa immediately adjacent to neoplasms, the fraction-labeled-mitoses curve showed a flat second wave, indicating that the group of cells initially labeled by the pulse became a mixture of cells, some continuing the proliferative cycle normally, some going out of cycle, some slowing down in their passage from S through G2 to M, and some being arrested in mitotic phase. Such heterogeneous behavior of cells may be closely related to expansion of neoplasms. With some assumptions, however, cell cycle parameters of those normally cycling cells were estimated: the cell cycle time and the duration of G1 phase and mitotic phase were prolonged as compared to neoplastic cells and epithelial cells of normal colon.     

Metabolism of methylglyoxal and malignant neoplasms

The present notions on the metabolism of methylglyoxal, an endogenic controller of cellular proliferation, are adduced. The interaction between metabolism of methylglyoxal and that of carbohydrates, proteins and lipids is demonstrated. The metabolic chart has been worked out and enzymes catalyzing methylglyoxal metabolic reactions are determined. The effect of methylglyoxal and its bisguanylhydrazones derivatives on the processes of cellular proliferation control has been examined.     

Cellular expression patterns of genes upregulated in murine and human colonic neoplasms.

Markers overexpressed in colonic tumors of the multiple intestinal neoplasia (Min) mouse have been recently identified by cDNA subtractive hybridization and by microarray analysis. The significance of such a marker depends on its expression in tumor vs stromal lineages and on its expression pattern in normal tissue. From 34 differentially expressed markers, 14 were found to be expressed from supporting lineages. The markers expressed in the tumor lineage were grouped into three classes on the basis of ISH in mouse models and IHC in human adenomas. The first class includes markers expressed both in neoplastic cells and in the proliferating cells residing at the bottom of normal colonic crypts. The second class of markers shows elevated expression in neoplastic cells and also in the postmitotic Paneth cells of the small intestine. Finally, the third class of marker shows detectable intestinal expression only within tumors but not in the normal intestinal epithelium. Is such a tumor-associated marker uniquely essential for tumor growth? Deficiency for the tumor-associated glycoprotein clusterin does not affect the multiplicity or growth rate of intestinal tumors in Min mice. Thus, clusterin is a candidate secreted colon cancer marker but not a single target for chemoprevention or therapy. (J Histochem Cytochem 56:433–441, 2008)