Germline mutations of the putative tumor suppressor gene APC are associated in high frequency with the familial adenomatous polyposis, predisposing the patients to colorectal neoplasia. Similarly, sequence analyses have revealed that in more than half of patients with sporadic colorectal carcinoma or adenoma, the APC gene was mutated. By employing genomic sequencing, i.e., base-specific analysis of methylated cytosines, we show here that the promoter region of the APC gene is heavily methylated at CpG sites in patients with colorectal carcinoma in comparison with normal colonic mucosa and premalignant adenomas. Our results suggest that cytosine methylation of the regulatory sequences of the APC gene could be involved in the progression of human colorectal cancer. Int. J. Cancer 70:644-648, 1997.r 1997 Wiley-Liss, Inc.The APC (adenomatous Polyposis coli) gene has been convincingly linked to the development of colorectal cancer. The human APC gene located at 5q21 (Cunningham and Dunlop, 1994) and encoding a large protein interacting with the cell adhesion protein b-catenin (Munemitsu et al., 1995) has been shown to be mutated in the germline of patients with familial adenomatous polyposis (Cunningham and Dunlop, 1994). Similar somatic mutations of the APC gene have also been found at very early stages of tumorigenesis in the majority of patients with sporadic colorectal cancer or adenoma (Powell et al., 1992). Most of the mutations of the gene result from premature termination of the translation leading to a truncated protein that can no longer associate with the b-catenin (Powell et al., 1992;Munemitsu et al., 1995). The close association of the mutations of the APC gene with the early stages of colorectal tumorigenesis makes it a strong candidate for a tumor suppressor gene.In addition to the well-documented mutations of the APC gene, the development and progression of colorectal cancer appear to be associated with mutations of the tumor suppressor gene p53, the DCC (deleted in colon cancer) gene and the oncogene ras (Cunningham and Dunlop, 1994). The progression of colorectal carcinogenesis likewise includes epigenetic changes such as altered DNA methylation. Restriction enzyme analyses with a number of gene probes indicated that DNA from both benign polyps and malignant colorectal carcinomas is substantially hypomethylated (Goelz et al., 1985), and quantitative determination of the 5-methylcytosine content of DNA revealed significant hypomethylation with no difference between benign and malignant tumors (Feinberg et al., 1988). Specific hypomethylation at a CCGG site of the third exon of the c-myc oncogene was also shown to be associated with human colorectal neoplasia (Sharrard et al., 1992). Despite the overall genomic hypomethylation, there appears to be regional hypermethylation associated with human colorectal tumorigenesis. The calcitonin gene at 11p15, a locus residing in a number of putative tumor suppressor genes (Ichikawa et al., 1992;Loh et al., 1992), was reported to be hypermethylated in human col...
Overexpression of p53 is associated with favorable disease-free and overall survival in laryngeal squamous cell carcinoma. It may also have an independent prognostic value in laryngeal cancer. M/V index, p53 overexpression, and stage predict with significant accuracy the 10-year overall survival.
A series of 688 women with breast cancer were followed-up for a mean of 13 years. Tumour size, axillary lymph node status, histological grade, histological type and two mitotic indexes (M/V; MAI) were assessed and related to disease outcome. Primary tumour size (P less than 0.0001), the volume-corrected mitotic index (M/V) (P less than 0.0001), the mitotic activity index (MAI) (P = 0.0001), and histological grade (P = 0.0074) predicted axillary lymph node status. Recurrence as well as recurrence-free survival was significantly related to the axillary lymph node status (P less than 0.0001), M/V index (P less than 0.0001), MAI (P less than 0.0001), tumour size (P = 0.0031) and histological grade (P = 0.0208). Multivariate analyses disclosed the tumour size and M/V index as independent predictors of axillary metastasis at diagnosis. Recurrence was related independently to M/V index, axillary metastasis and tumour size. Independent predictors of recurrence-free survival in Cox's analysis were M/V index and axillary lymph node status. Axillary lymph node status (P less than 0.0001), tumour size (P less than 0.0001), M/V index (P less than 0.0001), MAI (P less than 0.0001) and histological grade (P = 0.0009) predicted survival in that order. Cox's analysis showed that axillary lymph node status was the most important independent predictor of survival followed by tumour size and M/V index. In a separate Cox's analysis of axillary-lymph-node-negative patients the M/V index and tumour size were independently related to survival. In conclusion the M/V index is an important prognostic factor in breast cancer and also in axillary-lymph-node-negative breast tumours.
Summary A retrospective analysis of 321 gastric cancer patients was made to assess the prognostic value of TNM classification, tumour differentiation, Lauren classification, proliferative rate, inflammatory reaction and tumour invasion in vascular or neural structures of the gastric wall. The TNM classification showed the strongest correlation with survival in univariate and multivariate analyses (P<0.0001). The invasion in lymphatic or vascular system and Lauren classification were also independent prognosticators in multivariate analysis (P<0.05). In univariate analysis, the WHO-grade, the size and the location of the tumour and perinueral invasion were significant prognostic factors (P<0.01), as were the infiltration of lymphocytes and plasma cells in the tumour (P<0.05). On the other hand, the mitotic indices reflecting the proliferative activity of the tumour cells showed no significant correlation with the prognosis. The results indicate that the prognostic power of the TNM classification can be further increased by assessment of the above special histological features in gastric cancer.
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