Search

Background & Aims: Synchronous activation of the Wnt signaling pathway, mostly because of loss of function of the APC tumor suppressor, and of the oncogenic KRAS-signaling pathway is very frequent in colorectal cancer and is associated with poor prognosis. Methods: We have generated a compound transgenic mouse model, KRASV12G/Apc+/1638N, to recapitulate the human disease and compared it with single transgenic littermates. Results: Compound mutant mice are characterized by a 10-fold increase in tumor multiplicity and by accelerated tumor progression, resulting in strongly enhanced morbidity and mortality. Tumors from compound mutant mice proliferate faster and show decreased levels of apoptosis. Several lines of evidence indicate that the observed increase in tumor multiplicity and malignant transformation is caused by the synergistic activation of Wnt signaling in cells with oncogenic KRAS and loss-of-function Apc mutations. Activated KRAS is known to induce tyrosine phosphorylation of β-catenin, leading to its release from E-cadherin at the adherens junction. This results in an increased β-catenin pool in the cytoplasma, its subsequent translocation to the nucleus, and the transcriptional activation of Wnt downstream target genes. Accordingly, intestinal tumors from KRASV12G/Apc+/1638N mice show a significant increase in cells with nuclear accumulation of β-catenin when compared with Apc+/1638N animals. Moreover, Apc/KRAS-mutant embryonic stem cells show a significantly enhanced β-catenin/T-cell factor–mediated transcriptional activation, accompanied by increased β-catenin nuclear localization. Conclusions: This KRAS-induced increase in Wnt/β-catenin signaling may enhance the plasticity and self-renewal capacity of the tumor, thus resulting in the drastically augmented tumor multiplicity and malignant behavior in compound mutant animals.

BACKGROUND & AIMS: Hereditary nonpolyposis colorectal cancer is characterized by early-onset colorectal cancer and the occurrence of various other cancers. The recent isolation of four mismatch repair genes responsible for hereditary nonpolyposis colorectal cancer allows for the identification of carriers within affected families. The purpose of this study was to assess the age-specific cancer risk in a large series of gene carriers. METHODS: Thirty-four families were studied by mutation analysis. In 19 of these families, pathogenic mutations were found at hMSH2 or hMLH1. Of 382 relatives, 124 had a mutation in hMLH1 and 86 in hMSH2. RESULTS: The lifetime risk of colorectal cancer was the same in both groups of gene carriers (80%). The risk of endometrial cancer was greater in hMSH2 gene carriers compared with hMLH1 gene carriers (61% vs. 42%), but the difference was not statistically significant. A very high relative risk of cancer of the small bowel (relative risk of >100) was observed in carriers of either gene. Only the carriers of hMSH2 mutations had a significantly increased relative risk of cancer of the urinary tract (kidney and ureter) (relative risk of 75.3), stomach (relative risk of 19.3), and ovaries (relative risk of 8.0). CONCLUSIONS: This study provides estimates of cancer risk that may contribute to the appropriate management of gene carriers within families with hereditary nonpolyposis colorectal cancer. (Gastroenterology 1996 Apr;110(4):1020-7)