Purpose: The issue of whether colon and rectal cancer should be considered as a single entity or two distinct entities is still debated, and there is a need to improve studies addressing the heterogeneity of the pathogenetic pathway leading to sporadic colorectal cancers (SCRCs) as well as to identify biological and/or molecular differences between colon and rectal cancers.Experimental Design: Specimens of SCRCs were analyzed for somatic mutations in APC, K-ras, and TP53 genes and loss-of-heterozygosity of chromosome 18.Results: Eleven SCRCs showed microsatellite instability. APC mutation frequency was significantly lower in microsatellite instability (MIN؉) than in MIN؊ SCRCs. All MIN؊ SCRCs showed -catenin overexpression. A combined analysis of the biomarkers revealed two pathways mainly represented by MIN؊ SCRCs and differently followed on the basis of tumor location, APC-K-ras-TP53-Ch18q and APC-TP53-Ch18q.Conclusions: The APC--catenin pathway is inactivated in MIN؊ SCRCs and represents the first hit of SCRC development. Two preferential pathways followed by SCRCs occur, one K-ras dependent, in agreement with the Fearon and Vogelstein model, and the other K-ras independent. Significant differences between colon and rectal tumors occur in our series of MIN؊ SCRCs. The different pathways observed and their distribution can be summarized as follows: (a) K-ras mutations were more commonly detected in colon than in rectum; (b) the number of mutations detected was significantly higher in colon than in rectal tumors; and (c) a mutational pattern restricted to the APC gene was more common in rectal than in colon tumors. This molecular characterization can be translated into a clinical setting to improve diagnosis and to direct a rationale pharmacological treatment.
The Smad4(+/E6sad) mouse carries a null mutation in the endogenous Smad4 gene resulting in serrated adenomas and mixed polyposis of the upper gastrointestinal (GI) tract with 100% penetrance. Here, we show by loss of heterozygosity (LOH) analysis and immunohistochemistry (IHC) that, although the majority of the tumors appear at 9 months of age, somatic loss of the wild-type Smad4 allele occurs only at later stages of tumor progression. Hence, haploinsufficiency underlies Smad4-driven tumor initiation in the GI tract. As both the Apc and Smad4 tumor suppressor genes map to mouse chromosome 18, we have bred Smad4(+/E6sad) with the Apc(+/1638N) model to generate two distinct compound heterozygous lines carrying both mutations either in cis (CAS) or in trans (TAS). Strikingly, both models show increased tumor multiplicities when compared with the single mutant littermates, although CAS mice are more severely affected and became moribund at only 5-6 weeks of age. Phenotypic and molecular analyses indicate that Smad4 haploinsufficiency is sufficient to significantly affect tumor initiation and progression both prior to and upon loss of Apc function. Moreover, complete loss of Smad4 strongly enhances Apc-driven tumor formation.
Background: For stage I–II colon cancer a significant number (5–25%) of patients has recurrent disease within 5 years. There is need to identify these high-risk patients as they might benefit from additional treatment.Stroma-tissue surrounding the cancer cells plays an important role in the tumor behavior. The proportion of intra-tumor stroma was evaluated for the identification of high-risk patients. In addition, protein expression of markers involved in pathways related to stroma production and epithelial-to-mesenchymal transition (EMT) was analyzed: β-catenin, TGF-β-R2 and SMAD4.Methods: In a retrospective study of 135 patients with stage I–II colon cancer, the amount of stroma was estimated on routine haematoxylin–eosin stained histological sections. Sections were also immunohistochemically stained for β-catenin, TGF-β-R2 and SMAD4.Results: Of 135 analyzed patients 34 (25.2%) showed a high proportion of stroma (stroma-high) and 101 (74.8%) a low proportion (stroma-low). Significant differences in overall-survival and disease-free-survival were observed between the two groups, with stroma-high patients showing poor survival (OS p < 0.001, HZ 2.73, CI 1.73–4.30; DFS p < 0.001, HZ 2.43, CI 1.55–3.82). A high-risk group was identified with stroma-high and SMAD4 loss (OS p = 0.008, HZ 7.98, CI 4.12–15.44, DFS p = 0.005, HZ 6.57, CI 3.43–12.56); 12 of 14 (85.7%) patients died within 3 years. In a logistic-regression analysis a high proportion of stroma and SMAD4 loss were strongly related (HZ 5.42, CI 2.13–13.82, p < 0.001).Conclusion: Conventional haematoxylin–eosin stained tumor slides contain more prognostic information than previously fathomed. This can be unleashed by assessing the tumor–stroma ratio. The combination of analyzing the tumor–stroma ratio and staining for SMAD4 results in an independent parameter for confident prediction of clinical outcome.
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