Mutations in APC, Kirsten-ras, and p53—alternative genetic pathways to colorectal cancer

Abstract

Colorectal cancer is one of the most significant causes of cancer death. A genetic model for colorectal cancer has been proposed in which the sequential accumulation of mutations in specific genes, including adenomatous polyposis coli (APC), Kirsten-ras (K-ras), and p53, drives the transition from healthy colonic epithelia through increasingly dysplastic adenoma to colorectal cancer. We have characterized tumor mutation spectra in a large cohort of colorectal cancer patients. In marked contrast to the predictions of the sequential model of mutation accumulation, only 6.6% of tumors were found to contain mutations in APC, K-ras, and p53, with 38.7% of tumors containing mutations in only one of these genes. The most common combination of mutations was p53 and APC (27.1%), whereas mutations in both p53 and K-ras were extremely rare. Statistical analysis (two-sided Fisher's exact test) confirmed that mutations in K-ras and p53 co-occurred less frequently than expected by chance (P < 0.01, Fisher's exact test). This finding suggests that these mutations lie on alternate pathways of colorectal tumor development. The heterogeneous pattern of tumor mutations in our patient cohort suggests that multiple alternative genetic pathways to colorectal cancer exist and that the widely accepted genetic model of cancer development is not representative of the majority of colorectal tumors.

Aberrant O‐glycosylation contributes to tumorigenesis in human colorectal cancer

“…Notably, an exome‐sequence analysis of Tn‐positive cancerous tissues exhibited no mutations in T‐synthase, Cosmc or C3GnT, all of which are essential for mature O‐glycosylation in colonic tissues (Figure S3). By contrast, a high frequency of somatic mutations was detected in TP‐53 , APC , and K‐ras , etc., which was in agreement with published literature 4. These findings suggest that genetic alterations in T‐synthase, Cosmc and/or C3GnT are not prevailing mechanisms for such a high incidence of aberrant O‐glycosylation in CRC tissues.…”

ECA39 is a novel distant metastasis-related biomarker in colorectal cancer

“…Molecular determinants occurring during the development of sporadic CRC include mutations in certain tumor suppressor genes (APC, DCC, Smad-2, Smad-4, p53) and oncogenes (K-ras) that have been summarized in the adenoma-carcinoma sequence initially proposed by Fearon and Vogelstein [21] . However, because only 8% of CRC harbor concomitant mutations of APC, K-ras, and p53, it seems likely that additional pathogenic alterations are instrumental in the mediation of the progression and metastasis of CRC [22] . Cellular transformation provokes tissue remodeling inside neoplastic lesions and in the periphery of the tumor.…”

Faecal tumour M2 pyruvate kinase: a new, sensitive screening tool for colorectal cancer

“…HIF-1 is stabilised by p53 mutations (Kress et al, 1998;Ravi et al, 2000). Indeed, mutations in the ras oncogene and p53 antioncogene are detectable in 40 -60% of colorectal cancers (Bos, 1989;Kinzler and Vogelstein, 1996;Dong et al, 2001;Rengucci et al, 2001;Nishikawa et al, 2002;Smith et al, 2002).…”