APC Mutations and Other Genetic and Epigenetic Changes in Colon Cancer

Abstract

Relationships between adenomatous polyposis coli (APC) mutations, BRAF V600E mutations, and the CpG island methylator phenotype (CIMP) in colon cancer have not been explored. In addition, controversies exist about the proportion of tumors with APC mutations in the mutation cluster region (MCR); how commonly APC, Ki-ras, and p53 mutations occur in the same tumor; and whether APC mutations occur in sporadic microsatellite-unstable tumors. The APC gene was therefore sequenced in 90 colonic adenocarcinomas previously evaluated for CIMP, microsatellite instability, BRAF, Ki-ras, and p53. APC mutations were inversely related to BRAF mutations (P = 0.0003) and CIMP (P = 0.02) and directly related to p53 and Ki-ras mutations (P = 0.04). Slightly more than half of APC mutations occurred outside of the MCR, and frameshift mutations were more likely than nonsense mutations to occur in the MCR (21 of 28 versus 12 of 40, P = 0.0003). APC mutations were found in sporadic microsatellite-unstable tumors and were more likely to be frameshifts in short nucleotide repeats (P = 0.007). The occurrence of APC, Ki-ras, and p53 mutations together in the same tumor was uncommon (11.1%).In conclusion, an analysis restricted to the MCR will miss more than half of APC mutations as well as mischaracterize their mutational spectrum. The conventional wisdom that most colon cancers contain APC, Ki-ras, and p53 mutations is incorrect. Microsatellite instability may precede acquisition of APC mutations in sporadic microsatellite-unstable tumors. The relationships of APC mutations to other genetic and epigenetic alterations add to the already impressive genetic heterogeneity of colon cancer. (Mol Cancer Res 2007;5(2):165 -70)

Factors Affecting Prognosis in Metastatic Colorectal Cancer Patients

“…According to this finding, in accordance with Wang and Xavier's findings, CA 19-9 was identified as a significant independent prognostic predictor in our study (Filella et al, 1992;Wang et al, 2002). Also, in a recent study it was demonstrated that CA 19-9 was superior to CEA in post-operative follow-up (Samowitz et al, 2007).…”

“…Primary tumor resection is recommended even for stage IV patients (Samowitz et al, 2007;Chew et al, 2012;Padman et al, 2013;Yoon et al, 2014). In a study by Moghimi-Dehkordi et al it was determined that a surgical intervention targeting primary tumors was significantly associated with survival in univariate analysis but this significance diminished in multivariate analysis, leading to not being considered an independent prognostic factor.…”

Selective inhibition of proliferation in colorectal carcinoma cell lines expressing mutant APC or activated B‐Raf

“…23 Finally, TP53, a gatekeeper gene that controls cell cycle arrest and apoptosis, is mutated in 20-40% of colorectal cancers. 24,25 Expression of functional p53 is important in the prevention of cancer development from precancerous lesions, 26 and mutations of p53 frequently occur together with mutations of tumor-suppressor genes or of proto-oncogenes. 24 Thus, in colorectal cancer, the 4 signaling pathways-wnt, Ras/MAPK, PI3K and p53-each contribute to important aspects of tumorigenesis and act in concert during tumor development.…”

“…24,25 Expression of functional p53 is important in the prevention of cancer development from precancerous lesions, 26 and mutations of p53 frequently occur together with mutations of tumor-suppressor genes or of proto-oncogenes. 24 Thus, in colorectal cancer, the 4 signaling pathways-wnt, Ras/MAPK, PI3K and p53-each contribute to important aspects of tumorigenesis and act in concert during tumor development.Our increased understanding of the processes that lead to cancer development has shifted the focus of new cancer therapies to targeted interventions, which attempt to block selectively the pathways activated by the genetic mutations present in individual cancers. 27,28 Given the complexity of the genetic changes present in cancer, and the still incomplete knowledge of how different pathways interact to establish and maintain tumors, much of the development phase relies on ''in vitro'' model systems.…”

Molecular models of carcinogenesis in colorectal cancer

“…Obecnie oczywiste jest, że istnieje wiele szlaków prowadzących do powstania nowotworu w tym narządzie. Okazało się bowiem, że tylko ok. 10% nowotworów jelita ma mutacje w trzech "klasycznych" genach modelu Fearona-Vogelsteina: APC, KRAS i P53 [15]. Dlatego powstały kolejne wersje ogólnych modeli kancerogenezy: jedną z najczęściej cytowanych prac podsumowujących aktualny stan wiedzy w tej dziedzinie jest praca Hanahana i Weinberga [16].…”