The adenomas into invasive carcinomas 20. The

The CRC is the result of a long and complex process that consists of multiple steps and takes years to clinically manifest. CRC is well described from a genetic perspective, and it is well known that during CRC pathogenesis the normal intestinal tissue can switch to a carcinoma following a sequence of well-defined observable phenotypes 15. When mutations determine the impairment of specific signalling pathways, such as the inactivation of tumour-suppressor genes or the activation of oncogenes, the development of CRC can occur 16.

The first mutation that leads to CRC onset is the inactivation of the APC gene that constitutively activates the Wnt signalling pathway, followed by the accumulation of ?-catenin into the nucleus 17-19. The second step is the inactivation of the p53 pathway that inhibits cell cycle arrest and allows the transition of adenomas into invasive carcinomas 20. The third step is the inactivation of the transforming growth factor ? (TGF-?) 21.

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This anti-inflammatory cytokine exerts an anti-tumorigenic effect by promoting apoptosis and inhibiting cell proliferation and protumorigenic cytokine expression. Epithelial cells mutations in this pathway can sustain tumour growth in the colon. Oncogenic mutations of RAS and BRAF genes 21-23 could lead to the activation of the mitogen-activated protein kinase (MAPK) signalling cascade 24 that in turn induce cell proliferation, angiogenesis, cell motility, and metastasis. RAS mutations can lead to the production of a permanently activated protein with GTPase activity 25. BRAF mutations deal with BRAF serine-threonine kinase activity and, on the whole, they drive the MAPK signalling pathway 26. Genomic instability also plays a pivotal role in CRC. Chromosomal instability refers to changes in the chromosome copy number and structure or the loss of the wild-type copy of tumour suppressor genes, such as APC and TP53 27. Mammano et al.

28 performed an interesting case-control study by analysing p53 codon72 polymorphisms in 90 CRC patients, 322 centenarians and 321 age-matched controls. The results revealed that the p53 codon72 homozygosity polymorphism might play a role in CRC developing and progression, representing a potential genetic risk factor. Authors speculated that control subjects, as they are age-matched to cases, can still develop CRC while centenarians constitute a group of people that are no longer cancer-prone. In the same work, an arginine-proline variant at codon72, a 16bp tandem repeat and a MspI RFLP in intron 6 have been analysed, and an association between these three p53 gene variants and CRC has been observed. This finding can be explained considering that the described polymorphic variants result in a change of the primary structure of the protein which alters its biological activity. The presence of Arg72 in p53 is more efficient in inducing apoptosis than a Pro72, as Pro72 promotes cell cycle arrest in G1. This may explain why, in most cases of CRC, homozygous Arg is found with high frequency 28.Mutations in mismatch repair (MMR) genes can induce a premature ageing phenotype, characterised by phenomena such as immunodeficiency and cancer 29.

Age-related alterations of the DNA MMR system leads to the accumulation, in different tissues with different rates, of genetic damages, and this process seems to be involved in the onset of different kind of tumours. Indeed, inactivation or deficiency of genes involved in this system significantly accelerates the development of cancer in HNPCC patients 29. These damages are often seen with advancing age; in fact, most malignancies occur in old people that have a reduced DNA repair capacity. MMR system contributes to genomic stability by repairing errors that lead to mismatches in the DNA sequence. Defects in this pathway often result in microsatellite instability (MSI) that determine changes in the number of mono- or di-nucleotide repeats. A strong relationship between MSI, ageing and cancer has already been reported 30. It was hypothesised that MMR system defects could lead to MSI and therefore, with age, the genetic damages increase. Authors suppose that these findings could be involved in the alteration of the physiological cellular state and thus could increase the incidence of CRC in elderly people.

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Transforming growth factor beta receptor type II inactivation promotes the establishment and progression of colon cancer. Cancer Res 2004; 64: 4687-92. 22 Grady WM, Carethers JM. Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology 2008; 135: 107999. 23 Takaku K, Oshima M, Miyoshi H, Matsui M, Seldin MF, Taketo MM.

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PLoS One 2008; 3: e3698. 25 Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 2002; 418: 934.

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Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol 2003; 21: 1174-9. 30 Neri S, Gardini A, Facchini A, et al. Mismatch repair system and aging: microsatellite instability in peripheral blood cells from differently aged participants. J Gerontol A Biol Sci Med Sci 2005; 60: 285-92.


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