36 However, it must be stressed that outside of a selected small number of proven adverse histopathological features which are influential in a large heterogenous patient group with lymph node positive tumors,29,49 most promoted prognostic factors fail to impact on patient survival independently of stage. An example

of this is the controversy surrounding the potential for “tumor budding” to independently LY2157299 solubility dmso influence survival in patients with node positive colon cancer.50 Reasons for this are complex and largely methodological yet underline the need for agreement on assessment methods and cut-off values which must be clearly defined to correctly evaluate this and other variables before inclusion into routine surgical pathology reporting.36 Nowhere is this more apparent than in the evaluation of prognostic molecular biomarkers.51 In this regard we strongly agree with Jass that new prognostic factors must be evaluated

critically in relation to clinical end points rather than simply assessing them in terms of their expression by stage.15 Over the last 20 years the wealth of research into the genetic basis of disease has greatly advanced the understanding of colorectal carcinogenesis, but the impact of this on routine clinical practice has so far been limited. Two genetic pathways have been delineated. The chromosome instability (CIN) pathway, first described MAPK inhibitor in 1988, involves an accumulation of defects in long segments of DNA coding sequences that result in the loss of tumor suppressor genes and activation of oncogenes.52 This is the pathway through which cancer develops via the classical adenoma-carcinoma sequence in familial adenomatous polyposis (FAP) and the majority of sporadic CRCs. A second pathway, the microsatellite instability (MSI) pathway elucidated in the 1990s, involves the loss of DNA Farnesyltransferase microsatellite mismatch repair (MMR)

protein function, resulting in multiple defects in repetitive non-coding regions of DNA (microsatellites).53 MMR deficiency is the genetic defect in Lynch syndrome (hereditary non-polyposis colorectal cancer) and accounts for about 15% of sporadic CRCs. MMR deficient CRCs are more frequently right-sided and show distinctive histological features including prominent tumor-infiltrating lymphocytes, a pushing invasive tumor front, and mucinous or poor differentiation.54 These tumors have been reported to have a more favourable prognosis,55 to be associated with higher risk of synchronous and metachronous tumors,56 and possibly to show reduced responsiveness to 5FU-based chemotherapy.57 A third mechanism that has been proposed, the CpG Island Methylator Phenotype (CIMP), which is associated with a propensity for widespread DNA methylation, has been implicated in the development of CRC via serrated adenomas.