Survival in stage II/III colorectal cancer is independently predicted by chromosomal and microsatellite instability, but not by specific driver mutations

Abstract

Microsatellite instability (MSI) is an established marker of good prognosis in colorectal cancer (CRC).Chromosomal instability (CIN) is strongly negatively associated with MSI and has been shown to be a marker of poor prognosis in a small number of studies. However, a substantial group of " doublenegative " (MSI − / CIN − ) CRCs exists. The prognosis of these patients is unclear. Furthermore, MSI and CIN are each associated with specifi c molecular changes, such as mutations in KRAS and BRAF , that have been associated with prognosis. It is not known which of MSI, CIN, and the specifi c gene mutations are primary predictors of survival. METHODS:We evaluated the prognostic value (disease-free survival, DFS) of CIN, MSI, mutations in KRAS , NRAS , BRAF , PIK3CA , FBXW7 , and TP53 , and chromosome 18q loss-of-heterozygosity (LOH) in 822 patients from the VICTOR trial of stage II / III CRC. We followed up promising associations in an Australian community-based cohort ( N = 375). RESULTS:In the VICTOR patients, no specifi c mutation was associated with DFS, but individually MSI and CIN showed signifi cant associations after adjusting for stage, age, gender, tumor location, and therapy. A combined analysis of the VICTOR and community-based cohorts showed that MSI and CIN were independent predictors of DFS (for MSI, hazard ratio (HR) = 0.58, 95 % confi dence interval (CI) 0.36 -0.93, and P = 0.021; for CIN, HR = 1.54, 95 % CI 1.14 -2.08, and P = 0.005), and joint CIN / MSI testing signifi cantly improved the prognostic prediction of MSI alone ( P = 0.028). Higher levels of CIN were monotonically associated with progressively poorer DFS, and a semi-quantitative measure of CIN was a better predictor of outcome than a simple CIN + / − variable . All measures of CIN predicted DFS better than the recently described Watanabe LOH ratio. SUPPLEMENTARY MATERIAL is linked to the online version of the paper at

Lymphocytic response to tumour and deficient DNA mismatch repair identify subtypes of stage II/III colorectal cancer associated with patient outcomes

“…Lastly, other molecular events or epidemiological factors within the TIL/MMR subtypes may impact prognosis or chemosensitivity, which could contribute to the observed subtype-specific survival differences. Evidence supports potential roles for APC mutation,44 chromosome instability,45 tumour-associated stroma,24 body mass index,46 smoking47 and aspirin,48 among other factors.…”

Portrait of the PI3K/AKT pathway in colorectal cancer

“…Neumann et al investigated AKT and EGFR expression in addition to mutation in the four abovementioned genes, and found that approximately 75% of the tumors had alterations in one or more of these components, and that this was associated with advanced disease [270]. Finally, in contrast to the studies arguing for a prognostic value of one or more of the genes in the PI3K/AKT pathway, Mouradov and colleagues reported that stage II and III CRC patient disease-free survival (n=822) is independently predicted by CIN and MSI, rather than by mutations in KRAS, BRAF, PIK3CA, loss of 18q, and other individual genomic alterations [271]. In conclusion, the development of robust prognostic biomarker panels for stage II and III patients is ongoing, and whether such panels will include components of the PI3K/AKT pathway remains to be seen.…”

Microsatellite instability in colorectal cancer: clinicopathological significance

“…There was no evidence for prognostic value in MSI or right-sided tumors. Data obtained from a recently published Australian community-based cohort (n = 375) indicate that survival in AJCC/UICC stage II/III CRCs is independently predicted by CIN and MSI, but not by specific driver mutations, such as mutations in KRAS or BRAF [71].…”