Association between chromosomal instability and prognosis in colorectal cancer: a meta-analysis

Walther, Axel; Houlston, Richard S.; Tomlinson, Ian

doi:10.1136/gut.2007.135004

Cited by 312 publications

(258 citation statements)

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“…Furthermore, although CIN to be a prognostic factor in patients with CRC, its precise role in tumor biology and its relation to MSI remains unclear. 11 To the best of our knowledge, and as derived from a recent metanalysis, 11 this study on MSI and DNA ploidy in patients with CRC is the second of only 2 publications that have examined these 2 features in combination, and the other study investigated only patients with colonic cancers who were recruited to adjuvant chemotherapy trials; those investigators demonstrated a prognostic significance for aneuploid cancers, but not for MSI. 17 Obviously, the roles of MSI and CIN will require further investigation to clarify their precise role in CRC development, prognosis, and prediction.…”

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

“…[11][12][13] CIN is associated with aneuploid tumors; thus, ploidy serves as a surrogate marker for CIN in CRC. 11,12 Most previous studies on MSI status in patients with CRC have focused on survival and response to chemotherapy, for which recent data continue to produce equivocal results. [14][15][16][17][18][19] Conversely, few, if any, studies have investigated the effect of MSI status in CRC on recurrence patterns and survival among patients who were included in a strict surveillance program.…”

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Microsatellite instability and DNA ploidy in colorectal cancer

Søreide

Slewa

Stokkeland

et al. 2009

Cancer

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BACKGROUND:Appropriate stratification tools for targeted surveillance after resection for colorectal cancer (CRC) are lacking. The objective of the current study was to investigate the effect of microsatellite instability (MSI) and DNA ploidy on surveillance after surgery.METHODS:The authors evaluated 186 consecutive, population‐based patients with stage I through III CRC who underwent surgery with curative intent and who entered a systematic surveillance program. MSI was analyzed with polymerase chain reaction for 5 known quasimonomorphic markers (BAT‐26, BAT‐25, NR‐21, NR‐24, and NR‐27), and DNA ploidy was analyzed with automated cytometry. Recurrence, recurrence‐free survival (RFS), and disease‐specific survival (DSS) were evaluated by univariate and multivariate statistical tests.RESULTS:Patients with MSI (20%) were significantly younger than patients without MSI (median age, 61 years vs 67 years; P = .016). Proximal location (adjusted odds ratio [AOR], 5.4; 95% confidence interval [95% CI], 2.1‐14.1 [P = .001]), large tumor size (≥5 cm: AOR, 3.5; 95% CI, 1.3–9.6 [P = .015]), and poor tumor differentiation (AOR, 6.6; 95% CI, 2–21.8 [P = .002]) were associated with MSI. MSI conveyed an increased risk for locoregional recurrence (OR, 2.9; 95% CI, 1.2–7 [P = .016]), with a trend toward a shorter time to recurrence (P = .060). Neither MSI status nor DNA ploidy predicted distant metastasis, RFS, or DSS. Lymph node status was the best predictor of distant spread (AOR, 3.9; 95% CI, 2–7.9 [P < .001]) and DSS (hazard ratio, 4.9; 95% CI, 2.6–9 [P < .001]).CONCLUSIONS:Patients who had microsatellite instable tumors were at increased risk for locoregional recurrence, whereas lymph node status was the best predictor of distant metastasis. Clinical surveillance and choice of modality (ie, endoscopy vs radiologic imaging) may be improved when patients are stratified according to these cancer features. Cancer 2009. © 2009 American Cancer Society.

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Microsatellite instability and DNA ploidy in colorectal cancer

Søreide

Slewa

Stokkeland

et al. 2009

Cancer

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“…CIN is more diffi cult to assess than MSI and hence is assayed less oft en. However, a meta-analysis of 3,094 patients with stage II or III CRC reported inferior overall survival associated with CIN (HR = 1.45, 95 % CI 1.27 -1.65) ( 16 ).…”

Section: Introductionmentioning

confidence: 99%

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

Mouradov

Domingo

Gibbs

et al. 2013

American Journal of Gastroenterology

125

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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

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“…Oversikt over arbeider der man har studert den prognostiske verdien av DNA-ploidianalyse for pasienter med tykktarmskarsinom (2000 -16 I tillegg er det i tre store metaanalyser, som alle inkluderte over 5 000 pasienter (7,48,49), konkludert med at pasienter med aneuploide svulster har signifikant lavere femårsoverlevelse (hasardratio 1,45) enn pasienter med diploide svulster (48,49). Videre er det observert en mortalitetsreduksjon på >15 % for pasienter med diploide svulster (48) og sammenheng mellom aneuploiditet og mer avanserte kreftstadier (7).…”

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