Association Between Molecular Subtypes of Colorectal Cancer and Patient Survival

Abstract

Background and Aims. Colorectal cancer (CRC) is a heterogeneous disease that can develop via several pathways. Different CRC subtypes, identified based on tumor markers, have been proposed to reflect these pathways. We evaluated the significance of these previously proposed classifications to survival. Methods. Participants in the population-based Seattle Colon Cancer Family Registry were diagnosed with invasive CRC from 1998 through 2007 in western Washington State (n=2706), and followed for survival through 2012. Tumor samples were collected from 2050 participants and classified into 5 subtypes based on combinations of tumor markers: type 1 (microsatellite instability [MSI] high, CpG island methylator phenotype [CIMP] positive, positive for BRAF mutation, negative for KRAS mutation); type 2 (microsatellite stable [MSS] or MSI-low, CIMP-positive, positive for BRAF mutation, negative for KRAS mutation); type 3 (MSS or MSI-low, non-CIMP, negative for BRAF mutation, positive for KRAS mutation); type 4 (MSS or MSI-low, non-CIMP, negative for mutations in BRAF and KRAS); and type 5 (MSI-high, non-CIMP, negative for mutations in BRAF and KRAS). Multiple imputation was used to impute tumor markers for those missing data on 1-3 markers. We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations of subtypes with disease-specific and overall mortality, adjusting for age, sex, body mass, diagnosis year, and smoking history. Results. Compared to participants with type 4 tumors (the most predominant), participants with type 2 tumors had the highest disease-specific mortality (HR=2.20, 95% CI: 1.47-3.31); subjects with type 3 tumors also had higher disease-specific mortality (HR=1.32, 95% CI: 1.07-1.63). Subjects with type 5 tumors had the lowest disease-specific mortality (HR=0.30, 95% CI: 0.14-0.66). Associations with overall mortality were similar to those with disease-specific mortality. Conclusions. Based on a large, population-based study, CRC subtypes, defined by proposed etiologic pathways, are associated with marked differences in survival. These findings indicate the clinical importance of studies into the molecular heterogeneity of CRC.

The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

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LINE-1 methylation status in prostate cancer and non-neoplastic tissue adjacent to tumor in association with mortality

“…This method imputes missing data while acknowledging the uncertainty associated with the imputed values and provides valid statistical inferences under the missing at random (MAR) assumption. 41,42,43 Indeed, when data are MAR, analyses based on complete cases may be biased because cases with missing values may differ systematically from the completely observed cases. In our study, results obtained using multiple imputations or a complete case approach were similar.…”

Heterogén vastagbéldaganat: a fogazott útvonalon kialakuló, sporadikus laesiók jelentősége a klinikai gyakorlatban

“…Általánosságban a fogazott útvonalon kialakuló vastagbéldaganat agreszszívebb viselkedésű és rosszabb prognózisú, mint a klaszszikus útvonalon létrejövő CRC. Több vizsgálatban az OS és a DFS -és néhány vizsgálatban a CSS tekintetében is -a molekuláris besorolás szerinti 2-es típusú (CIMP-H/MSI-L/MSS) daganatok bizonyultak a legkedvezőt-lenebb prognózisúnak, melyek a fogazott útvonal képvi-selői [37]. Az egyes biomarkereket külön vizsgálva az MSI-H-fenotípus önmagában számos vizsgálatban kedvező prognosztikai faktornak bizonyult.…”