The BRAF V600E mutation has been associated with microsatellite instability and the CpG island methylator phenotype (CIMP) in colon cancer. We evaluated a large populationbased sample of individuals with colon cancer to determine its relationship to survival and other clinicopathologic variables. The V600E BRAF mutation was seen in 5% (40 of 803) of microsatellite-stable tumors and 51.8% (43 of 83) of microsatellite-unstable tumors. In microsatellite-stable tumors, this mutation was related to poor survival, CIMP high, advanced American Joint Committee on Cancer (AJCC) stage, and family history of colorectal cancer [odds ratio, 4.23; 95% confidence interval (95% CI), 1.65-10.84]. The poor survival was observed in a univariate analysis of 5-year survival (16.7% versus 60.0%; P < 0.01); in an analysis adjusted for age, stage, and tumor site [hazard rate ratio (HRR), 2.97; 95% CI, 2.05-4.32]; in stage-specific, age-adjusted analyses for AJCC stages 2 to 4 (HRR, 4.88, 3.60, and 2.04, respectively); and in Kaplan-Meier survival estimates for AJCC stages 2 to 4 (P < 0.01 for all three stages). Microsatellite-unstable tumors were associated with an excellent 5-year survival whether the V600E mutation was present or absent (76.2% and 75.0%, respectively). We conclude that the BRAF V600E mutation in microsatellite-stable colon cancer is associated with a significantly poorer survival in stages 2 to 4 colon cancer but has no effect on the excellent prognosis of microsatelliteunstable tumors. (Cancer Res 2005; 65(14): 6063-9)
Previously identified associations between smoking and colon cancer, whether microsatellite unstable or stable, appear to be explained by the association of smoking with CIMP and BRAF mutations.
Associations of dietary patterns with breast cancer risk varied by menopausal and body mass index status, but there was little difference in associations between non-Hispanic white and Hispanic women.
SummaryRoughly 27% of miRNAs are commonly expressed in colonic tissue; of these, over 86% are dysregulated between carcinoma and normal tissue when applying a false discovery rate of 0.05. MiRNA expression from normal to adenoma to carcinoma varied by miRNA and its frequency of expression in the population.
Breast cancer incidence rates are characterized by unique racial and ethnic differences. Native American ancestry has been associated with reduced breast cancer risk. We explore the biological basis of disparities in breast cancer risk in Hispanic and non-Hispanic white women by evaluating genetic variation in genes involved in inflammation, insulin and energy homeostasis in conjunction with genetic ancestry. Hispanic (2111 cases, 2597 controls) and non-Hispanic white (1481 cases, 1586 controls) women enrolled in the 4-Corner's Breast Cancer Study, the Mexico Breast Cancer Study and the San Francisco Bay Area Breast Cancer Study were included. Genetic admixture was determined from 104 ancestral informative markers that discriminate between European and Native American ancestry. Twenty-one genes in the CHIEF candidate pathway were evaluated. Higher Native American ancestry was associated with reduced risk of breast cancer (odds ratio = 0.79, 95% confidence interval 0.65, 0.95) but was limited to postmenopausal women (odds ratio = 0.66, 95% confidence interval 0.52, 0.85). After adjusting for genetic ancestry and multiple comparisons, four genes were significantly associated with breast cancer risk, NFκB1, NFκB1A, PTEN and STK11. Within admixture strata, breast cancer risk among women with low Native American ancestry was associated with IkBKB, NFκB1, PTEN and RPS6KA2, whereas among women with high Native American ancestry, breast cancer risk was associated with IkBKB, mTOR, PDK2, PRKAA1, RPS6KA2 and TSC1. Higher Native American ancestry was associated with reduced breast cancer risk. Breast cancer risk differed by genetic ancestry along with genetic variation in genes involved in inflammation, insulin, and energy homeostasis.
MiRNAs have been implicated in CRC development and associated with prognostic indicators such as disease stage and survival. Prognostic associations are often based on few individuals and imprecise. In this study, we utilize population-based data from 1141 colorectal cancer (CRC) cases to replicate previously reported associations between 121 miRNAs and disease stage and survival. The Agilent Human miRNA Microarray V19.0 was used to generate miRNA data following a stringent quality control protocol. Assessment of survival was done using Cox Proportional Hazard models adjusting for age, disease stage, and tumor molecular phenotype.
Five miRNAs were associated with more advanced disease stage; hsa-miR-145-5p and hsa-miR-31-5p showed increased expression with more advanced tumor stage, while hsa-miR-200b-3p, hsa-miR-215, and hsa-miR-451a had decreased expression with more advanced tumors. Thirteen miRNAs were associated with colorectal cancer mortality among individuals diagnosed with colon cancer while fourteen were associated with colorectal cancer mortality after a diagnosis with rectal cancer. Strongest associations were observed for those miRNAs that were expressed in a small subset of tumors. Most notable associations were for hsa-miR-145-3p (HR 2.94 95% CI 1.54, 5.61), and hsa-miR-9-3p (HR 10.28 95% CI1.31 80.84) with colon cancer and hsa-miR-335-5p (HR 0.17 95% CI 0.05, 0.54) for rectal cancer. Hsa-miR-374a-5p, hsa-miR-570-3p and hsa-miR-18a-5p significantly reduced the hazard of dying for all cases, regardless of tumor site.
Our findings illustrate the need for a large sample to evaluate the association of miRNAs with survival and disease stage in order to determine associations by tumor site.
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