Purpose Observational studies have reported increased colon cancer recurrence and mortality in patients with states of hyperinsulinemia, including type 2 diabetes, obesity, sedentary lifestyle, and high glycemic load diet. Nut intake has been associated with a lower risk of type 2 diabetes, metabolic syndrome, and insulin resistance. However, the effect of nut intake on colon cancer recurrence and survival is not known. Patients and Methods We conducted a prospective, observational study of 826 eligible patients with stage III colon cancer who reported dietary intake on food frequency questionnaires while enrolled onto a randomized adjuvant chemotherapy trial. Using Cox proportional hazards regression, we assessed associations of nut intake with cancer recurrence and mortality. Results After a median follow-up of 6.5 years, compared with patients who abstained from nuts, individuals who consumed two or more servings of nuts per week experienced an adjusted hazard ratio (HR) for disease-free survival of 0.58 (95% CI, 0.37 to 0.92; P trend = .03) and an HR for overall survival of 0.43 (95% CI, 0.25 to 0.74; P trend = .01). In subgroup analysis, the apparent benefit was confined to tree nut intake (HR for disease-free survival, 0.54; 95% CI, 0.34 to 0.85; P trend = .04; and HR for overall survival, 0.47; 95% CI, 0.27 to 0.82; P trend = .04). The association of total nut intake with improved outcomes was maintained across other known or suspected risk factors for cancer recurrence and mortality. Conclusion Diets with a higher consumption of nuts may be associated with a significantly reduced incidence of cancer recurrence and death in patients with stage III colon cancer.
Telomere shortening occurs as an early event in pancreatic tumorigenesis, and genetic variants at the telomerase reverse transcriptase (TERT) gene region have been associated with pancreatic cancer risk. However, it is unknown whether prediagnostic leucocyte telomere length is associated with subsequent risk of pancreatic cancer.
Design
We measured prediagnostic leucocyte telomere length in 386 pancreatic cancer cases and 896 matched controls from five prospective US cohorts. ORs and 95% CIs were calculated using conditional logistic regression. Matching factors included year of birth, cohort (which also matches on sex), smoking status, fasting status and month/year of blood collection. We additionally examined single-nucleotide polymorphisms (SNPs) at the TERT region in relation to pancreatic cancer risk and leucocyte telomere length using logistic and linear regression, respectively.
Results
Shorter prediagnostic leucocyte telomere length was associated with higher risk of pancreatic cancer (comparing extreme quintiles of telomere length, OR 1.72; 95% CI 1.07 to 2.78; ptrend=0.048). Results remained unchanged after adjustment for diabetes, body mass index and physical activity. Three SNPs at TERT (linkage disequilibrium r2<0.25) were associated with pancreatic cancer risk, including rs401681 (per minor allele OR 1.33; 95% CI 1.12 to 1.59; p=0.002), rs2736100 (per minor allele OR 1.36; 95% CI 1.13 to 1.63; p=0.001) and rs2736098 (per minor allele OR 0.75; 95% CI 0.63 to 0.90; p=0.002). The minor allele for rs401681 was associated with shorter telomere length (p=0.023).
Conclusions
Prediagnostic leucocyte telomere length and genetic variants at the TERT gene region were associated with risk of pancreatic cancer.
<p>Kaplan-Meier graphs in the validation cohort with number of subjects at risk showing colorectal cancer-specific survival according to SMAD4 status.</p>
<div>Abstract<p><b>Purpose:</b> DNA methyltransferase-3B (<i>DNMT3B</i>) plays an important role in <i>de novo</i> CpG island methylation. Dnmt3b can induce colon tumor in mice with methylation in specific CpG islands. We hypothesized that cellular DNMT3B level might influence the occurrence of widespread CpG island methylation (i.e., the CpG island methylator phenotype, CIMP) in colon cancer.</p><p><b>Experimental Design:</b> Utilizing 765 colorectal cancers in two cohort studies, we detected DNMT3B expression in 116 (15%) tumors by immunohistochemistry. We assessed microsatellite instability, quantified DNA methylation in repetitive long interspersed nucleotide element-1 (LINE-1) by Pyrosequencing, eight CIMP-specific promoters [<i>CACNA1G, CDKN2A</i> (p16), <i>CRABP1, IGF2, MLH1, NEUROG1, RUNX3</i>, and <i>SOCS1</i>], and eight other CpG islands (<i>CHFR, HIC1, IGFBP3, MGMT</i>, MINT1, MINT31, p14, and <i>WRN</i>) by real-time PCR (MethyLight).</p><p><b>Results:</b> Tumoral DNMT3B overexpression was significantly associated with CIMP-high [≥6/8 methylated CIMP-specific promoters; odds ratio (OR), 3.34; 95% confidence interval, 2.11-5.29; <i>P</i> < 0.0001]. The relations between DNMT3B and methylation in 16 individual CpG islands varied substantially (OR, 0.80-2.96), suggesting variable locus-to-locus specificities of DNMT3B activity. DNMT3B expression was not significantly related with LINE-1 hypomethylation. In multivariate logistic regression, the significant relation between DNMT3B and CIMP-high persisted (OR, 2.39; 95% confidence interval, 1.11-5.14; <i>P</i> = 0.026) after adjusting for clinical and other molecular features, including p53, β-catenin, LINE-1, microsatellite instability, <i>KRAS, PIK3CA</i>, and <i>BRAF</i>. DNMT3B expression was unrelated with patient outcome, survival, or prognosis.</p><p><b>Conclusions:</b> Tumoral DNMT3B overexpression is associated with CIMP-high in colorectal cancer. Our data support a possible role of DNMT3B in nonrandom <i>de novo</i> CpG island methylation leading to colorectal cancer.</p></div>
