Citations

Abstract Nonselective cyclooxygenase (COX) inhibitors target many of the same cancer-associated molecular pathways as COX-2–specific inhibitors. Although these nonsteroidal anti-inflammatory drugs (NSAIDs) are often associated with gastrointestinal toxicity, there is renewed interest in their use as colorectal cancer (CRC) chemopreventive agents due to the adverse side effects associated with long-term use of selective COX-2 inhibitors. In this study, we investigated the effects of long-term use (up to 25 years) of NSAIDs (ibuprofen or aspirin) on adenoma pathology and β-catenin–mediated signaling in sporadic human colon adenomas. Although NSAID use did not impact overall adenoma size or degree of dysplasia, it did cause a significant inhibition of nuclear β-catenin localization, which correlated with suppression of cyclin D1 expression. To further elucidate the effect of these agents in regulating β-catenin, we treated SW480 colon cancer cells with a panel of NSAIDs and determined their effects on β-catenin levels and cellular localization. In agreement with our in vivo results, both S-ibuprofen and aspirin were found to decrease total levels of β-catenin while increasing its phosphorylation. In addition, S-ibuprofen induced both degradation of IκBα and nuclear localization of NF-κB. Despite its nuclear localization, however, the activation of the NF-κB target genes, Bcl-2, survivin, and cyclin D1, was suppressed. This reduction in NF-κB transcriptional activity may be due to increased phosphorylation of GSK-3β following S-ibuprofen treatment. These data suggest that ibuprofen can effectively target both the Wnt/β-catenin and NF-κB pathways, and potentially uncovers a novel mechanism through which NSAIDS may exert their chemopreventive efficacy. Cancer Prev Res; 4(1); 161–71. ©2011 AACR.

Abstract Multiple genome-wide association studies have identified several susceptibility variants for colon cancer at 8q24. However, the functional roles of these variants have yet to be elucidated. Here, we evaluated the potential role of these markers in tumor progression and examined association with commonly observed structural abnormalities in this region, c-MYC amplification and chromosome fragility at FRA8C and FRA8D. We first replicated the previously reported association by testing 1,178 cases and 1,009 clinic-based controls with eight markers localized to three specific regions at 8q24. We observed significant associations with colon cancer risk with markers rs13254738 (ordinal odds ratio, 0.82; 95% confidence interval, 0.072-0.94; Ptrend = 0.0037) and rs6983267 (ordinal odds ratio, 1.17; 95% confidence interval, 1.03-1.32, Ptrend = 0.013). Survival analysis was done using a separate set of 460 cases to evaluate the clinical significance of these markers. Overall, univariate analysis did not detect survival differences for any of the markers. We also tested a subset of the 460 cases (n = 380) for structural abnormalities at or near the c-MYC locus using fluorescence in situ hybridization analysis. Furthermore, we evaluated a small number of cases homozygous for the rs6983267 alleles to test for differences in fragile site induction. None of the 8q markers correlated with amplification at the c-MYC locus as detected by fluorescence in situ hybridization, and no clear pattern of breakage was observed at the FRA8C and FRA8D sites. In this study, we confirm the association for several single nucleotide polymorphisms at 8q24 in colon cancer but have not detected any structural role relating to c-MYC amplification or chromosomal fragility. Finally, these risk alleles do not seem to be associated with survival. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2492–500)

Abstract Base excision repair and nucleotide excision repair are vital responses to multiple types of DNA damage, including damage from tobacco exposure. Single-nucleotide polymorphisms (SNP) in these pathways may affect DNA repair capacity and therefore influence risk for cancer development. We performed a clinic-based, case-control study comprising 481 consecutive patients with confirmed pancreatic adenocarcinoma and 625 healthy controls. Allele and genotype frequencies for 16 SNPs in DNA repair genes ERCC1, XPD/ERCC2, XPC, XPF/ERCC4, OGG1, and XRCC1 were compared after adjusting for age, sex, and smoking history. Subgroup analysis by sex and smoking history was performed. Carriers of one or two XPF/ERCC4 minor alleles at R415Q had decreased risk of pancreatic adenocarcinoma compared with those who had two major alleles [odds ratio (OR), 0.59; 95% confidence interval (95% CI), 0.40–0.85]. Heavy smokers (>40 pack-years) had increased risk for cancer if they were carriers of at least one minor allele for XPD/ERCC2 at D312N (OR, 2.78; 95% CI, 1.28–6.04) or D711D (OR, 2.19; 95% CI, 1.01–4.73). No other significant differences in risk were identified. Minor alleles in DNA repair genes XPF/ERCC4 and XPD/ERCC2 were associated with altered risk for pancreatic cancer. [Cancer Res 2008;68(12):4928–35]

Abstract The frequency of colorectal cancer (CRC) among the Alaska Native people is the highest of any ethnic group in the United States. In this study, CRC from 329 Alaska Native people (165 Eskimo, 111 Indians, and 53 Aleut) were evaluated for evidence of defective DNA mismatch repair (MMR) by testing tumors for altered protein expression (hMLH1, hMSH2, and hMSH6) and for the presence of microsatellite instability. Of the 329 samples tested, 46 (14%) showed both microsatellite instability and altered protein expression; 42 (91%) with a loss of hMLH1, 3 (7%) hMSH2, and 1 (2%) hMLH1/hMSH6. Tumors with loss of hMLH1 were further evaluated for hMLH1 promoter hypermethylation and for the presence of the BRAF-V600E mutation. Among cases tested, all 19 (100%) tumors among the Eskimo patients showed hMLH1 promoter hypermethylation, whereas this was the case for only 3 of the 7 (42%) tumors among the Aleut (P = 0.002) and 5 of the 10 (50%) tumors from the Indians (P = 0.002). The majority of hypermethylated cases (23 of 27) tested positive for the V600E alteration. Of the nine tumors from the Aleut and Indian patients that did not exhibit hMLH1 hypermethylation, eight tested negative for V600E. Overall, the frequency of defective MMR among the three groups was not statistically different (P = 0.75). However, the data suggest that the pathogenesis of CRC may differ between the three groups. The CRC with defective MMR among the Eskimo sample fit the typical profile for hMLH1-related cancer associated with sporadic CRC, whereas the pattern in the Aleut and Indian suggests the possibility that germ line hMLH1 mutations may be present. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2344–50)

Abstract The role of genes that influence the risk of developing pancreatic cancer (PC) has not been well studied. The mitochondrion, conventionally thought to be an organelle specific to energy metabolism, is in fact multifunctional and has been implicated in many diseases, including cancer. To evaluate whether single nucleotide polymorphisms in mitochondrial DNA (mtSNP) are associated with increased risk of PC, we screened Caucasian cases diagnosed or seen at the Mayo Clinic with primary pancreatic adenocarcinoma (n = 955), and healthy clinic-based Caucasian controls (n = 1,102). A total of 24 mtSNPs, including 10 of the most common tagSNPs, 7 non-tagSNPs in the coding region, and 7 common SNPs in the regulatory region were genotyped. For analysis, these samples were grouped into two phases, the “testing” set (474 cases and 615 controls), and the “validation” set (481 cases and 487 controls). In the testing set, one mtSNP (SNP11719) suggested an association in single SNP analysis, with an odds ratio of 1.34 (95% confidence intervals, 1.05-1.72; P = 0.020), but did not remain statistically significant after correction for multiple testing. In the validation set, none of the 24 variants indicated any association with PC. For haplogroup analysis, 10 core SNPs that form common haplogroups in Caucasians (1719, 4580, 7028, 8251, 9055, 10398, 12308, 13368, 13708, and 16391) were evaluated. No significant associations with PC were identified either by analyzing the two sets separately or combined (combined global P = 0.17). Overall, these results do not support a significant involvement of mitochondrial DNA variation in the risk of developing PC. Investigation of other mitochondrial genetic variations (i.e., nuclear-encoded mitochondrial proteins) would be necessary to elucidate any role of mitochondrial DNA variation in PC. (Cancer Epidemiol Biomarkers Prev 2007;16(7):1455–9)

AbstractPurpose: Colorectal carcinoma (CRC) can be divided into two nonoverlapping groups: those that are chromosomally unstable but microsatellite stable (MSS CIN+) and those that are chromosomally stable but microsatellite unstable (MSI CIN−). However, a third group with neither chromosome nor microsatellite instability (MSS CIN−) makes a substantial contribution to the total CRC burden. The clinicopathologic features of MSS CIN− CRC are not well delineated. We assessed the relationship between age and chromosomal instability (CIN) status as measured by ploidy and allelic imbalance in a series of MSS tumors.Experimental Design: We studied a prospectively collected series of CRC patients at Mayo Clinic Rochester. A total of 84 samples of MSS CRC in patients ≤50 years old were identified between 1994 and 1997. A consecutive series of 90 MSS CRC in patients ≥65 years old served as a comparison group. CIN status was assessed using two techniques: ploidy analysis by flow cytometry and small chromosome changes as measured by genomewide fractional allelic imbalance.Results: CRC in the young-onset group was more likely to involve the rectum and to be high stage. MSS tumors in the young-onset group were more often diploid (46%) than those in older patients (26%; P = 0.006). This difference was maintained in the subset of MSS CRC that were high stage (42% versus 18%; P = 0.02) and in rectal cancers (50% versus 23%; P = 0.04).Conclusion: A greater proportion of young patients with MSS CRC has diploid tumors than patients who develop MSS CRC over age 65.

Abstract Background: Although an increased cancer risk in Peutz-Jeghers syndrome is established, data on the spectrum of tumors associated with the disease and the influence of germ-line STK11/LKB1 (serine/threonine kinase) mutation status are limited. Experimental Design: We analyzed the incidence of cancer in 419 individuals with Peutz-Jeghers syndrome, and 297 had documented STK11/LKB1 mutations. Results: Ninety-six cancers were found among individuals with Peutz-Jeghers syndrome. The risk for developing cancer at ages 20, 30, 40, 50, 60, and 70 years was 2%, 5%, 17%, 31%, 60%, and 85%, respectively. The most common cancers represented in this analysis were gastrointestinal in origin, gastroesophageal, small bowel, colorectal, and pancreatic, and the risk for these cancers at ages 30, 40, 50, and 60 years was 1%, 9%, 15%, and 33%, respectively. In women with Peutz-Jeghers syndrome, the risk of breast cancer was substantially increased, being 8% and 31% at ages 40 and 60 years, respectively. Kaplan-Meier analysis showed that cancer risks were similar in Peutz-Jeghers syndrome patients with identified STK11/LKB1 mutations and those with no detectable mutation (log-rank test of difference χ2 = 0.62; 1 df; P = 0.43). Furthermore, the type or site of STK11/LKB1 mutation did not significantly influence cancer risk. Conclusions: The results from our study provide quantitative information on the spectrum of cancers and risks of specific cancer types associated with Peutz-Jeghers syndrome.