A Bayesian framework for pathway-guided identification of cancer subgroups by integrating multiple types of genomic data.

In recent years, comprehensive cancer genomics platforms, such as The Cancer Genome Atlas (TCGA), provide access to an enormous amount of high throughput genomic datasets for each patient, including gene expression, DNA copy number alterations, DNA methylation, and somatic mutation. While the integration of these multi-omics datasets has the potential to provide novel insights that can lead to personalized medicine, most existing approaches only focus on gene-level analysis and lack the ability to facilitate biological findings at the pathway-level. In this article, we propose Bayes-InGRiD (Bayesian Integrative Genomics Robust iDentification of cancer subgroups), a novel pathway-guided Bayesian sparse latent factor model for the simultaneous identification of cancer patient subgroups (clustering) and key molecular features (variable selection) within a unified framework, based on the joint analysis of continuous, binary, and count data. By utilizing pathway (gene set) information, Bayes-InGRiD does not only enhance the accuracy and robustness of cancer patient subgroup and key molecular feature identification, but also promotes biological understanding and interpretation. Finally, to facilitate an efficient posterior sampling, an alternative Gibbs sampler for logistic and negative binomial models is proposed using Pólya-Gamma mixtures of normal to represent latent variables for binary and count data, which yields a conditionally Gaussian representation of the posterior. The R package "INGRID" implementing the proposed approach is currently available in our research group GitHub webpage (https://dongjunchung.github.io/INGRID/).

Exploring dimensions of coping in advanced colorectal cancer: implications for patient-centered care.

Promoting patient-centered care from diagnosis to end of life requires a better understanding of physical, psychological, social, and spiritual coping factors in advanced cancer. Using qualitative methods, the authors explored diagnosis, care planning, and treatment experiences of individuals with metastatic colorectal cancer (N=26). The main physical factors salient to patients during all care phases included symptoms and physical functioning. Key psychological factors included persistent uncertainty and a range of emotions that varied by care phase. Participants also relied heavily on social and spiritual factors for guidance. Results highlight the complex nature of coping with advanced cancer and the resources needed to facilitate high-quality care.

Association between folate levels and CpG Island hypermethylation in normal colorectal mucosa.

Gene-specific promoter methylation of several genes occurs in aging normal tissues and may predispose to tumorigenesis. In the present study, we investigate the association of blood folate levels and dietary and lifestyle factors with CpG island (CGI) methylation in normal colorectal mucosa. Subjects were enrolled in a multicenter chemoprevention trial of aspirin or folic acid for the prevention of large bowel adenomas. We collected 1,000 biopsy specimens from 389 patients, 501 samples from the right colon and 499 from the rectum at the follow-up colonoscopy. We measured DNA methylation of estrogen receptor alpha (ERα) and secreted frizzled related protein-1 (SFRP1), using bisulfite pyrosequencing. We used generalized estimating equations regression analysis to examine the association between methylation and selected variables. For both ERα and SFRP1, percentage methylation was significantly higher in the rectum than in the right colon (P = 0.001). For each 10 years of age, we observed a 1.7% increase in methylation level for ERα and a 2.9% increase for SFRP1 (P < 0.0001). African Americans had a significantly lower level of ERα and SFRP1 methylation than Caucasians and Hispanics. Higher RBC folate levels were associated with higher levels of both ERα (P = 0.03) and SFRP1 methylation (P = 0.01). Our results suggest that CGI methylation in normal colorectal mucosa is related to advancing age, race, rectal location, and RBC folate levels. These data have important implications regarding the safety of supplementary folate administration in healthy adults, given the hypothesis that methylation in normal mucosa may predispose to colorectal neoplasia.

Global DNA hypomethylation (LINE-1) in the normal colon and lifestyle characteristics and dietary and genetic factors.

BACKGROUND: Global loss of methylated cytosines in DNA, thought to predispose to chromosomal instability and aneuploidy, has been associated with an increased risk of colorectal neoplasia. Little is known about the relationships between global hypomethylation and lifestyle, demographics, dietary measures, and genetic factors. METHODS: Our data were collected as part of a randomized clinical trial testing the efficacy of aspirin and folic acid for the prevention of colorectal adenomas. At a surveillance colonoscopy approximately 3 years after the qualifying exam, we obtained two biopsies of the normal-appearing mucosa from the right colon and two biopsies from the left colon. Specimens were assayed for global hypomethylation using a pyrosequencing assay for LINE-1 (long interspersed nucleotide elements) repeats. RESULTS: The analysis included data from 388 subjects. There was relatively little variability in LINE methylation overall. Mean LINE-1 methylation levels in normal mucosa from the right bowel were significantly lower than those on the left side (P < 0.0001). No significant associations were found between LINE-1 methylation and folate treatment, age, sex, body mass index, smoking status, alcohol use, dietary intake, or circulating levels of B vitamins, homocysteine, or selected genotypes. Race, dietary folic acid, and plasma B(6) showed associations with global methylation that differed between the right and the left bowel. The effect of folic acid on risk of adenomas did not differ according to extent of LINE-1 methylation, and we found no association between LINE-1 methylation and risk of adenomas. CONCLUSIONS: LINE-1 methylation is not influenced by folic acid supplementation but differs by colon subsite.

Selenium and risk of bladder cancer: a population-based case-control study.

Emerging evidence indicates a potential role of selenium in the prevention of several types of cancer, including bladder cancer. We investigated the association between toenail selenium concentrations and bladder cancer risk in a population-based case-control study in New Hampshire. We analyzed data from 857 incidence cases diagnosed between July 1, 1994 and June 30, 2001 and 1,191 general population controls. Newly diagnosed cases of bladder cancer were identified from the New Hampshire State Cancer Registry, which operates a rapid reporting system. Controls were selected from population lists (driver's license and Medicare enrollment). We used logistic regression analyses to generate odds ratios (OR) and 95% confidence intervals (95% CI), controlling for age, sex, and pack-years of smoking and conducted separate analyses according to the intensity of p53 immunohistochemical staining of the tumor. Overall, toenail selenium concentrations were not significantly related to bladder cancer [OR Q4 versus Q1, 0.90 (95% CI, 0.68-1.19); P(trend) = 0.15]. However, within specific subgroups there were inverse associations, i.e., among moderate smokers [OR, 0.61 (95% CI, 0.39-0.96); P(trend) = 0.004], women [OR, 0.66 (95% CI, 0.40-1.10); P(trend) = 0.11], and those with p53-positive cancers [OR Q4 versus Q1, 0.57 (95% CI, 0.34-0.94); P(trend) = 0.01]. Our results indicate that selenium is not inversely related to risk of bladder cancer overall; however, they raise the possibility that selenium may be preventive in certain molecular phenotypes of tumors (e.g., p53 positive) or within certain subsets of a population (e.g., women or moderate smokers).

MTHFR genotype and colorectal adenoma recurrence: data from a double-blind placebo-controlled clinical trial.

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism. We assessed the association between two common MTHFR variants, 677C>T and 1298A>C, and adenoma recurrence in the context of a randomized double- blind clinical trial of aspirin use and folate supplementation. We used generalized linear regression to estimate risk ratios and 95% confidence intervals (95% CI) for recurrence, adjusting for age, sex, clinical center, follow-up time, and treatment status. Neither MTHFR polymorphism was associated with overall or advanced adenoma recurrence. Compared with those with two wild-type alleles, the relative risk for advanced adenoma was 0.75 (95% CI, 0.36-1.55) for the MTHFR 677 TT genotype and 1.16 (95% CI, 0.58-2.33) for the MTHFR 1298 CC genotype. The effect of folate supplementation on recurrence risk did not differ by genotype. Our findings indicate that the MTHFR genotype does not change adenoma risk in a manner similar to its effect on colorectal cancer, and does not modify the effect of folate supplementation on metachronous adenoma risk.

Prolonged effect of calcium supplementation on risk of colorectal adenomas in a randomized trial.

BACKGROUND: Calcium supplementation has been shown to decrease the risk of recurrence of colorectal adenomas in randomized trials. However, the duration of this protective effect after cessation of active supplementation is not known. METHODS: In the Calcium Polyp Prevention Study, 930 subjects with a previous colorectal adenoma were randomly assigned from November 1988 through April 1992 to receive placebo or 1200 mg of elemental calcium daily for 4 years. The Calcium Follow-up Study was an observational phase of the trial that tracked adenoma occurrence for an average of 7 years after the end of randomized treatment and gathered information regarding the use of medications, vitamins, and supplements during that time. We obtained follow-up information for 822 subjects, 597 of whom underwent at least one colonoscopy after the end of study treatment and are included in this analysis. Generalized linear models were used to compute relative risks (RRs) and 95% confidence intervals (CIs) for the effect of randomized calcium treatment on risk of adenoma recurrence during the first 5 years after study treatment ended and during the subsequent 5 years. Statistical tests were two-sided. RESULTS: During the first 5 years after randomized treatment ended, subjects in the calcium group still had a substantially and statistically significantly lower risk of any adenoma than those in the placebo group (31.5% versus 43.2%; adjusted RR = 0.63, 95% CI = 0.46 to 0.87, P = .005) and a smaller and not statistically significant reduction in risk of advanced adenomas (adjusted RR = 0.85, 95% CI = 0.43 to 1.69, P = .65). However, the randomized treatment was not associated with the risk of any type of polyp during the next 5 years. The findings were broadly similar when the analysis was restricted to subjects who did not report use of any calcium supplements after the treatment phase of the trial ended. CONCLUSION: The protective effect of calcium supplementation on risk of colorectal adenoma recurrence extends up to 5 years after cessation of active treatment, even in the absence of continued supplementation.

K-ras mutations in incident sporadic colorectal adenomas.

BACKGROUND: Although K-ras is the most frequently mutated protooncogene in colorectal carcinoma, the specific role and timing of K-ras mutations in colorectal carcinogenesis remains controversial. In the current study, the authors investigated associations with K-ras mutation in incident sporadic colorectal adenomas that occurred during a chemoprevention trial of calcium supplementation. METHODS: K-ras genotyping was performed on 303 colorectal adenomas that were removed from 207 participants during the follow-up phase of the Calcium Polyp Prevention Study. Mutations in codons 12 or 13 of K-ras were detected by denaturing high-performance liquid chromatography and were confirmed by direct sequencing. RESULTS: The adenomas analyzed had a mean estimated size of 0.5 cm, and 3.0% were identified with mutations (95% confidence interval [95% CI], 1.3-4.4%). These mutations were more common in larger adenomas (risk ratio [RR], 12.7 for tumors that measured > 0.5 cm vs. < or = 0.5 cm; 95% CI, 2.7-59.7), in adenomas with more advanced histology (RR, 20.6 for tubulovillous/villous vs. tubular; 95% CI, 4.4-96.0), and in adenomas that were located in the rectum compared with the colon (RR, 8.4; 95% CI, 2.3-30.5). CONCLUSIONS: Compared with previous studies, the current analysis was novel, because it focused on incident adenomas that were diagnosed within a few years of a previous "clean" colonoscopy. The results provided evidence for a very low rate of K-ras mutation among these small, early adenomas and strong support for a role of K-ras mutations in adenoma progression.

Risk of prostate cancer in a randomized clinical trial of calcium supplementation.

BACKGROUND: In some studies, high calcium intake has been associated with an increased risk of prostate cancer, but no randomized studies have investigated this issue. METHODS: We randomly assigned 672 men to receive either 3 g of calcium carbonate (1,200 mg of calcium), or placebo, daily for 4 years in a colorectal adenoma chemoprevention trial. Participants were followed for up to 12 years and asked periodically to report new cancer diagnoses. Subject reports were verified by medical record review. Serum samples, collected at randomization and after 4 years, were analyzed for 1,25-(OH)2 vitamin D, 25-(OH) vitamin D, and prostate-specific antigen (PSA). We used life table and Cox proportional hazard models to compute rate ratios for prostate cancer incidence and generalized linear models to assess the relative risk of increases in PSA levels. RESULTS: After a mean follow-up of 10.3 years, there were 33 prostate cancer cases in the calcium-treated group and 37 in the placebo-treated group [unadjusted rate ratio, 0.83; 95% confidence interval (95% CI), 0.52-1.32]. Most cases were not advanced; the mean Gleason's score was 6.2. During the first 6 years (until 2 years post-treatment), there were significantly fewer cases in the calcium group (unadjusted rate ratio, 0.52; 95% CI, 0.28-0.98). The calcium risk ratio for conversion to PSA >4.0 ng/mL was 0.63 (95% CI, 0.33-1.21). Baseline dietary calcium intake, plasma 1,25-(OH)2 vitamin D and 25-(OH) vitamin D levels were not materially associated with risk. CONCLUSION: In this randomized controlled clinical trial, there was no increase in prostate cancer risk associated with calcium supplementation and some suggestion of a protective effect.

Effect of calcium supplementation on the risk of large bowel polyps.

BACKGROUND: Clinical trials have shown that calcium supplementation modestly decreases the risk of colorectal adenomas. However, few studies have examined the effect of calcium on the risk of different types of colorectal lesions or dietary determinants of this effect. METHODS: Our analysis used patients from the Calcium Polyp Prevention Study, a randomized, double-blind, placebo-controlled chemoprevention trial among patients with a recent colorectal adenoma. Nine hundred thirty patients were randomly assigned to calcium carbonate (1200 mg/day) or placebo. Follow-up colonoscopies were conducted approximately 1 and 4 years after the qualifying examination. We used general estimating equation (GEE) and generalized linear regression analyses to compute risk ratios and 95% confidence intervals (CIs) to assess the effect of calcium treatment versus placebo on the risk of hyperplastic polyps, tubular adenomas, and more advanced lesions. Additionally, we used GEE analyses to compare the calcium treatment effects for various types of polyps with that for tubular adenomas. We also examined the interaction between calcium treatment and baseline intake of dietary calcium, fat, and fiber. All P values were obtained using Wald tests based on the corresponding models. All tests of statistical significance were two-sided. RESULTS: The calcium risk ratio for hyperplastic polyps was 0.82 (95% CI = 0.67 to 1.00), that for tubular adenomas was 0.89 (95% CI = 0.77 to 1.03), and that for histologically advanced neoplasms was 0.65 (95% CI = 0.46 to 0.93) compared with patients assigned to placebo. There were no statistically significant differences between the risk ratio for tubular adenomas and that for other types of polyps. The effect of calcium supplementation on adenoma risk was most pronounced among individuals with high dietary intakes of calcium and fiber and with low intake of fat, but the interactions were not statistically significant. CONCLUSION: Our results suggest that calcium supplementation may have a more pronounced antineoplastic effect on advanced colorectal lesions than on other types of polyps.

Prediagnostic serum selenium concentration and the risk of recurrent colorectal adenoma: a nested case-control study.

Several studies have suggested that selenium may help to prevent colorectal neoplasia. To investigate the relation between prediagnostic serum selenium concentrations and colorectal adenomas, we conducted a nested case-control study using data from a large, multicenter, adenoma prevention trial. Cases comprised a total of 276 patients who developed a colorectal adenoma between the year 1 and year 4 follow-up exam. Controls were 276 patients who did not develop an adenoma during this time interval, matched to case subjects on age, sex, and clinical center. Total and bound selenium concentrations were measured from baseline or year 1 serum samples using instrumental neutron activation analysis. We estimated the odds ratios of colorectal adenoma in relation to serum selenium concentrations adjusting for age, clinical center, and sex. Compared with the lowest quintile, the odds ratio for the highest quintile was 0.76 (95% confidence interval, 0.44-1.30) for total selenium and 0.60 (95% confidence interval, 0.34-1.05) for bound selenium, and there was no apparent trend in risk (P for trend = 0.50 for total selenium and P for trend = 0.20 for bound selenium). Thus, our findings do not indicate a clear association between serum selenium concentrations and adenoma recurrence.