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Stratified pathway analysis to identify gene sets associated with oral contraceptive use and breast cancer.

ABSTRACT: Cancer biomarker discovery can facilitate drug development, improve staging of patients, and predict patient prognosis. Because cancer is the result of many interacting genes, analysis based on a set of genes with related biological functions or pathways may be more informative than single gene-based analysis for cancer biomarker discovery. The relevant pathways thus identified may help characterize different aspects of molecular phenotypes related to the tumor. Although it is well known that cancer patients may respond to the same treatment differently because of clinical variables and variation of molecular phenotypes, this patient heterogeneity has not been explicitly considered in pathway analysis in the literature. We hypothesize that combining pathway and patient clinical information can more effectively identify relevant pathways pertinent to specific patient subgroups, leading to better diagnosis and treatment. In this article, we propose to perform stratified pathway analysis based on clinical information from patients. In contrast to analysis using all the patients, this more focused analysis has the potential to reveal subgroup-specific pathways that may lead to more biological insights into disease etiology and treatment response. As an illustration, the power of our approach is demonstrated through its application to a breast cancer dataset in which the patients are stratified according to their oral contraceptive use.

SUBMITTER: Pang H

PROVIDER: S-EPMC4263464 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Stratified pathway analysis to identify gene sets associated with oral contraceptive use and breast cancer.

Pang Herbert H Zhao Hongyu H

Cancer informatics 20141209 Suppl 4

Cancer biomarker discovery can facilitate drug development, improve staging of patients, and predict patient prognosis. Because cancer is the result of many interacting genes, analysis based on a set of genes with related biological functions or pathways may be more informative than single gene-based analysis for cancer biomarker discovery. The relevant pathways thus identified may help characterize different aspects of molecular phenotypes related to the tumor. Although it is well known that ca ...[more]

PMID: 25574128

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Project description:Purpose: The hypoxic tumor microenvironment was reported to be involved in different tumorigenesis mechanisms of breast cancer (BC). We aimed to establish a hypoxia-related gene signature to identify a new BC subtype through the clustering analysis and explore potential compounds targeting the BC subtypes. Methods: Gene expression data and clinical features of BC and adjacent non-tumor tissues were downloaded from the Cancer Genome Atlas-Breast cancer (TCGA-BRCA) database. We comprehensively revealed the activity changes of Gene Ontology (GO) biological processes (BP) gene sets in BC by gene set variation analysis (GSVA) and identified three hypoxia-related BC subtypes. We then matched the differentially expressed gene profile of each subtype with the gene profile in CMap database to identify the potential agents targeting the BC subtypes. Results: 562 of Gene Ontology biological processes gene sets significantly correlated with hypoxia score in breast cancer. 969 BC patients were clustered into three subtypes based on the enrichment score of hypoxia-associated gene sets. Subtype 1 patients displayed better survival than subtype 2 and 3. KEGG pathway enrichment analysis of each subtype was performed based on the unique differential expression genes profile. In subtype 1, the upregulated genes were associated with lipid and amino acid metabolism regulation; in subtype 2, the upregulated genes were associated with metabolic energy regulation, while in subtype 3, the upregulated genes were associated with apoptosis and protein process. Using the CMap database, 55, 111 and 63 compounds were identified, targeting subtype 1, 2, and 3, respectively. Conclusion: In this study, novel hypoxia-related subtypes were developed for patients with BC. In addition, biological processes associated with differential expression genes profile and potential therapeutic target compounds were identified in each subtype. The new classification might provide a better understanding of the role of hypoxia in breast cancer and more individualized treatment for patients.

Project description:ImportanceAlthough oral contraceptive (OC) use is common, the influence of OC use on carcinogenesis is not fully understood. A recent Agency for Healthcare Research and Quality report identified a need to understand the consistency of OC use and cancer associations across subpopulations, including smokers and obese women.ObjectiveTo determine whether associations between duration of OC use and risk of specific cancers were modified by lifestyle characteristics.Design, setting, and participantsThe prospective NIH-AARP Diet and Health Study (enrolled 1995-1996, followed until 2011), with population-based recruitment of AARP members in 6 states and 2 metropolitan areas. All analyses included at least 100 000 women who reported OC use at enrollment. We identified 1241 ovarian, 2337 endometrial, 11 114 breast, and 3507 colorectal cancer cases during follow-up. Data analysis was performed between September 2016 and April 2017.ExposuresDuration of OC use (never or <1 year [reference], 1-4, 5-9, or ≥10 years).Main outcomes and measuresDevelopment of ovarian, endometrial, breast, and colorectal cancers. We examined effect modification by modifiable lifestyle characteristics: cigarette smoking, alcohol consumption, body mass index (BMI), and physical activity. We used Cox models adjusted for age, race, age at menarche, and the modifiers of interest.ResultsThe analytic population was aged 50 to 71 years (median, 62 years) at enrollment and largely white (91%) and postmenopausal (96%). For ovarian cancer, OC use-associated risk reductions strengthened with duration of use (long-term OC use [≥10 years] HR, 0.60; 95% CI, 0.47-0.76; P < .001 for trend) and were similar across modifiable lifestyle factors. Risk reductions for endometrial cancer strengthened with duration of use (long-term OC use HR, 0.66; 95% CI, 0.56-0.78; P < .001 for trend); the most pronounced reductions were among long-term OC users who were smokers (HR, 0.47; 95% CI, 0.25-0.88), had obese BMIs (0.36; 95% CI, 0.25-0.52), and who exercised rarely (HR, 0.40; 95% CI, 0.29-0.56). Associations between OC use and breast and colorectal cancers were predominantly null.Conclusions and relevanceLong-term OC use is consistently associated with reduced ovarian cancer risk across lifestyle factors. We observed the greatest risk reductions for endometrial cancer among women at risk for chronic diseases (ie, smokers, obese BMI). Oral contraceptive use may be beneficial for chemoprevention for a range of women with differing baseline cancer risks.

Project description:Introduction: The majority of young women use oral contraceptives (OCs). Use of OCs has been associated with lower myofibrillar protein and tendon collagen synthesis rates, but it is unknown whether OCs will limit the adaptive response of myotendinous tissue to resistance training. Design and Methods: Fourteen healthy untrained young regular OC users (24 ± 1 years, fat% 32 ± 1, 35 ± 2 ml?min-1?kg-1) and 14 NOC users (non-OC, controls) (24 ± 1 years, fat% 32 ± 2, 34 ± 2 ml?min-1?kg-1) performed a 10-week supervised lower extremity progressive resistance training program. Before and after the intervention biopsies from the vastus lateralis muscle and the patellar tendon were obtained. Muscle (quadriceps) and tendon cross-sectional area (CSA) was determined by magnetic resonance imaging (MRI) scans, and muscle fiber CSA was determined by histochemistry. Maximal isometric knee extension strength was assessed by dynamometry while 1 repetition maximum (RM) was determined during knee extension. Results: Training enhanced CSA in both muscle (p < 0.001) and tendon (p < 0.01). A trend toward a greater increase in muscle CSA was observed for OC (11%) compared to NOC (8%) (interaction p = 0.06). Analysis of mean muscle fiber type CSA showed a trend toward an increase in type II muscle fiber area in both groups (p = 0.11, interaction p = 0.98), whereas type I muscle fiber CSA increased in the OC group (n = 9, 3821 ± 197 to 4490 ± 313 mm2, p < 0.05), but not in NOC (n = 7, 4020 ± 348 to 3777 ± 354 mm2, p = 0.40) (interaction p < 0.05). Post hoc analyses indicated that the effect of OCs on muscle mass increase was induced by the OC-users (n = 7), who used OCs containing 30 ?g ethinyl estradiol (EE), whereas the response in users taking OCs with 20 ?g EE (n = 7) did not differ from NOC. Both the OC and NOC group experienced an increase in maximal knee strength (p < 0.001) and 1RM leg extension (p < 0.001) after the training period with no difference between groups. Conclusion: Use of OCs during a 10-week supervised progressive resistance training program was associated with a trend toward a greater increase in muscle mass and a significantly greater increase in type I muscle fiber area compared to controls. Yet, use of OCs did not influence the overall increase in muscle strength related to training.

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Stratified pathway analysis to identify gene sets associated with oral contraceptive use and breast cancer.

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Stratified pathway analysis to identify gene sets associated with oral contraceptive use and breast cancer.

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