Genetic and epigenetic associations of circadian gene <i>TIMELESS</i> and breast cancer risk

Fu, Alan; Leaderer, Derek; Zheng, Tongzhang; Hoffman, Aaron E.; Stevens, Richard G.; Zhu, Yong

doi:10.1002/mc.20862

Cited by 64 publications

(53 citation statements)

References 18 publications

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“…While altered expressions of TIMELESS and DLX1 have been reported for a variety of cancers,2021222324 they have not been associated with prostate cancer metastasis. The elevated expression of TIMELESS found in our metastatic xenografts ( Table 1 ), as well as in metastatic prostate cancer patients’ samples (MSKCC cohort; Figure 2a ) and a strong correlation between elevated TIMELESS expression and poor clinical patients’ outcome (increased seminal vesicle invasion and lymph node involvement; Figure 2b ), suggest that this gene has a role in prostate cancer metastasis and perhaps as a metastasis-driving gene.…”

Section: Discussionmentioning

confidence: 90%

Prostate cancer metastasis-driving genes: hurdles and potential approaches in their identification

2014

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Metastatic prostate cancer is currently incurable. Metastasis is thought to result from changes in the expression of specific metastasis-driving genes in nonmetastatic prostate cancer tissue, leading to a cascade of activated downstream genes that set the metastatic process in motion. Such genes could potentially serve as effective therapeutic targets for improved management of the disease. They could be identified by comparative analysis of gene expression profiles of patient-derived metastatic and nonmetastatic prostate cancer tissues to pinpoint genes showing altered expression, followed by determining whether silencing of such genes can lead to inhibition of metastatic properties. Various hurdles encountered in this approach are discussed, including (i) the need for clinically relevant, nonmetastatic and metastatic prostate cancer tissues such as xenografts of patients’ prostate cancers developed via subrenal capsule grafting technology and (ii) limitations in the currently available methodology for identification of master regulatory genes.

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Section: Discussionmentioning

confidence: 90%

Prostate cancer metastasis-driving genes: hurdles and potential approaches in their identification

2014

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“…Previous studies also reported that variants in NPAS2 (Zhu et al 2008), CRY2 (Hoffman et al 2010b,c), TIMELESS (Fu et al 2012), and ARNTL (BMAL1) (Zienolddiny et al 2013) were associated with breast cancer. These associations were study specific and were not replicated in our data.…”

Section: Main Genetic Effectsmentioning

confidence: 83%

Breast cancer risk, nightwork, and circadian clock gene polymorphisms

Truong¹,

Liquet²,

Ménégaux³

et al. 2014

Endocrine-Related Cancer

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Night shift work has been associated with an increased risk of breast cancer pointing to a role of circadian disruption. We investigated the role of circadian clock gene polymorphisms and their interaction with nightwork in breast cancer risk in a population-based case-control study in France including 1126 breast cancer cases and 1174 controls. We estimated breast cancer risk associated with each of the 577 single nucleotide polymorphisms (SNPs) in 23 circadian clock genes. We also used a gene-and pathway-based approach to investigate the overall effect on breast cancer of circadian clock gene variants that might not be detected in analyses based on individual SNPs. Interactions with nightwork were tested at the SNP, gene, and pathway levels. We found that two SNPs in RORA (rs1482057 and rs12914272) were associated with breast cancer in the whole sample and among postmenopausal women. In this subpopulation, we also reported an association with rs11932595 in CLOCK, and with CLOCK, RORA, and NPAS2 in the analyses at the gene level. Breast cancer risk in postmenopausal women was also associated with overall genetic variation in the circadian gene pathway (PZ0.04), but this association was not detected in premenopausal women. There was some evidence of an interaction between PER1 and nightwork in breast cancer in the whole sample (PZ0.024), although the effect was not statistically significant after correcting for multiple testing (PZ0.452). Our results support the hypothesis that circadian clock gene variants modulate breast cancer risk.

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“…Nonetheless, a lack of standardization for these potential differences represents a study uncertainty. 36,82,83 Other studies that targeted clock genes in PBLs indicated that DNA hypomethylation was associated with breast cancer diagnoses ( CLOCK ), 84 or with advanced stage (II-IV) breast cancer ( TIMELESS ), 85 whereas promoter hypermethylation was associated with postmenopausal breast cancer ( CRY2 ), 86 and with chronic myeloid leukemia ( PER3 ) 68 relative to controls. The mechanism through which PER1 or PER3 gene methylation may impact adenoma formation is unknown and may depend on tissue context, timing of expression relative to other cellular processes, location of epigenetic changes within the gene, or other factors that may disrupt clock gene expression, such as shift work.…”

Section: Discussionmentioning

confidence: 99%

Case-control study of candidate gene methylation and adenomatous polyp formation

Alexander

Burch

Steck

et al. 2016

Int J Colorectal Dis

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Purpose Colorectal cancer (CRC) is one of the most common and preventable forms of cancer, but remains the second leading cause of cancer-related death. Colorectal adenomas are precursor lesions that develop in 70–90% of CRC cases. Identification of peripheral biomarkers for adenomas would help to enhance screening efforts. This exploratory study examined the methylation status of 20 candidate markers in peripheral blood leukocytes and their association with adenoma formation. Methods Patients recruited from a local endoscopy clinic provided informed consent, and completed an interview to ascertain demographic, lifestyle, and adenoma risk factors. Cases were individuals with a histopathologically confirmed adenoma, and controls included patients with a normal colonoscopy, or those with histopathological findings not requiring heightened surveillance (normal biopsy, hyperplastic polyp). Methylation-specific polymerase chain reaction was used to characterize candidate gene promoter methylation. Odds ratios and 95% confidence intervals (OR, 95% CI) were calculated using unconditional multivariable logistic regression to test the hypothesis that candidate gene methylation differed between cases and controls, after adjustment for confounders. Results Complete data were available for 107 participants; 36% had adenomas (men: 40%, women: 31%). Hypomethylation of the MINT1 locus (OR: 5.3, 95% CI: 1.0–28.2), and the PER1 (OR: 2.9, 95% CI: 1.1–7.7) and PER3 (OR: 11.6, 95% CI: 1.6–78.5) clock gene promoters was more common among adenoma cases. While specificity was moderate to high for the three markers (71–97%), sensitivity was relatively low (18–45%). Conclusion Follow-up of these epigenetic markers is suggested to further evaluate their utility for adenoma screening or surveillance.

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Genetic and epigenetic associations of circadian gene TIMELESS and breast cancer risk

Cited by 64 publications

References 18 publications

Prostate cancer metastasis-driving genes: hurdles and potential approaches in their identification

Prostate cancer metastasis-driving genes: hurdles and potential approaches in their identification

Breast cancer risk, nightwork, and circadian clock gene polymorphisms

Case-control study of candidate gene methylation and adenomatous polyp formation

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