Gene Summary

Gene:PER1; period circadian regulator 1
Aliases: PER, hPER, RIGUI
Summary:This gene is a member of the Period family of genes and is expressed in a circadian pattern in the suprachiasmatic nucleus, the primary circadian pacemaker in the mammalian brain. Genes in this family encode components of the circadian rhythms of locomotor activity, metabolism, and behavior. This gene is upregulated by CLOCK/ARNTL heterodimers but then represses this upregulation in a feedback loop using PER/CRY heterodimers to interact with CLOCK/ARNTL. Polymorphisms in this gene may increase the risk of getting certain cancers. Alternative splicing has been observed in this gene; however, these variants have not been fully described. [provided by RefSeq, Jan 2014]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:period circadian protein homolog 1
Source:NCBIAccessed: 30 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Immunohistochemistry
  • Circadian Rhythm
  • Down-Regulation
  • Adenocarcinoma
  • DNA Methylation
  • Cell Cycle Proteins
  • Stomach Cancer
  • Liver Cancer
  • Basic Helix-Loop-Helix Transcription Factors
  • Biomarkers, Tumor
  • Gene Expression Profiling
  • Sirtuin 1
  • Circadian Clocks
  • Cervical Cancer
  • Prostate Cancer
  • Nuclear Proteins
  • Messenger RNA
  • CLOCK Proteins
  • Promoter Regions
  • Colorectal Cancer
  • Molecular Sequence Data
  • Genetic Predisposition
  • Apoptosis
  • Case-Control Studies
  • Single Nucleotide Polymorphism
  • Transcription
  • Cancer Gene Expression Regulation
  • Proto-Oncogene Proteins c-myc
  • Base Sequence
  • Cell Proliferation
  • Chromosome 17
  • RT-PCR
  • Genetic Association Studies
  • ARNTL Transcription Factors
  • Cryptochromes
  • Breast Cancer
  • China
  • Period Circadian Proteins
  • Gene Expression
Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: PER1 (cancer-related)

Lim YC, Kim H, Lim SM, Kim JS
Genetic analysis of a novel antioxidant multi-target iron chelator, M30 protecting against chemotherapy-induced alopecia in mice.
BMC Cancer. 2019; 19(1):149 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Chemotherapy-induced alopecia has been well documented as a cause of distress to patients undergoing cancer treatment. Almost all traditional chemotherapeutic agents cause severe alopecia. Despite advances in the treatment of chemotherapy-induced alopecia, there is no effective treatment for preventing chemotherapy-induced alopecia.
METHODS: In the present study, we investigated the potential role of a multi-target iron chelator, M30 in protecting against cyclophosphamide-induced alopecia in C57BL/6 mice implanted with an osmotic pump. M30 enhanced hair growth and prevented cyclophosphamide-induced abnormal hair in the mice. Furthermore, we examined the gene expression profiles derived from skin biopsy specimens of normal mice, cyclophosphamide-treated mice, and cyclophosphamide treated mice with M30 supplement.
RESULTS: The top genes namely Tnfrsf19, Ercc2, Lama5, Ctsl, and Per1 were identified by microarray analysis. These genes were found to be involved in the biological processes of hair cycle, hair cycle phase, hair cycle process, hair follicle development, hair follicle maturation, hair follicle morphogenesis, regulation of hair cycle.
CONCLUSION: Our study demonstrates that M30 treatment is a promising therapy for cyclophosphamide-induced alopecia and suggests that the top five genes have unique preventive effects in cyclophosphamide-induced transformation.

Orhan T, Nielsen PB, Hviid TVF, et al.
Expression of Circadian Clock Genes in Human Colorectal Cancer Tissues Using Droplet Digital PCR.
Cancer Invest. 2019; 37(2):90-98 [PubMed] Related Publications
Increasing evidence indicates that disruption of circadian rhythms may be directly linked to cancer. Here we report that the expression levels of the core clock genes Per1 and Per3 measured by droplet digital polymerase chain reaction are significantly decreased in tumour tissue from 16 patients undergoing colorectal cancer surgery compared to paired normal mucosa. No differences were observed in the expression of Per2, Bmal1, and Clock. In conclusion, abnormal expression levels of the clock genes Per1 and Per3 in CRC tissue may be related to tumourigenesis and may provide future diagnostic and prognostic information.

Benna C, Rajendran S, Spiro G, et al.
Associations of clock genes polymorphisms with soft tissue sarcoma susceptibility and prognosis.
J Transl Med. 2018; 16(1):338 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Dysfunction of the circadian clock and polymorphisms of some circadian genes have been linked to cancer development and progression. We investigated the relationship between circadian genes germline variation and susceptibility or prognosis of patients with soft tissue sarcoma.
PATIENTS AND METHODS: We considered the 14 single nucleotide polymorphisms (SNPs) of 6 core circadian genes that have a minor allele frequency > 5% and that are known to be associated with cancer risk or prognosis. Genotyping was performed by q-PCR. Peripheral blood and clinic-pathological data were available for 162 patients with liposarcoma or leiomyosarcoma and 610 healthy donors. Associations between the selected clock genes polymorphisms and sarcoma susceptibility or prognosis were tested assuming 3 models of inheritance: additive, recessive and dominant. Subgroup analysis based on sarcoma histotype was performed under the additive genetic model. Multivariate logistic regression and multivariate Cox proportional hazard regression analyses were utilized to assess the association between SNPs with patient susceptibility and survival, respectively. Pathway variation analysis was conducted employing the Adaptive Rank Truncated Product method.
RESULTS: Six out of the 14 analyzed SNPs were statistically significantly associated with susceptibility or prognosis of soft tissue sarcoma (P < 0.05). The present analysis suggested that carriers of the minor allele of the CLOCK polymorphism rs1801260 (C) or of PER2 rs934945 (T) had a reduced predisposition to sarcoma (26% and 35% respectively with the additive model) and liposarcoma (33% and 41% respectively). The minor allele (A) of NPAS2 rs895520 was associated with an increased predisposition to sarcoma of 33% and leiomyosarcoma of 44%. RORA rs339972 C allele was associated with a decreased predisposition to develop sarcoma assuming an additive model (29%) and leiomyosarcoma (36%). PER1 rs3027178 was associated with a reduced predisposition only in liposarcoma subgroup (32%). rs7602358 located upstream PER2 was significantly associated with liposarcoma survival (HR: 1.98; 95% CI 1.02-3.85; P = 0.04). Germline genetic variation in the circadian pathway was associated with the risk of developing soft tissue sarcoma (P = 0.035).
CONCLUSIONS: Genetic variation of circadian genes appears to play a role in the determinism of patient susceptibility and prognosis. These findings prompt further studies to fully dissect the molecular mechanisms.

Ren W, Sun Q, Wu PY, et al.
Profiles of genomic alterations in primary esophageal follicular dendritic cell sarcoma: A case report.
Medicine (Baltimore). 2018; 97(48):e13413 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Follicular dendritic cell (FDC) sarcoma is a rare tumor with FDC differentiation that typically arises within lymph nodes but can also occur extranodally. To date, the primary esophageal FDC sarcoma has not been reported in the English literature.
PATIENT CONCERNS: We described a 67-year-old female who foremostly presented with dysphagia, and the patient was readmitted due to a dry cough and pain of his right shoulder 2 years after initial treatment.
DIAGNOSES: Primary esophageal FDC sarcoma with the right superior mediastinal lymph node metastasis.
INTERVENTIONS: The esophageal tumor was removed by endoscopic submucosal dissection at the first hospitalization. At the second hospitalization 2 years after the initial visit, the tracheal stent loaded with (125) iodine radioactive seeds was placed. The profiles of genetic variations and immunotherapeutic biomarkers were also explored by next-generation sequencing protocol from the patient's blood, esophageal primary, and mediastinal metastatic tumor samples.
OUTCOMES: The patient's symptom transitorily relieved, but she gave up further treatment and died 2 months after the tracheal stent was placed. As for the genomic alterations, we found 9 gene mutations in all the samples, including checkpoint kinase 2(CHEK2), FAT atypical cadherin 1 (FAT1), tumor protein 53 (TP53), DPYD, ERBB2 interacting protein (ERBB2IP), FBXW7, KMT2D, PPP2R1A, TSC2, whereas amplification of MYC was only in the metastatic example. The analysis of clonal evolution and phylogenetic tree showed the propagation and replay of polyclonal esophageal FDC sarcoma. At the same time, the detection of biomarkers for immunotherapy revealed microsatellite stable and mismatch repair-proficient (pMMR), which predicted a relatively poor anti-programmed death (PD-1)/programmed death ligand (PD-L1) immunotherapy outcome. On the contrary, the tumor mutational burdens were 10 mutations per 1 million bases in both the primary and metastatic tumor sample, which ranked the top 23.3% in solid tumors mutational burdens database of Geneseeq and might be a good predictor of the efficacy of anti-PD-1/PD-L1 immunotherapy.
LESSONS: To the best of our knowledge, this case report announced the first case of extranodal primary esophageal FDC sarcoma in the world, and firstly revealed its unique genetic alterations profiles, which might contribute to further in-depth study of this rare disease.

Hou S, Zheng S, Chen X, et al.
[Electroacupuncture Intervention Regulates Circadian Rhythms by Down-regulating Per Gene Expression in Hypothalamic Suprachiasmatic Nucleus of Hepatocellular Carcinoma Mice].
Zhen Ci Yan Jiu. 2018; 43(10):632-9 [PubMed] Related Publications
OBJECTIVE: To observe the effect of electroacupuncture (EA) on the rhythm of running-wheel activity of hepatocellular carcinoma (HCC) mice and the expression of
METHODS: A total of 108 male C 57 BL / 6 J mice were randomly divided into control, HCC model and EA groups which were further assigned to six zeitbeger (environmental light-dark cycle) time (ZT) point (ZT 0, ZT 4, ZT 8, ZT 12, ZT 16 and ZT 20) subgroups. The HCC model was established by injection of H 22 cancer cell (abdominal 3
RESULTS: (1) Following modeling, the amplitude of periodogram of running-wheel activity was significantly lowered at ZT 0, ZT 4, ZT 8, ZT 12, ZT 16, and ZT 20 relevant to the control group (
CONCLUSION: EA can benignly regulate the rhythm of running-wheel activity of HCC mice, which may be closely related to its effect in down-regulating the expression of circadian rhythm genes

Libé R
Clinical and molecular prognostic factors in adrenocortical carcinoma.
Minerva Endocrinol. 2019; 44(1):58-69 [PubMed] Related Publications
INTRODUCTION: Adrenocortical carcinoma (ACC) is a rare cancer, with an incidence less than 0.7-1.5 per 1 million people per year, with a poor prognosis. The overall survival (OS) depends on the ENSAT stage: in particular in metastatic ACC the OS varies from 10 to 20 months, with a 5-year survival around 10%. ACC has a different behavior, probably due to a different biology. For this reason, a careful prognostic classification is mandatory, in order to stratify the patients and propose a specific management.
EVIDENCE ACQUISITION: Prognostic factors can be divides in three groups: clinical factors (tumor stage, age, hormone-related symptoms), pathological factors (Weiss Score, mitotic count, Ki-67, SF-1 and AVA2, P53, beta-catenin immunohistochemistry, resection status), molecular factors (chromosomal aberrations, methylation profile, altered gene expression and miRNA expression, gene mutations).
EVIDENCE SYNTHESIS: The best way to stratify ACC patients and propose the best therapeutic option is to combine clinical, pathological and molecular factors.
CONCLUSIONS: Individualizing patients' prognosis and tumor biology appears as a necessary step for personalized medicine. In addition to tumor stage and tumor grade, the genomic classification may precise the risk stratification and thus help defining therapeutic strategy.

Yang C, Ren J, Li B, et al.
Identification of clinical tumor stages related mRNAs and miRNAs in cervical squamous cell carcinoma.
Pathol Res Pract. 2018; 214(10):1638-1647 [PubMed] Related Publications
OBJECTIVES: The aim of this study is to identify the clinical tumor stage related mRNAs and miRNAs, shedding light on the potential molecular mechanisms of cervical squamous cell carcinoma (CSCC).
METHODS: Firstly, the mRNA and miRNA next-generation sequencing data were downloaded. Secondly, clinical tumor stage correlation analysis of mRNAs and miRNA was performed, followed by the functional enrichment analysis of all clinical tumor stage related mRNAs. Thirdly, differentially expression analysis of mRNAs and miRNA between different clinical tumor stages was performed, followed by target gene prediction of these differentially expressed miRNAs.
RESULTS: 3 mRNAs (PER1, PRKAB1 and PMM2) and 5 miRNAs (hsa-mir-486, hsa-mir-451, hsa-mir-424, hsa-mir-144 and hsa-mir-450a-2) were overlapped from stage 1, stage 2, stage 3 and stage 4.
CONCLUSIONS: Alterations of differentially expressed mRNAs and miRNAs may offer important insights into the molecular mechanisms in the pathology of CSCC.

Lesicka M, Jabłońska E, Wieczorek E, et al.
Altered circadian genes expression in breast cancer tissue according to the clinical characteristics.
PLoS One. 2018; 13(6):e0199622 [PubMed] Free Access to Full Article Related Publications
Breast cancer has a multifactorial etiology. One of the supposed and novel mechanisms is an alteration of circadian gene expression. Circadian genes play a crucial role in many physiological processes. These processes, such as genomic stability, DNA repair mechanism and apoptosis, are frequently disrupted in breast tumors. To assess the significance of circadian gene expression in breast cancer, we carried out an analysis of CLOCK, BMAL1, NPAS2, PER1, PER2, PER3 and CRY1, CRY2, TIMELESS, CSNK1E expression by the use of the quantitative Real-Time PCR technique in tumor tissue and non-tumor adjacent normal tissue sampled from 107 women with a newly diagnosed disease. The obtained data were compared to the clinical and histopathological features. PER1, PER2, PER3, CRY2 were found to be significantly down-expressed, while CLOCK, TIMELESS were over-expressed in the studied tumor samples compared to the non-tumor samples. Only gene expression of CRY1 was significantly down-regulated with progression according to the TNM classification. We found significantly decreased expression of CRY2, PER1, PER2 genes in the ER/PR negative breast tumors compared to the ER/PR positive tumors. Additionally, expression of CRY2, NPAS2 genes had a decreased level in the poorly differentiated tumors in comparison with the well and moderately differentiated ones. Our results indicate that circadian gene expression is altered in breast cancer tissue, which confirms previous observations from various animal and in vitro studies.

Huang CF, Wang SC, Yeh ML, et al.
Association of serial serum major histocompatibility complex class I chain-related A measurements with hepatocellular carcinoma in chronic hepatitis C patients after viral eradication.
J Gastroenterol Hepatol. 2019; 34(1):249-255 [PubMed] Related Publications
BACKGROUND AND AIM: Major histocompatibility complex class I chain-related A (MICA) genetic variants and their serum levels (sMICA) were associated with the development of hepatitis C virus-related hepatocellular carcinoma (HCC) in untreated cohorts. The dynamic changes in serial sMICA levels and their association with HCC in the post-curative status are elusive.
METHODS: Single nucleotide polymorphism rs2596542 of MICA and serial sMICA levels were analyzed in chronic hepatitis C patients with a sustained virologic response after antivirals. Forty-two patients who developed HCC and 84 age-matched, gender-matched, and cirrhosis propensity score-matched non-HCC controls were compared. Serial sMICA levels were measured within 6 months before treatment initiation (pre-sMICA), 6 months after the end of treatment (post-sMICA), and on the last visit before the development (or not) of HCC (last-sMICA).
RESULTS: Cox regression analysis revealed that last-sMICA was the only predictive factor of HCC development (hazard ratio/95% confidence interval: 2.27 (per 1 log pg/mL increase)/1.672-3.082, P < 0.001). Patients without HCC development showed a significantly reduced trend of sMICA levels during follow-up (trend P = 0.001), which was observed only in GG genotype (trend P < 0.001) but not A allele carriers (P = 0.88). In contrast, patients with HCC showed an increased trend of sMICA levels (trend P = 0.024). However, only the GG genotype "high expressors" (trend P = 0.06) but not A allele carriers (P = 0.18) showed a correlation of substantially increased trend of sMICA levels and HCC development.
CONCLUSIONS: Serial sMICA levels were associated with HCC development in SVR patients. The clinical utility of this finding is restricted to MICA rs2596542 GG genotype carriers.

Wagner PM, Sosa Alderete LG, Gorné LD, et al.
Proliferative Glioblastoma Cancer Cells Exhibit Persisting Temporal Control of Metabolism and Display Differential Temporal Drug Susceptibility in Chemotherapy.
Mol Neurobiol. 2019; 56(2):1276-1292 [PubMed] Related Publications
Even in immortalized cell lines, circadian clocks regulate physiological processes in a time-dependent manner, driving transcriptional and metabolic rhythms, the latter being able to persist without transcription. Circadian rhythm disruptions in modern life (shiftwork, jetlag, etc.) may lead to higher cancer risk. Here, we investigated whether the human glioblastoma T98G cells maintained quiescent or under proliferation keep a functional clock and whether cells display differential time responses to bortezomib chemotherapy. In arrested cultures, mRNAs for clock (Per1, Rev-erbα) and glycerophospholipid (GPL)-synthesizing enzyme genes,

Yu Y, Li Y, Zhou L, et al.
Cryptochrome 2 (CRY2) Suppresses Proliferation and Migration and Regulates Clock Gene Network in Osteosarcoma Cells.
Med Sci Monit. 2018; 24:3856-3862 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Circadian disruption is a potential cancer risk factor in humans. However, the role of the clock gene, cryptochrome 2 (CRY2), in osteosarcoma (OS) is still not clear. MATERIAL AND METHODS To evaluate the potential role of CRY2 in HOS osteosarcoma cells, CRY2-silenced cell lines were established. Furthermore, we investigated the effect of CRY2 knockdown on HOS cells by CCK-8, colony formation, migration assay, and flow cytometry, in vitro. RESULTS CRY2 knockdown promoted HOS OS cell proliferation and migration. We used a cell cycle assay to show that CRY2 knockdown increased the S phase cell population and reduced the G1 phase cell population. Western blot analyses showed that CRY2 knockdown decreased P53 expression and increased expression of c-myc and cyclin D1. Simultaneously, CRY2 knockdown increased the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, but did not change the phosphorylation of c-Jun N terminal kinase (JNK) and P38. CRY2 knockdown also increased the expression of matrix metalloproteinase (MMP)-2 and β-catenin, and increased OS cell proliferation and migration by inducing cell cycle progression and promoting mitogen-activated protein kinase (MAPK) and Wnt/β-catenin signaling pathways. Although it has previously been unclear whether the expression of CRY2 affects the expression of other clock genes in the clock gene network, our results show that knockdown of CRY2 significantly increased the mRNA expression of CRY1, Period (PER) 1, PER2, BMAL1, and CLOCK. CONCLUSIONS Our results suggest that CRY2 may be an anti-oncogene in OS, whose functions involve both downstream genes and other circadian genes.

Sánchez DI, González-Fernández B, Crespo I, et al.
Melatonin modulates dysregulated circadian clocks in mice with diethylnitrosamine-induced hepatocellular carcinoma.
J Pineal Res. 2018; 65(3):e12506 [PubMed] Related Publications
Disruption of circadian rhythms, which are regulated by the circadian clock machinery, plays an important role in different long-term diseases including hepatocellular carcinoma (HCC). Melatonin has been reported to alleviate promotion and progression of HCC, but the potential contribution of circadian clock modulation is unknown. We investigated the effects of melatonin in mice which received diethylnitrosamine (DEN) (35 mg/kg body weight ip) once a week for 8 weeks. Melatonin was given at 5 or 10 mg kg

Das R, Kundu S, Laskar S, et al.
Assessment of DNA repair susceptibility genes identified by whole exome sequencing in head and neck cancer.
DNA Repair (Amst). 2018 Jun - Jul; 66-67:50-63 [PubMed] Related Publications
Head and neck cancer (HNC), the sixth most common cancer globally, stands second in India. In Northeast (NE) India, it is the sixth most common cause of death in males and seventh in females. Prolonged tobacco and alcohol consumption constitute the major etiological factors for HNC development, which induce DNA damage. Therefore, DNA repair pathway is a crucial system in maintaining genomic integrity and preventing carcinogenesis. The present work was aimed to predict the consequence of significant germline variants of the DNA repair genes in disease predisposition. Whole exome sequencing was performed in Ion Proton™ platform on 15 case-control samples from the HNC-prevalent states of Manipur, Mizoram, and Nagaland. Variant annotation was done in Ion Reporter™ as well as wANNOVAR. Subsequent statistical and bioinformatics analysis identified significant exonic and intronic variants associated with HNC. Amongst our observed variants, 78.6% occurred in ExAC, 94% reported in dbSNP and 5.8% & 9.3% variants were present in ClinVar and HGMD, respectively. The total variants were dispersed among 199 genes with DSBR and FA pathway being the most mutated pathways. The allelic association test suggested that the intronic variants in HLTF and RAD52 gene significantly associated (P < 0.05) with the risk (OR > 5), while intronic variants in PARP4, RECQL5, EXO1 and PER1 genes and exonic variant in TDP2 gene showed protection (OR < 1) for HNC. MDR analysis proposed the exonic variants in MSH6, BRCA2, PALB2 and TP53 genes and intronic variant in RECQL5 genetic region working together during certain phase of DNA repair mechanism for HNC causation. In addition, other intronic and 3'UTR variations caused modifications in the transcription factor binding sites and miRNA target sites associated with HNC. Large-scale validation in NE Indian population, in-depth structure prediction and subsequent simulation of our recognized polymorphisms is necessary to identify true causal variants related to HNC.

Morgan H, Olivero C, Patel GK
Identification of Human Cutaneous Basal Cell Carcinoma Cancer Stem Cells.
Methods Mol Biol. 2019; 1879:435-450 [PubMed] Related Publications
The cancer stem cell model states that a subset of tumor cells, called "cancer stem cells," can initiate and propagate tumor growth through self-renewal, high proliferative capacity, and their ability to recreate tumor heterogeneity. In basal cell carcinoma (BCC), we have shown that tumor cells that express the cell surface protein CD200 fulfill the cancer stem cell hypothesis. CD200+ CD45- BCC cells represent 0.05-3.96% of all BCC cells and reside in small clusters at the tumor periphery. Using a novel, reproducible in vivo xenograft growth assay, we determined that tumor-initiating cell (TIC) frequencies are approximately 1 per 1.5 million unsorted BCC cells. The CD200+ CD45- BCC subpopulation recreated BCC tumor growth in vivo with typical histological architecture and expression of sonic hedgehog-regulated genes. Reproducible in vivo BCC growth was achieved with as few as 10,000 CD200+ CD45- cells, representing ~1500-fold enrichment. The methods used to identify and purify CD200+ CD45- BCC cells, as well as characterize gene expression, are described herein.

Sadowski SM, Pusztaszeri M, Brulhart-Meynet MC, et al.
Identification of Differential Transcriptional Patterns in Primary and Secondary Hyperparathyroidism.
J Clin Endocrinol Metab. 2018; 103(6):2189-2198 [PubMed] Related Publications
Context: Hyperparathyroidism is associated with hypercalcemia and the excess of parathyroid hormone secretion; however, the alterations in molecular pattern of functional genes during parathyroid tumorigenesis have not been unraveled. We aimed at establishing transcriptional patterns of normal and pathological parathyroid glands (PGs) in sporadic primary (HPT1) and secondary hyperparathyroidism (HPT2).
Objective: To evaluate dynamic alterations in molecular patterns as a function of the type of PG pathology, a comparative transcript analysis was conducted in subgroups of healthy samples, sporadic HPT1 adenoma and hyperplasia, and HPT2.
Design: Normal, adenomatous, HPT1, and HPT2 hyperplastic PG formalin-fixed paraffin-embedded samples were subjected to NanoString analysis. In silico microRNA (miRNA) analyses and messenger RNA-miRNA network in PG pathologies were conducted. Individual messenger RNA and miRNA levels were assessed in snap-frozen PG samples.
Results: The expression levels of c-MET, MYC, TIMP1, and clock genes NFIL3 and PER1 were significantly altered in HPT1 adenoma compared with normal PG tissue when assessed by NanoString and quantitative reverse transcription polymerase chain reaction. RET was affected in HPT1 hyperplasia, whereas CaSR and VDR transcripts were downregulated in HPT2 hyperplastic PG tissue. CDH1, c-MET, MYC, and CaSR were altered in adenoma compared with hyperplasia. Correlation analyses suggest that c-MET, MYC, and NFIL3 exhibit collective expression level changes associated with HPT1 adenoma development. miRNAs, predicted in silico to target these genes, did not exhibit a clear tendency upon experimental validation.
Conclusions: The presented gene expression analysis provides a differential molecular characterization of PG adenoma and hyperplasia pathologies, advancing our understanding of their etiology.

Angelousi A, Kassi E, Nasiri-Ansari N, et al.
Clock genes alterations and endocrine disorders.
Eur J Clin Invest. 2018; 48(6):e12927 [PubMed] Related Publications
BACKGROUND: Various endocrine signals oscillate over the 24-hour period and so does the responsiveness of target tissues. These daily oscillations do not occur solely in response to external stimuli but are also under the control of an intrinsic circadian clock.
DESIGN: We searched the PubMed database to identify studies describing the associations of clock genes with endocrine diseases.
RESULTS: Various human single nucleotide polymorphisms of brain and muscle ARNT-like 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK) genes exhibited significant associations with type 2 diabetes mellitus. ARNTL2 gene expression and upregulation of BMAL1 and PER1 were associated with the development of type 1 diabetes mellitus. Thyroid hormones modulated PER2 expression in a tissue-specific way, whereas BMAL1 regulated the expression of type 2 iodothyronine deiodinase in specific tissues. Adrenal gland and adrenal adenoma expressed PER1, PER2, CRY2, CLOCK and BMAL1 genes. Adrenal sensitivity to adrenocorticotrophin was also affected by circadian oscillations. A significant correlation between the expression of propio-melanocorticotrophin and PER 2, as well as between prolactin and CLOCK, was found in corticotroph and lactosomatotroph cells, respectively, in the pituitary. Clock genes and especially BMAL1 showed an important role in fertility, whereas oestradiol and androgens exhibited tissue-specific effects on clock gene expression. Metabolic disorders were also associated with circadian dysregulation according to studies in shift workers.
CONCLUSIONS: Clock genes are associated with various endocrine disorders through complex mechanisms. However, data on humans are scarce. Moreover, clock genes exhibit a tissue-specific expression representing an additional level of regulation. Their specific role in endocrine disorders and their potential implications remain to be further clarified.

Okamoto T, Takada K, Sato S, et al.
Clinical and Genetic Implications of Mutation Burden in Squamous Cell Carcinoma of the Lung.
Ann Surg Oncol. 2018; 25(6):1564-1571 [PubMed] Related Publications
BACKGROUND: Lung squamous cell carcinoma (LSCC) is a major histological subtype of lung cancer. In this study, we investigated genomic alterations in LSCC and evaluated the clinical implications of mutation burden (MB) in LSCC.
METHODS: Genomic alterations were determined in Japanese patients with LSCC (N = 67) using next-generation sequencing of 415 known cancer genes. MB was defined as the number of non-synonymous mutations per 1 Mbp. Programmed death-ligand 1 (PD-L1) protein expression in cancer cells was evaluated by immunohistochemical analysis.
RESULTS: TP53 gene mutations were the most common alteration (n = 51/67, 76.1%), followed by gene alterations in cyclin-dependent kinase inhibitor 2B (CDKN2B; 35.8%), CDKN2A (31.3%), phosphatase and tensin homolog (30.0%), and sex-determining region Y-box 2 (SOX2, 28.3%). Histological differentiation was significantly poorer in tumors with high MB (greater than or equal to the median MB) compared with that in tumors with low MB (less than the median MB; p = 0.0446). The high MB group had more tumors located in the upper or middle lobe than tumors located in the lower lobe (p = 0.0019). Moreover, cancers in the upper or middle lobes had significantly higher MB than cancers in the lower lobes (p = 0.0005), and tended to show higher PD-L1 protein expression (p = 0.0573). SOX2 and tyrosine kinase non-receptor 2 amplifications were associated with high MB (p = 0.0065 and p = 0.0010, respectively).
CONCLUSIONS: The MB level differed according to the tumor location in LSCC, suggesting that the location of cancer development may influence the genomic background of the tumor.

Mocellin S, Tropea S, Benna C, Rossi CR
Circadian pathway genetic variation and cancer risk: evidence from genome-wide association studies.
BMC Med. 2018; 16(1):20 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Dysfunction of the circadian clock and single polymorphisms of some circadian genes have been linked to cancer susceptibility, although data are scarce and findings inconsistent. We aimed to investigate the association between circadian pathway genetic variation and risk of developing common cancers based on the findings of genome-wide association studies (GWASs).
METHODS: Single nucleotide polymorphisms (SNPs) of 17 circadian genes reported by three GWAS meta-analyses dedicated to breast (Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Consortium; cases, n = 15,748; controls, n = 18,084), prostate (Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) Consortium; cases, n = 14,160; controls, n = 12,724) and lung carcinoma (Transdisciplinary Research In Cancer of the Lung (TRICL) Consortium; cases, n = 12,160; controls, n = 16,838) in patients of European ancestry were utilized to perform pathway analysis by means of the adaptive rank truncated product (ARTP) method. Data were also available for the following subgroups: estrogen receptor negative breast cancer, aggressive prostate cancer, squamous lung carcinoma and lung adenocarcinoma.
RESULTS: We found a highly significant statistical association between circadian pathway genetic variation and the risk of breast (pathway P value = 1.9 × 10
CONCLUSIONS: Our findings, based on the largest series ever utilized for ARTP-based gene and pathway analysis, support the hypothesis that circadian pathway genetic variation is involved in cancer predisposition.

Moraes MN, de Assis LVM, Magalhães-Marques KK, et al.
Melanopsin, a Canonical Light Receptor, Mediates Thermal Activation of Clock Genes.
Sci Rep. 2017; 7(1):13977 [PubMed] Free Access to Full Article Related Publications
Melanopsin (OPN4) is a photo-pigment found in a small subset of intrinsically photosensitive ganglion cells (ipRGCs) of the mammalian retina. These cells play a role in synchronizing the central circadian pacemaker to the astronomical day by conveying information about ambient light to the hypothalamic suprachiasmatic nucleus, the site of the master clock. We evaluated the effect of a heat stimulus (39.5 °C) on clock gene (Per1 and Bmal1) expression in cultured murine Melan-a melanocytes synchronized by medium changes, and in B16-F10 melanoma cells, in the presence of the selective OPN4 antagonist AA92593, or after OPN4 knockdown by small interfering RNA (siRNA). In addition, we evaluated the effects of heat shock on the localization of melanopsin by immunocytochemistry. In both cell lines melanopsin was found in a region capping the nucleus and heat shock did not affect its location. The heat-induced increase of Per1 expression was inhibited when melanopsin was pharmacologically blocked by AA92593 as well as when its protein expression was suppressed by siRNA in both Melan-a and B16-F10 cells. These data strongly suggest that melanopsin is required for thermo-reception, acting as a thermo-opsin that ultimately feeds the local circadian clock in mouse melanocytes and melanoma cells.

Lulla AR, Slifker MJ, Zhou Y, et al.
miR-6883 Family miRNAs Target CDK4/6 to Induce G
Cancer Res. 2017; 77(24):6902-6913 [PubMed] Related Publications
CDK4/6 targeting is a promising therapeutic strategy under development for various tumor types. In this study, we used computational methods and The Cancer Genome Atlas dataset analysis to identify novel miRNAs that target CDK4/6 and exhibit potential for therapeutic development in colorectal cancer. The 3'UTR of CDK4/6 mRNAs are targeted by a family of miRNAs, which includes miR-6883-5p, miR-149*, miR-6785-5p, and miR-4728-5p. Ectopic expression of miR-6883-5p or miR-149* downregulated CDK4 and CDK6 levels in human colorectal cancer cells. RNA-seq analysis revealed an inverse relationship between the expression of CDK4/6 and miR-149* and intronic miRNA-6883-5p encoding the clock gene PER1 in colorectal cancer patient samples. Restoring expression of miR-6883-5p and miR-149* blocked cell growth leading to G

Szalai E, Wells JR, Ward L, Grossniklaus HE
Uveal Melanoma Nuclear BRCA1-Associated Protein-1 Immunoreactivity Is an Indicator of Metastasis.
Ophthalmology. 2018; 125(2):203-209 [PubMed] Free Access to Full Article Related Publications
PURPOSE: To examine the BRCA1-associated protein-1 (BAP1) expression of primary uveal melanomas without and with metastasis, and to analyze the correlation between the BAP1 immunoreactivity of primary uveal melanoma and other clinicopathologic features.
DESIGN: Retrospective case series.
PARTICIPANTS: Forty patients with uveal melanoma (mean age, 57.98±14.75 years) were included in this analysis, of whom 20 had no metastatic disease and 20 had metastasis.
METHODS: Medical records and histology slides of patients with primary uveal melanoma treated by enucleation were reviewed. BAP1 expression was evaluated by immunohistochemical staining of formalin-fixed, paraffin-embedded sections. Immunoreactivity in the nucleus and cytoplasm were graded by estimating the percentage of primary tumor cells showing a positive staining of their nucleus or cytoplasm per 1 high-power field 200× (grades 0-3).
MAIN OUTCOME MEASURES: Tumor size, histologic features, nuclear and cytoplasmic BAP1 immunoreactivity grade, and patient outcome, including development of metastasis.
RESULTS: Significantly lower (P = 0.025) nuclear BAP1 immunoreactivity was observed in the metastatic melanoma group. Greater tumor thickness, basal diameter, and more advanced TNM stage were associated with an increased odds ratio of developing metastasis (P < 0.05). In addition, tumors with a higher proportion of cells expressing nuclear BAP1 had decreased odds of developing metastatic disease in a multivariate model (P = 0.042). Metastasis-free survival was significantly longer in patients with uveal melanoma with high nuclear BAP1 stain (P = 0.004).
CONCLUSIONS: Time to metastasis differs in patients with primary uveal melanoma with different grades of nuclear BAP1 immunoreactivity. Nuclear BAP1 stain is the only significant independent predictor of metastatic disease in this study. Our data support the role of BAP1 immunohistochemical staining of primary uveal melanoma to evaluate metastatic risk.

Wang P, Yang Y, Lin L, et al.
Complete genome sequencing and characterization revealed a recombinant subgroup B isolate of avian leukosis virus with a subgroup J-like U3 region.
Virus Genes. 2017; 53(6):927-930 [PubMed] Related Publications
One natural recombinant subgroup B avian leukosis virus (ALV) with a subgroup J-like U3 region was isolated from commercial native chickens that experienced disease in 2014 and named GX14FF03. GX14FF03 was isolated by DF-1 cell culture and then identified with ELISA detection of avian leukosis virus p27 group-specific antigen, the detection of subtype specific PCR, and indirect immunofluorescence assay with ALV-B-specific monoclonal antibody. Its complete proviral genome was sequenced and compared with the reference strains of ALVs and found that the gag and pol were relatively conservative. The gp85 of GX14FF03 showed 91.3-96.2% amino acid identity to the other ALV-B reference strains and 36.0-37.1% identity to the ALV-J reference strains, and its U3 region showed 49.4-89.3% nucleotide identity to ALV-A, B, C, D, E, K reference strains and 91.6-95.3% identity to ALV-J reference strains. Phylogenetic analysis of U3 region showed that GX14FF03 and ALV-J reference strains were in the same cluster. Moreover, an additional AIB REP1 retroviral transcription regulatory element was found in GX14FF04 U3 region which was only presenting in ALV-J strains. These results suggested that isolate GX14FF03 may be a recombinant ALV-B with the ALV-J-like U3 region.

Yadav S, Yadav D, Zakalik D
Squamous cell carcinoma of the breast in the United States: incidence, demographics, tumor characteristics, and survival.
Breast Cancer Res Treat. 2017; 164(1):201-208 [PubMed] Related Publications
PURPOSE: Squamous cell carcinoma of breast accounts for less than 0.1% of all breast cancers. The purpose of this study is to describe the epidemiology and survival of this rare malignancy.
METHODS: Data were extracted from the National Cancer Institute's Surveillance, Epidemiology and End Results Registry to identify women diagnosed with squamous cell carcinoma of breast between 1998 and 2013. SEER*Stat 8.3.1 was used to calculate age-adjusted incidence, age-wise distribution, and annual percentage change in incidence. Kaplan-Meier curves were plotted for survival analysis. Univariate and multivariate Cox proportional hazard regression model was used to determine predictors of survival.
RESULTS: A total of 445 cases of squamous cell carcinoma of breast were diagnosed during the study period. The median age of diagnosis was 67 years. The overall age-adjusted incidence between 1998 and 2013 was 0.62 per 1,000,000 per year, and the incidence has been on a decline. Approximately half of the tumors were poorly differentiated. Stage II was the most common stage at presentation. Majority of the cases were negative for expression of estrogen and progesterone receptor. One-third of the cases underwent breast conservation surgery while more than half of the cases underwent mastectomy (unilateral or bilateral). Approximately one-third of cases received radiation treatment. The 1-year and 5-year cause-specific survival was 81.6 and 63.5%, respectively. Excluding patient with metastasis or unknown stage at presentation, in multivariate Cox proportional hazard model, older age at diagnosis and higher tumor stage (T3 or T4) or nodal stage at presentation were significant predictors of poor survival.
CONCLUSIONS: Our study describes the unique characteristics of squamous cell carcinoma of breast and demonstrates that it is an aggressive tumor with a poor survival. Older age and higher tumor or nodal stages at presentation were independent predictors of poor survival for loco-regional stages.

Yang R, Stöcker S, Schott S, et al.
The association between breast cancer and S100P methylation in peripheral blood by multicenter case-control studies.
Carcinogenesis. 2017; 38(3):312-320 [PubMed] Related Publications
Breast cancer (BC) is the leading cancer in women worldwide. Changes in DNA methylation in peripheral blood could be associated with malignant diseases. Making use of screening results by llumina 27K Methylation Assay, we validated demethylation of five CpG sites of S100P gene in blood cell DNA of BC patients by three independent retrospective studies with subjects from different centers (Validation I: 235 familial BC case and 206 controls, odds ratio per -1% methylation > 1.03, and P < 6.00 × 10-8 for all five CpG sites; Validation II: 189 sporadic BC case and 189 controls, odds ratio per -1% methylation > 1.03, P < 8.0 × 10-5 for four CpG sites; Validation III: 156 sporadic BC case and 151 controls, odds ratio per -1% methylation > 1.03, P < 6.0 × 10-4 for four CpG sites). In addition, the blood-based S100P methylation pattern was similar among BC patients with differential clinical characteristics regardless of stage, receptor status and menopause status. The observed BC-associated decreased S100P methylation in blood mainly originates from the leucocytes subpopulations but not B cells. The methylation levels of most S100P CpG sites were inversely correlated with the expression of S100P in leucocytes (P < 1.2 × 10-4) and in tissue (P < 1.1 × 10-4). This study reveals significant association between blood-based decreased S100P methylation and BC, and provides another proof for the application of altered DNA methylation signatures from blood cells as potential markers for the detection of BC, especially for the early stage.

Qin Z, Yiran A, Kai Y, et al.
[Effect of clock gene PER1 knockdown on clock gene networks in human oral squamous cell carcinoma].
Hua Xi Kou Qiang Yi Xue Za Zhi. 2017; 35(1):57-62 [PubMed] Related Publications
OBJECTIVE: This study investigated the effect of clock gene PER1 on the expression levels of other clock genes in clock gene networks in oral squamous cell carcinoma cells.
METHODS: We used RNA interference mediated by short hairpin RNAs (shRNAs) to effectively knock down PER1 in SCC15 human oral squamous cell carcinoma cells. Flow cytometry was used to detect the degree of proliferation and apoptosis of the cells after PER1 knockdown, and quantitative real-time PCR was used to detect the mRNA expression levels of the clock genes CLOCK, BMAL1, PER1, PER2, PER3, DEC1, DEC2, CRY1, CRY2, TIM, CKIE, RORA, NPAS2, and REV-ERBA.
RESULTS: The proliferation index of SCC15 cells increased significantly while the apoptotic index decreased significantly after PER1 knockdown (P<0.05). The mRNA expression levels of PER1, PER2, DEC1, DEC2, CRY1, CRY2, and NPAS2 markedly decreased (P<0.05) while those of PER3, TIM, RORA, and REV-ERBA markedly increased (P<0.05). By contrast, no obvious changes were observed in the mRNA expression levels of CLOCK, BMAL1, and CKIE (P>0.05).
CONCLUSIONS: The clock gene PER1 can regulate the expression levels of other clock genes in the clock gene networks; these genes include PER2, DEC1, DEC2, CRY1, CRY2, NPAS2, PER3, TIM, RORA, and REV-ERBA. PER1 gene thus plays an important role in the regulation of clock gene networks.

Gunge VB, Andersen I, Kyrø C, et al.
Adherence to a healthy Nordic food index and risk of myocardial infarction in middle-aged Danes: the diet, cancer and health cohort study.
Eur J Clin Nutr. 2017; 71(5):652-658 [PubMed] Related Publications
BACKGROUND/OBJECTIVES: For decades, the Mediterranean diet has been in focus regarding healthy eating as it has been associated with reduced risk of non-communicable diseases. Less interest has been given to health benefits of other regional diets. The aim of the present study was to assess whether adherence to a healthy Nordic food index was associated with lower risk of myocardial infarction (MI) among middle-aged Danes.
SUBJECTS/METHODS: Data were obtained from the Danish Diet, Cancer and Health cohort study of 57 053 men and women aged 50-64 years recruited between 1993 and 1997. The healthy Nordic food index comprised healthy Nordic food items selected a priori (fish, cabbage, rye bread, oatmeal, apple and pears and root vegetables). Information on incident MI was ascertained through linkage with national registries. Hazard ratios (HR) with 95% confidence intervals (CI) were estimated from sex-specific Cox proportional hazard models.
RESULTS: In total, 1669 men and 653 women developed MI during follow-up (13.6 median years). In adjusted models, those with an index score of 5-6 points (highest scores) had significantly lower MI risk (men: HR=0.77, 95% CI=0.62, 0.97; women: HR=0.55, 95% CI=0.37, 0.82) relative to those scoring 0 points in the index (lowest score). A significantly lower MI risk was found per 1-point increment in the index in both men (HR=0.95, 95% CI=0.92, 0.99) and women (HR=0.93, 95% CI=0.88, 0.98).
CONCLUSIONS: A healthy Nordic diet is associated with lower MI risk among middle-aged Danes, suggesting that Nordic diets should be considered in recommendations for dietary changes in the promotion of coronary health.

Reszka E, Przybek M, Muurlink O, Pepłonska B
Circadian gene variants and breast cancer.
Cancer Lett. 2017; 390:137-145 [PubMed] Related Publications
The endogenous and self-sustained circadian rhythm generated and maintained in suprachiasmatic nucleus and peripheral tissues can coordinate various molecular, biochemical and physiological processes in living organisms resulting in the adaptation to environmental cues, e.g. light. Multifactorial breast cancer etiology also involves circadian gene alterations, especially among individuals exposed to light at night. Indeed, shift work that causes circadian disruption has been classified by the International Agency for Research on Cancer as a probable human carcinogen, group 2A. Thus it seems extremely important to recognize specific susceptible gene variants among around 20 candidate circadian genes that may be linked with breast cancer etiology. The aim of this review was to evaluate recent data investigating a putative link between circadian gene polymorphisms and breast cancer risk. We summarize fifteen epidemiological studies, including five studies on shift work that have indicated BMAL1, BMAL2, CLOCK, NPAS2, CRY1, CRY2, PER1, PER3 and TIMELESS as a candidate breast cancer risk variants.

Li H, Lu YF, Chen H, Liu J
Dysregulation of metallothionein and circadian genes in human hepatocellular carcinoma.
Chronobiol Int. 2017; 34(2):192-202 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is the major threat to human health, and disruption of circadian clock genes is implicated in hepatocarcinogenesis. This study examined the dysregulation of metallothioneins and circadian genes in achieved human HCC (n = 24), peri-HCC tissues (n = 24) as compared with normal human livers (n = 36). Total RNA was extracted and reverse transcribed. Real-time RT-qPCR was performed to determine the expression of genes of interest. The results demonstrated the downregulation of metallothionein-1 (MT-1), MT-2, and metal transcription factor-1 (MFT-1) in human HCC as compared with Peri-HCC and normal tissues. MTs are a biomarker for HCC and have typical circadian rhythms; the expression of major circadian clock genes was also determined. HCC produced a dramatic decrease in the expression of core clock genes, circadian locomotor output cycles kaput (Clock) and brain and muscle Arnt-like protein 1 (Bmal1), and decreased the expression of the clock feedback control genes, Periods (Per1, Per2) and Cryptochromes (Cry1, Cry2). On the other hand, the expression of clock target genes nuclear orphan receptor factor protein (Nr1d1) and D-box-binding protein (Dbp) was upregulated as compared with Peri-HCC and normal livers. Peri-HCC also had mild alterations in these gene expressions. In summary, the present study clearly demonstrated the dysregulation of MTs and circadian clock genes in human HCC, which could provide the information of targeting MT and circadian clock in HCC management.

Alexander M, Burch JB, Steck SE, et al.
Case-control study of candidate gene methylation and adenomatous polyp formation.
Int J Colorectal Dis. 2017; 32(2):183-192 [PubMed] Free Access to Full Article Related Publications
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 (ORs) and 95 % confidence intervals (95% CIs) 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.

Chang L, Li L, Li W, et al.
Research on radiotherapy at different times of the day for inoperable cervical cancer.
Int J Clin Pharmacol Ther. 2016; 54(11):856-864 [PubMed] Related Publications
PURPOSE: To investigate the radiation effects and acute damage in inoperable cervical cancer patients irradiated at different times as well as the underlying mechanisms.
METHODS: 67 patients were randomized to a morning group (MG, 9:00 - 11:00 AM) and an evening group (EG, 9:00 - 11:00 PM) and both received external beam radiotherapy (RT) (50 Gy in 25 fractions) at different times. Brachytherapy (36 - 42 Gy in 6 - 7 fractions) was also performed to enhance the radiation response twice every week in all patients at the same time. Clinical therapeutic effects and acute toxicities were evaluated after RT. Flow cytometry was analyzed before and after RT.
RESULTS: Patients' response to radiation was similar in the two groups. Incidences of overall and high-grade (III - IV) diarrhea in the MG vs. the EG were 75.0% vs. 57.6% and 12.5% vs. 6.1%, respectively. The incidence of severe hematological toxicity in the EG was significantly increased compared to the MG group. Cell apoptosis in the EG was significantly higher at 9:00 - 11:00 PM than that at 9:00 - 11:00 AM after RT. No significant differences were found in Gap Phase 0/Gap Phase 1 (G0/G1), Gap Phase 2/Metaphase Phase (G2/M), and Synthesis Phase (S) phase between different times and groups, nor were expressions of Per1, Per2, and Clock. But expressions of Per1, Per2, and Clock were significantly negative with G2/M phase and positively correlated with cell apoptosis.
CONCLUSION: RT at different time intervals results in similar efficacy. However, RT in the morning reduces severe hematological toxicity. Radiation responses may be associated with circadian genes by influence of cell cycles and apoptosis.

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