Highlights • There was a significant interaction between 5-HTTLPR genotype and job-related stress in the risk of insomnia. • Job-related stress played a predominant role in the risk of insomnia. • ...The effect of 5-HTTLPR for insomnia was relatively weaker than high job-related stress.
Abstract Lin-28 and lin-28B are RNA-binding proteins which can block microRNA let-7 maturation and affect the differentiation and proliferation of embryonic stem cells. Lin-28 may also regulate the ...expression of insulin-like growth factor II (IGF-II). As one of the pluripotent factors involved in making induced pluripotent stem cells (iPS), lin-28 is considered a potential therapeutic target for cancer treatment. To further understand the role of lin-28 in cancer, we analysed the expression of lin-28 and its homologue lin-28B in tumour samples, and evaluated their associations with let-7a maturation, IGF-II expression, disease features and outcomes in 211 patients with primary epithelial ovarian cancer. The analysis showed that both lin-28 and lin-28B were positively correlated with primary and pre-let-7a-3; lin-28B , not lin-28 , was inversely correlated with mature let-7a. A positive correlation was also observed between lin-28B and IGF-II expression, while no association was found between lin-28B and IGF-I or IGFBP-3. The study further demonstrated that lin-28B expression was associated with the risk of disease progression and death; patients with high lin-28B had shorter progression-free and overall survival than those with low lin-28B . These results seem to support the findings of recent in vitro experiments, showing that lin-28 blocks the process of let-7a maturation. Our study also suggests that lin-28B may promote ovarian cancer progression and serve as an unfavourable prognostic marker for the disease. The correlation between lin-28B and IGF-II indicates that the growth factor may mediate the effect of lin-28B on tumour growth.
Background
Disease stage at diagnosis and molecular subtypes are the main determinants of breast cancer treatment strategies and prognosis. We aimed at examining the disparities and factors ...associated with the stage at diagnosis among the molecular subtypes in breast cancer patients in China.
Methods
We identified patients with first primary breast cancer diagnosed between January 1, 2016, and December 31, 2017, from 23 hospitals in 12 provinces in China. We analyzed the proportion of non‐early‐stage (stages II–IV) breast cancer cases based on the family history of breast cancer, body mass index (BMI), insurance status, and molecular subtypes. Multivariable analyses were used to estimate the factors associated with non‐early‐stage diagnosis among the molecular subtypes. We further compared these estimates with that in the United States using the Surveillance, Epidemiology, and End Results database.
Results
A total of 9398 Chinese were identified with first primary invasive breast cancer. Of the 8767 patients with known stages, the human epidermal growth factor receptor 2 (HER2)‐enriched subtype had the highest proportion of stages II–IV (76.6%) patients, followed by triple‐negative breast cancer (73.2%), luminal B (69.9%), and luminal A (62.3%). The percentage of non‐early‐stage patients was higher in women with overweight or obesity than in those with a body mass index (BMI) <25 kg/m2 (adjusted odds ratio OR 1.3, 95% confidence interval (CI) 1.1–1.4). Patients with a family history of breast cancer had a higher likelihood of early‐stage (adjusted OR 0.7, 0.5–0.8) breast cancer. Patients with rural insurance had a substantially higher risk of non‐early‐stage disease than those with urban insurance (adjusted OR 1.8, 1.4–2.2). Regarding the subtype, being overweight/obese only increased the risk of non‐early‐stage in luminal A breast cancer. Compared with the United States, China had a higher proportion of non‐early‐stage breast cancer for all subtypes, with the largest gap in luminal A (adjusted OR 2.2, 95% CI 2.0–2.4).
Conclusion
The wide disparities in stage at breast cancer diagnosis imply that China urgently needs to improve early breast cancer diagnosis and health equity.
This is the first study to analyze the stage distribution by breast cancer molecular subtype between China and the United States. Compared with the United States, China had a higher proportion of HER2‐enriched subtypes and more advanced stage for all subtypes. The wide disparities in breast cancer diagnosis imply an urgent need for improved breast cancer early detection and healthy equity in China.
Several single-nucleotide polymorphisms (SNPs) of the stem cell-associated gene lin-28B have been identified in association with ovarian cancer and ovarian cancer-related risk factors. However, ...whether these SNPs are functional or might be potential biomarkers for ovarian cancer prognosis remains unknown. The purposes of this study were to investigate the functional relevance of the identified lin-28B SNPs, as well as the associations of genotype and phenotype with epithelial ovarian cancer (EOC) survival. We analyzed five SNPs and mRNA levels of lin-28B in 211 primary EOC tissues using Taqman(®) SNP genotyping assays and SYBR green-based real-time PCR, respectively. The RNA secondary structures at the region of a genome-wide association-identified intronic rs314276 were analyzed theoretically with mfold and experimentally with circular dichroism spectroscopy. We found that rs314276 was a cis-acting expression quantitative trait locus (eQTL) in both additive and dominant models, while rs7759938 and rs314277 were significant or of borderline significance in dominant models only. The rs314276 variant significantly affects RNA secondary structure. No SNPs alone were associated with patient survival. However, we found that among patients initially responding to chemotherapy, those with higher lin-28B expression had higher mortality risk (hazard ratio =3.27, 95% confidence interval: 1.63-6.56) and relapse risk (hazard ratio = 2.53, 95% confidence interval: 1.41-4.54) than those with lower expression, and these associations remained in multivariate analyses. These results suggest that rs314276 alters RNA secondary structure and thereby influences gene expression, and that lin-28B is a cancer stem cell-associated marker, which may be a pharmaceutical target in the management of EOC.
Childbearing at an older age has been associated with a lower risk of endometrial cancer, but whether the association is independent of the number of births or other factors remains unclear. ...Individual-level data from 4 cohort and 13 case-control studies in the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 8,671 cases of endometrial cancer and 16,562 controls were included in the analysis. After adjustment for known risk factors, endometrial cancer risk declined with increasing age at last birth (P(trend) < 0.0001). The pooled odds ratio per 5-year increase in age at last birth was 0.87 (95% confidence interval: 0.85, 0.90). Women who last gave birth at 40 years of age or older had a 44% decreased risk compared with women who had their last birth under the age of 25 years (95% confidence interval: 47, 66). The protective association was similar across the different age-at-diagnosis groups and for the 2 major tumor histologic subtypes (type I and type II). No effect modification was observed by body mass index, parity, or exogenous hormone use. In this large pooled analysis, late age at last birth was independently associated with a reduced risk of endometrial cancer, and the reduced risk persisted for many years.
Background
In randomized trials in women with breast cancer, exercise has been shown to have beneficial effects on cancer‐related circulating biomarkers that may impact survival. Such studies are ...lacking for ovarian cancer.
Methods
This secondary analysis of a published randomized controlled trial examined the impact of a 6‐month exercise intervention versus attention‐control on change in prespecified circulating biomarkers (cancer antigen 125 (CA‐125), C‐reactive protein (CRP), insulin‐like growth factor‐1(IGF‐1), insulin and leptin) in a subset of participants who provided a fasting blood draw (N = 104/144) at enrollment and at 6 months. Change in biomarkers between study arms was compared using a linear mixed effects model analysis. An exploratory analysis of the exercise intervention versus attention‐control on all‐cause mortality included all (N = 144) participants. All statistical tests were two‐sided.
Results
Participants included in the biomarker analysis were 57.0 ± 8.8 (mean ± SD) years old and 1.6 ± 0.9 years post‐diagnosis. Adherence to the exercise intervention was 176.4 ± 63.5 min/week. Post intervention IGF‐1 (group difference in change: −14.2 (−26.1 to −2.3) ng/mL (least squared means (95% CI))) and leptin (−8.9 (−16.5 to −1.4) ng/mL) were significantly reduced in the exercise group (N = 53) compared to those in attention‐control (N = 51). No group difference in change was seen for CA‐125 (p = 0.54), CRP (p = 0.95), or insulin (p = 0.37). With median follow‐up of 70 months range 6.6–105.4 months, 50/144 (34.7%) (exercise group; 24/74 (32.4%) versus attention‐control group; 26/70 (37.1%)) participants died with no between group difference in overall survival (p = 0.99).
Conclusions
Further studies are needed to determine the clinical significance of exercise‐induced changes in cancer‐related circulating biomarkers in women with ovarian cancer.
The interplay between the sex-specific differences in tumor metabolome and colorectal cancer (CRC) prognosis has never been studied and represents an opportunity to improve patient outcomes. This ...study examines the link between tumor metabolome and prognosis by sex for CRC patients. Using untargeted metabolomics analysis, abundances of 91 metabolites were obtained from primary tumor tissues from 197 patients (N = 95 females, N = 102 males) after surgical colectomy for stage I-III CRC. Cox Proportional hazard (PH) regression models estimated the associations between tumor metabolome and 5-year overall survival (OS) and recurrence-free survival (RFS), and their interactions with sex. Eleven metabolites had significant sex differences in their associations with 5-year OS, and five metabolites for 5-year RFS. The metabolites asparagine and serine had sex interactions for both OS and RFS. Furthermore, in the asparagine synthetase (ASNS)-catalyzed asparagine synthesis pathway, asparagine was associated with substantially poorer OS (HR (95% CI): 6.39 (1.78-22.91)) and RFS (HR (95% CI): 4.36 (1.39-13.68)) for female patients only. Similar prognostic disadvantages in females were seen in lysophospholipid and polyamine synthesis. Unique metabolite profiles indicated that increased asparagine synthesis was associated with poorer prognosis for females only, providing insight into precision medicine for CRC treatment stratified by sex.
Asparagine (Asn) and enzymes that catalyze the metabolism of Asn have been linked to the regulation and propagation of colorectal cancer (CRC). Increased Asn and asparagine synthetase (ASNS) ...expression, both contribute to CRC progression and metastasis. In contradistinction, L-asparaginase (ASNase) which breaks down Asn, exhibits an anti-tumor effect. Metabolic pathways such as KRAS/PI3K/AKT/mTORC1 signaling and high SOX12 expression can positively regulate endogenous Asn production. Conversely, the tumor suppressor, TP53, negatively impacts ASNS, thus limiting Asn synthesis and reducing tumor burden. Asn abundance can be altered by factors extrinsic to the cancer cell such as diet, the microbiome, and therapeutic use of ASNase. Recent studies have shown that sex-related factors can also influence the regulation of Asn, and high Asn production results in poorer prognosis for female CRC patients but not males. In this narrative review, we critically review studies that have examined endogenous and exogenous modulators of Asn bioavailability and summarize the key metabolic networks that regulate Asn metabolism. We also provide new hypotheses regarding sex-related influences on Asn, including the involvement of the sex-steroid hormone estrogen and estrogen receptors. Further, we hypothesize that sex-specific factors that influence Asn metabolism can influence clinical outcomes in CRC patients.
Gene–environment interactions may increase gastric cancer (GC) risk. Seven susceptibility loci identified by genome‐wide association studies (GWASs) suggest that genetic factors play a role in ...gastric carcinogenesis. Meanwhile, Helicobacter pylori (H. pylori) infection, smoking, and alcohol drinking are also important environmental factors for gastric cancer. However, studies to explore the role of gene–environment interactions in gastric carcinogenesis, and particularly the relationship between the seven susceptibility loci and their potential interactions with H. pylori infection, smoking, and alcohol drinking in risk of GC, and severe intestinal metaplasia (IM)/dysplasia, have been inconclusive. A total of 1273 subjects in a Chinese population were recruited, and genotyping was carried out using the competitive allele‐specific PCR (KASP) method. Unconditional logistic regression was applied to model the associations between genetic polymorphisms and the disease risk. Effect modifications by H. pylori infection, smoking and alcohol drinking were evaluated. PSCA rs2294008/rs2976392 showed a significant, multiplicative interaction with H. pylori infection in risk of GC. Meanwhile, PRKAA1 rs13361707 had an additive interaction with H. pylori infection. SLC52A3 rs13042395 showed an interaction with alcohol drinking in risk of GC. Moreover, three SNPs, MUC1 rs4072037, ZBTB20 rs9841504 and PRKAA1 rs13361707, were associated with precancerous gastric lesions (severe IM/dysplasia). Our data suggest that genetic predisposition factors identified by GWAS may interact with environmental risk factors, Particularly for H. pylori infection and alcohol consumption, to increase the risk of GC.
The gene–environment interaction has increased gastric cancer (GC) risk. Seven susceptibility loci identified by genome‐wide association studies (GWASs) suggest that genetic factors play a role in gastric carcinogenesis. Meanwhile, Helicobacter pylori (H. pylori) infection, smoking, and drinking are also important environmental factors for gastric cancer. To explore the role of gene–environment interactions in gastric carcinogenesis, study findings of the relationship between the seven susceptibility loci and their potential interactions with H. pylori infection, smoking, and drinking in risk of GC, and severe intestinal metaplasia (IM)/dysplasia have been inconclusive. A total of 1273 subjects in a Chinese population were recruited and genotyping were carried out with competitive allele‐specific PCR (KASP) method. Unconditional logistic regression was applied to model the associations between genetic polymorphisms and disease risk. Effect modifications by H. pylori infection, smoking, and drinking were evaluated. We found PSCA rs2294008/rs2976392 showed a significant interaction with H. pylori infection in risk of GC on a multiplicative scale. Meanwhile, PRKAA1 rs13361707 had an additive interaction with H. pylori infection. SLC52A3 rs13042395 showed interaction with drinking in risk of GC. Moreover, three SNPs, MUC1 rs4072037, ZBTB20 rs9841504, and PRKAA1 rs13361707 were associated with precancerous gastric lesions of severe IM/dysplasia. Our data suggest that genetic predisposition identified in the GWASs, may interact with environmental risk factors, especially for H. pylori infection and alcohol consumption to increase the risk of GC.
The insulin-like growth factor (IGF) axis is fundamentally important in cell growth, development and cancer. We used genomic technologies to better characterize the activity of the IGF axis in human ...breast cancer and to identify predictors of response to IGF targeted therapies. Analysis of the gene expression patterns and pathway analysis in 204 clinically annotated primary breast cancers were performed and compared to levels of mRNA for IGF ligands and receptors. Pathway activation scores were calculated by Pearson correlation (+1, −1). Network analysis was performed using Ingenuity software. IGF-1 ligand levels were strongly negatively correlated (
P
< 10
−6
) with a published IGF-IR activation signature. A signature of high IGF-1 ligand was associated with better prognosis (
P
= 0.025–1.5 × 10
−8
) in several public datasets. Pathway analysis revealed upregulation of pathways associated with breast differentiation (adipocyte growth factors, PPAR-gamma) and down-regulation of proliferation pathways (AKT/MAPK) in the IGF-1 ligand high group. Of note, the IGF-1 ligand signature was anti-correlated with IGFIR receptor levels (
P
= 0.07). In conclusion, a breast tumor-derived signature of high IGF-1 ligand is associated with favorable outcome, in contrast to a previously reported IGF-IR activation signature. The prognostic value of the IGF-I ligand signature is validated in three independent datasets. These signatures should be applied in study of IGF1-R targeted therapy.
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