Development of a modified ABC method among Helicobacter pylori infected but serum pepsinogen test-negative individuals.

BACKGROUND: Although the ABC method for gastric cancer (GC) screening has been widely adopted in Japan, it may not be suitable for other countries due to population heterogeneity and different tumor histology. We aim to develop a modified ABC method to improve GC screening performance, especially among Helicobacter pylori (Hp) infected but serum pepsinogen (sPG) test-negative individuals. METHODS: A total of 4745 participants were recruited from Tianjin, China, and were classified into four groups by combined assay for Hp infection and sPG concentrations: Group A (Hp [-], PG [-]), Group B (Hp [+], PG [-]), Group C (Hp [+], PG [+]), and Group D (Hp [-], PG [+]). We used receiver-operating characteristic (ROC) curves analysis and minimum p value method to determine the optimal cutoff point for PG II in Group B. We performed logistic regressions to examine the risk of GC across different subgroups. In addition to the derivation set, the performance of the modified ABC method was also evaluated in an external set involving 16,292 participants from Liaoning, China. RESULTS: In the modified ABC method, we further classified Group B as low-risk (Group B1) and high-risk subgroups (Group B2) using optimal sPG II cutoff point (20.0 ng/mL) by ROC curves analysis and minimum p value method. Compared with Group B1, Group B2 had a significantly higher risk of GC (adjusted OR = 2.54, 95% CI = 1.94-3.33). The modified ABC method showed good discrimination for GC (AUC = 0.61, 95% CI = 0.59-0.63) and improved risk reclassification (NRI = 0.11, p < .01). Similar results were observed in the validation dataset. CONCLUSIONS: The modified ABC method can effectively identify high-risk population for GC among Hp-infected but sPG test-negative participants in China.

Effect of estradiol as a continuous variable on breast cancer survival by menopausal status: a cohort study in China.

High levels of circulating estradiol (E2) are associated with increased risk of breast cancer, whereas its relationship with breast cancer prognosis is still unclear. We evaluated the effect of E2 concentration on survival endpoints among 8766 breast cancer cases diagnosed between 2005 and 2017 from the Tianjin Breast Cancer Cases Cohort. Levels of serum E2 were measured in pre-menopausal and post-menopausal women. Multivariable-adjusted Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) between quartile of E2 levels and overall survival (OS) and progression-free survival (PFS) of breast cancer. The penalized spline was then used to test for non-linear relationships between E2 (continuous variable) and survival endpoints. 612 deaths and 982 progressions occurred over follow-up through 2017. Compared to women in the quartile 3, the highest quartile of E2 was associated with reduced risk of both PFS in pre-menopausal women (HR 1.79, 95% CI 1.17-2.75, P = 0.008) and OS in post-menopausal women (HR 1.35, 95% CI 1.04-1.74, P = 0.023). OS and PFS in pre-menopausal women exhibited a nonlinear relation ("L-shaped" and "U-shaped", respectively) with E2 levels. However, there was a linear relationship in post-menopausal women. Moreover, patients with estrogen receptor-negative (ER-negative) breast cancer showed a "U-shaped" relationship with OS and PFS in pre-menopausal women. Pre-menopausal breast cancer patients have a plateau stage of prognosis at the intermediate concentrations of E2, whereas post-menopausal patients have no apparent threshold, and ER status may have an impact on this relationship.

Perfluoroalkyl substances (PFASs) as risk factors for breast cancer: a case-control study in Chinese population.

BACKGROUND: Perfluoroalkyl substances (PFASs) are a large family of synthetic chemicals, some of which are mammary toxicants and endocrine disruptors. Recent studies have implicated exposure to PFASs as a risk factor for breast cancer in Europe and America. Little is known about the role of PFASs with respect to breast cancer in the Chinese population. METHODS: Participants who were initially diagnosed with breast cancer at Tianjin Medical University Cancer Institute and Hospital between 2012 and 2016 were recruited as cases. The controls were randomly selected from the participants with available blood samples in the Chinese National Breast Cancer Screening Program (CNBCSP) cohort. Ultimately, we enrolled 373 breast cancer patients and 657 controls. Plasma PFASs were measured by an ultra-performance liquid chromatography (UPLC) system coupled to a 5500 Q-Trap triple quadrupole mass spectrometer. A logistic regression model with least absolute shrinkage and selection operator (LASSO) regularization was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to assess the relationships between PFASs and breast cancer. The three most predictive variables in the LASSO model were selected from 17 PFASs, which was based on the optimal penalty coefficient (λ = 0.0218) identified with the minimum criterion. Additionally, Bayesian kernel machine regression (BKMR) and quantile g-computation models were applied to evaluate the associations between separate and mixed exposure to PFASs and breast cancer. RESULTS: Perfluorooctanesulfonic acid (PFOS) exhibited the highest concentration in both the cases and controls. Perfluorooctanoic acid (PFOA) and perfluoro-n-decanoic acid (PFDA) were positively associated with breast cancer, and perfluoro-n-tridecanoic acid (PFTrDA) was negatively associated with breast cancer according to both the continuous-PFASs and the quartile-PFASs logistic regression models. Of note, PFOA was associated with the occurrence of estrogen receptor (ER)-, progesterone receptor (PR)-, and human epidermal growth factor receptor 2 (HER2)-positive breast cancer (ORER+ = 1.47, 95% CI: 1.19, 1.80; ORPR+ = 1.36, 95% CI: 1.09, 1.69; ORHER2 = 1.62, 95% CI: 1.19, 2.21). CONCLUSIONS: Overall, we observed that PFASs were associated with breast cancer in Chinese women. Prospective cohort studies and mechanistic experiments are warranted to elucidate whether these associations are causal.

Consumption of flavonoids and risk of hormone-related cancers: a systematic review and meta-analysis of observational studies.

BACKGROUND: Flavonoids seem to have hormone-like and anti-hormone properties so that the consumption of flavonoids may have potential effects on hormone-related cancers (HRCs), but the findings have been inconsistent so far. This meta-analysis was aimed to explore the association between flavonoids intake and HRCs risk among observational studies. METHODS: Qualified articles, published on PubMed, EMBASE, and China National Knowledge Infrastructure (CNKI) from January 1999 to March 2022 and focused on relationships between flavonoids (total, subclass of and individual flavonoids) and HRCs (breast, ovarian, endometrial, thyroid, prostate and testicular cancer), were retrieved for pooled analysis. Random effects models were performed to calculate the pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Funnel plots and Begg's/Egger's test were used to evaluate the publication bias. Subgroup analyses and sensitivity analyses were conducted to explore the origins of heterogeneity. RESULTS: All included studies were rated as medium or high quality. Higher consumption of flavonols (OR = 0.85, 95% CI: 0.76-0.94), flavones (OR = 0.85, 95% CI: 0.77-0.95) and isoflavones (OR = 0.87, 95% CI: 0.82-0.92) was associated with a decreased risk of women-specific cancers (breast, ovarian and endometrial cancer), while the higher intake of total flavonoids was linked to a significantly elevated risk of prostate cancer (OR = 1.11, 95% CI: 1.02-1.21). A little evidence implied that thyroid cancer risk was augmented with the higher intake of flavones (OR = 1.24, 95% CI: 1.03-1.50) and flavanones (OR = 1.31, 95% CI: 1.09-1.57). CONCLUSIONS: The present study suggests evidence that intake of total flavonoids, flavonols, flavones, flavanones, flavan-3-ols and isoflavones would be associated with a lower or higher risk of HRCs, which perhaps provides guidance for diet guidelines to a certain extent. TRIAL REGISTRATION: This protocol has been registered on PROSPERO with registration number CRD42020200720 .

Detection rate is not higher for women with BBD history in breast cancer screening.

BACKGROUND: To investigate whether women with benign breast disease (BBD) history have higher breast cancer detection rate in screening. METHODS: We reviewed data for 33 001 female participants in Multi-modality Independent Screening Trial (MIST). Corresponding data for 6823 breast cancer patients were retrieved from the Tianjin Breast Cancer Cases Cohort (TBCCC) and analyzed for comparison. RESULTS: The breast cancer detection rate was 2.83‰ among women with BBD history and 3.28‰ in women without. Moreover, the proportion of carcinoma in situ (CIS) was also lower in women with BBD history than women without (7.69 versus 20.31%). In contrast, analysis of TBCCC data revealed a higher proportion of CIS in patients with BBD history (5.05%) than patients without (3.26%). Our data showed that a larger proportion of women with BBD history had undergone previous breast examinations. Additionally, among participants diagnosed with both breast cancer and BBD in MIST, we found a lower proportion of CIS in women with BBD history (11.76%) compared to women without (32.14%). CONCLUSIONS: Women with BBD history were not found to have higher detection rate in breast cancer screening. Women with BBD history were more likely to be proactive in seeking breast examinations and to have breast cancer be diagnosed in clinic.

Performance of ultrasonography screening for breast cancer: a systematic review and meta-analysis.

BACKGROUND: To investigate the performance of primary ultrasound (P-US) screening for breast cancer, and that of supplemental ultrasound (S-US) screening for breast cancer after negative mammography (MAM). METHODS: Electronic databases (PubMed, Scopus, Web of Science, and Embase) were systematically searched to identify relevant studies published between January 2003 and May 2018. Only high-quality or fair-quality studies reporting any of the following performance values for P-US or S-US screening were included: sensitivity, specificity, cancer detected rate (CDR), recall rate (RR), biopsy rate (BR), proportion of invasive cancers among screening-detected cancers (ProIC), and proportion of node-negative cancers among screening-detected invasive cancers (ProNNIC). RESULTS: Twenty-three studies were included, including 12 studies in which S-US screening was used after negative MAM and 11 joint screening studies in which both primary MAM (P-MAM) and P-US were used. Meta-analyses revealed that S-US screening could detect 96% [95% confidential intervals (CIs): 82 to 99%] of occult breast cancers missed by MAM and identify 93% (95% CIs: 89 to 96%) of healthy women, with a CDR of 3.0/1000 (95% CIs: 1.8/1000 to 4.6/1000), RR of 8.8% (95% CIs: 5.0 to 13.4%), BR of 3.9% (95% CIs: 2.7 to 5.4%), ProIC of 73.9% (95% CIs: 49.0 to 93.7%), and ProNNIC of 70.9% (95% CIs: 46.0 to 91.6%). Compared with P-MAM screening, P-US screening led to the recall of significantly more women with positive screening results [1.5% (95% CIs:0.6 to 2.3%), P = 0.001] and detected significantly more invasive cancers [16.3% (95% CIs: 10.6 to 22.1%), P < 0.001]. However, there were no significant differences for other performance measures between the two screening methods, including sensitivity, specificity, CDR, BR, and ProNNIC. CONCLUSIONS: Current evidence suggests that S-US screening could detect occult breast cancers missed by MAM. P-US screening has shown to be comparable to P-MAM screening in women with dense breasts in terms of sensitivity, specificity, cancer detection rate, and biopsy rate, but with higher recall rates and higher detection rates for invasive cancers.

Genome-wide association studies identify susceptibility loci for epithelial ovarian cancer in east Asian women.

OBJECTIVE: Genome-wide association studies (GWASs) for epithelial ovarian cancer (EOC) have focused largely on populations of European ancestry. We aimed to identify common germline variants associated with EOC risk in Asian women. METHODS: Genotyping was performed as part of the OncoArray project. Samples with >60% Asian ancestry were included in the analysis. Genotyping was performed on 533,631 SNPs in 3238 Asian subjects diagnosed with invasive or borderline EOC and 4083 unaffected controls. After imputation, genotypes were available for 11,595,112 SNPs to identify associations. RESULTS: At chromosome 6p25.2, SNP rs7748275 was associated with risk of serous EOC (odds ratio [OR] = 1.34, P = 8.7 × 10-9) and high-grade serous EOC (HGSOC) (OR = 1.34, P = 4.3 × 10-9). SNP rs6902488 at 6p25.2 (r2 = 0.97 with rs7748275) lies in an active enhancer and is predicted to impact binding of STAT3, P300 and ELF1. We identified additional risk loci with low Bayesian false discovery probability (BFDP) scores, indicating they are likely to be true risk associations (BFDP <10%). At chromosome 20q11.22, rs74272064 was associated with HGSOC risk (OR = 1.27, P = 9.0 × 10-8). Overall EOC risk was associated with rs10260419 at chromosome 7p21.3 (OR = 1.33, P = 1.2 × 10-7) and rs74917072 at chromosome 2q37.3 (OR = 1.25, P = 4.7 × 10-7). At 2q37.3, expression quantitative trait locus analysis in 404 HGSOC tissues identified ESPNL as a putative candidate susceptibility gene (P = 1.2 × 10-7). CONCLUSION: While some risk loci were shared between East Asian and European populations, others were population-specific, indicating that the landscape of EOC risk in Asian women has both shared and unique features compared to women of European ancestry.

Assessment of performance of the Gail model for predicting breast cancer risk: a systematic review and meta-analysis with trial sequential analysis.

BACKGROUND: The Gail model has been widely used and validated with conflicting results. The current study aims to evaluate the performance of different versions of the Gail model by means of systematic review and meta-analysis with trial sequential analysis (TSA). METHODS: Three systematic review and meta-analyses were conducted. Pooled expected-to-observed (E/O) ratio and pooled area under the curve (AUC) were calculated using the DerSimonian and Laird random-effects model. Pooled sensitivity, specificity and diagnostic odds ratio were evaluated by bivariate mixed-effects model. TSA was also conducted to determine whether the evidence was sufficient and conclusive. RESULTS: Gail model 1 accurately predicted breast cancer risk in American women (pooled E/O = 1.03; 95% CI 0.76-1.40). The pooled E/O ratios of Caucasian-American Gail model 2 in American, European and Asian women were 0.98 (95% CI 0.91-1.06), 1.07 (95% CI 0.66-1.74) and 2.29 (95% CI 1.95-2.68), respectively. Additionally, Asian-American Gail model 2 overestimated the risk for Asian women about two times (pooled E/O = 1.82; 95% CI 1.31-2.51). TSA showed that evidence in Asian women was sufficient; nonetheless, the results in American and European women need further verification. The pooled AUCs for Gail model 1 in American and European women and Asian females were 0.55 (95% CI 0.53-0.56) and 0.75 (95% CI 0.63-0.88), respectively, and the pooled AUCs of Caucasian-American Gail model 2 for American, Asian and European females were 0.61 (95% CI 0.59-0.63), 0.55 (95% CI 0.52-0.58) and 0.58 (95% CI 0.55-0.62), respectively. The pooled sensitivity, specificity and diagnostic odds ratio of Gail model 1 were 0.63 (95% CI 0.27-0.89), 0.91 (95% CI 0.87-0.94) and 17.38 (95% CI 2.66-113.70), respectively, and the corresponding indexes of Gail model 2 were 0.35 (95% CI 0.17-0.59), 0.86 (95% CI 0.76-0.92) and 3.38 (95% CI 1.40-8.17), respectively. CONCLUSIONS: The Gail model was more accurate in predicting the incidence of breast cancer in American and European females, while far less useful for individual-level risk prediction. Moreover, the Gail model may overestimate the risk in Asian women and the results were further validated by TSA, which is an addition to the three previous systematic review and meta-analyses. TRIAL REGISTRATION: PROSPERO CRD42016047215 .

SNP rs2071095 in LincRNA H19 is associated with breast cancer risk.

PURPOSE: An increasing number of long intergenic non-coding RNAs (lincRNAs) appear to play critical roles in cancer development and progression. To assess the association between SNPs that reside in regions of lincRNAs and breast cancer risk, we performed a large case-control study in China. METHODS: We carried out a two-stage case-control study including 2881 breast cancer cases and 3220 controls. In stage I, we genotyped 17 independent (r2 < 0.5) SNPs located in 6 tumor-related lincRNAs by using the TaqMan platform. In stage II, SNPs potentially associated with breast cancer risk were replicated in an independent population. Quantitative real-time PCR was used to measure H19 levels in tissues from 228 breast cancer patients with different genotypes. RESULTS: We identified 2 SNPs significantly associated with breast cancer risk in stage I (P < 0.05), but not significantly replicated in stage II. We combined the data from stage I and stage II, and found that, compared with the rs2071095 CC genotype, AA and CA + AA genotypes were associated with significantly decreased risk of breast cancer (adjusted OR 0.83, 95% CI 0.69-0.99; adjusted OR 0.88, 95% CI 0.80-0.98, respectively). Stratified analyses showed that rs2071095 was associated with breast cancer risk in estrogen receptor (ER)-positive patients (P = 0.002), but not in ER-negative ones (P = 0.332). Expression levels of H19 in breast cancer cases with AA genotype were significantly lower than those with CC genotype. CONCLUSIONS: We identified that rs2071095 may contribute to the susceptibility of breast cancer in Chinese women via affecting H19 expression. The mechanisms underlying the association remain to be investigated.

Personal history of keratinocyte carcinoma is associated with reduced risk of death from invasive melanoma in men.

BACKGROUND: Previous studies have found an increased risk for invasive cutaneous melanoma (CM) among those with a history of keratinocyte carcinoma (KC). OBJECTIVE: The aim of this study was to evaluate the risk of CM death after KC. METHODS: The study was based on the Health Professionals Follow-up Study. A Cox proportional hazards model was used to examine the hazard ratio (HR) of death due to CM associated with personal history of KC among the entire study population (primary analysis) and among participants with invasive CM (secondary analysis), respectively. RESULTS: We documented a total of 908 participants with invasive CM over a total of 0.7 million person-years of follow-up. Among all participants, the risk for development of either lethal or nonlethal invasive CM increased for those with a history of KC. The risk for death due to melanoma based on KC history was not significantly increased, with an HR of 1.53 (95% confidence interval, 0.95-2.46). In the case-only analysis, those with a history of KC had a significantly lower risk for death due to melanoma than those with no such history (HR, 0.60; 95% confidence interval, 0.35-0.94). LIMITATIONS: Because the population covered by the Health Professionals Follow-up Study consists exclusively of male health professionals, the results of this study may not be extended to the entire population. CONCLUSION: Personal history of KC is associated with a decreased risk for melanoma-specific death among male patients with invasive CM.

Mutational landscape of gastric adenocarcinoma in Chinese: implications for prognosis and therapy.

Gastric cancer (GC) is a highly heterogeneous disease. To identify potential clinically actionable therapeutic targets that may inform individualized treatment strategies, we performed whole-exome sequencing on 78 GCs of differing histologies and anatomic locations, as well as whole-genome sequencing on two GC cases, each with three primary tumors and two matching lymph node metastases. The data showed two distinct GC subtypes with either high-clonality (HiC) or low-clonality (LoC). The HiC subtype of intratumoral heterogeneity was associated with older age, TP53 (tumor protein P53) mutation, enriched C > G transition, and significantly shorter survival, whereas the LoC subtype was associated with younger age, ARID1A (AT rich interactive domain 1A) mutation, and significantly longer survival. Phylogenetic tree analysis of whole-genome sequencing data from multiple samples of two patients supported the clonal evolution of GC metastasis and revealed the accumulation of genetic defects that necessitate combination therapeutics. The most recurrently mutated genes, which were validated in a separate cohort of 216 cases by targeted sequencing, were members of the homologous recombination DNA repair, Wnt, and PI3K-ERBB pathways. Notably, the drugable NRG1 (neuregulin-1) and ERBB4 (V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 4) ligand-receptor pair were mutated in 10% of GC cases. Mutations of the BRCA2 (breast cancer 2, early onset) gene, found in 8% of our cohort and validated in The Cancer Genome Atlas GC cohort, were associated with significantly longer survivals. These data define distinct clinicogenetic forms of GC in the Chinese population that are characterized by specific mutation sets that can be investigated for efficacy of single and combination therapies.

Association study of genetic variation in DNA repair pathway genes and risk of basal cell carcinoma.

DNA repair plays a critical role in protecting the genome from ultraviolet radiation and maintaining the genomic integrity of cells. Genetic variants in DNA repair-related genes can influence an individual's DNA repair capacity, which may be related to the risk of developing basal cell carcinoma (BCC). We comprehensively assessed the associations of 2,965 independent single-nucleotide polymorphisms (SNPs) across 165 DNA repair pathway genes with BCC risk in a genome-wide association meta-analysis totaling 17,187 BCC cases and 287,054 controls from two data sets. After multiple testing corrections, we identified three SNPs (rs2805831 upstream of XPA: OR = 0.93, P = 1.35 × 10-6 ; rs659857 in exon of MUS81: OR = 1.06, P = 3.09 × 10-6 and rs57343616 in 3' UTR of NABP2: OR = 1.11, P = 6.47 × 10-6 ) as significantly associated with BCC risk in meta-analysis, and all of them were nominally significant in both data sets. Furthermore, rs659857 [T] was significantly associated with decreased expression of MUS81 mRNA in the expression quantitative trait locus (eQTL) analysis. Our findings suggest that the inherited common variation in three DNA repair genes-XPA, MUS81 and NABP2-may be involved in the development of BCC. To our knowledge, our study is the first report thoroughly examining the effects of SNPs across DNA repair pathway genes on BCC risk based on a genome-wide association meta-analysis.

Estimation of heritability for nine common cancers using data from genome-wide association studies in Chinese population.

The familial aggregation indicated the inheritance of cancer risk. Recent genome-wide association studies (GWASs) have identified a number of common single-nucleotide polymorphisms (SNPs). Following heritability analyses have shown that SNPs could explain a moderate amount of variance for different cancer phenotypes among Caucasians. However, little information was available in Chinese population. We performed a genome-wide complex trait analysis for common cancers at nine anatomical sites in Chinese population (14,629 cancer cases vs. 17,554 controls) and estimated the heritability of these cancers based on the common SNPs. We found that common SNPs explained certain amount of heritability with significance for all nine cancer sites: gastric cancer (20.26%), esophageal squamous cell carcinoma (19.86%), colorectal cancer (16.30%), lung cancer (LC) (15.17%), and epithelial ovarian cancer (13.31%), and a similar heritability around 10% for hepatitis B virus-related hepatocellular carcinoma, prostate cancer, breast cancer and nasopharyngeal carcinoma. We found that nearly or less than 25% change was shown when removing the regions expanding 250 kb or 500 kb upward and downward of the GWAS-reported SNPs. We also found strong linear correlations between variance partitioned by each chromosome and chromosomal length only for LC (R2  = 0.641, p = 0.001) and esophageal squamous cell cancer (R2  = 0.633, p = 0.002), which implied us the complex heterogeneity of cancers. These results indicate polygenic genetic architecture of the nine common cancers in Chinese population. Further efforts should be made to discover the hidden heritability of different cancer types among Chinese.

A genome-wide analysis of gene-caffeine consumption interaction on basal cell carcinoma.

Animal models have suggested that oral or topical administration of caffeine could inhibit ultraviolet-induced carcinogenesis via the ataxia telangiectasia and rad3 (ATR)-related apoptosis. Previous epidemiological studies have demonstrated that increased caffeine consumption is associated with reduced risk of basal cell carcinoma (BCC). To identify common genetic markers that may modify this association, we tested gene-caffeine intake interaction on BCC risk in a genome-wide analysis. We included 3383 BCC cases and 8528 controls of European ancestry from the Nurses' Health Study and Health Professionals Follow-up Study. Single nucleotide polymorphism (SNP) rs142310826 near the NEIL3 gene showed a genome-wide significant interaction with caffeine consumption (P = 1.78 × 10-8 for interaction) on BCC risk. There was no gender difference for this interaction (P = 0.64 for heterogeneity). NEIL3, a gene belonging to the base excision DNA repair pathway, encodes a DNA glycosylase that recognizes and removes lesions produced by oxidative stress. In addition, we identified several loci with P value for interaction <5 × 10-7 in gender-specific analyses (P for heterogeneity between genders < 0.001) including those mapping to the genes LRRTM4, ATF3 and DCLRE1C in women and POTEA in men. Finally, we tested the associations between caffeine consumption-related SNPs reported by previous genome-wide association studies and risk of BCC, both individually and jointly, but found no significant association. In sum, we identified a DNA repair gene that could be involved in caffeine-mediated skin tumor inhibition. Further studies are warranted to confirm these findings.

Telomere structure and maintenance gene variants and risk of five cancer types.

Telomeres cap chromosome ends, protecting them from degradation, double-strand breaks, and end-to-end fusions. Telomeres are maintained by telomerase, a reverse transcriptase encoded by TERT, and an RNA template encoded by TERC. Loci in the TERT and adjoining CLPTM1L region are associated with risk of multiple cancers. We therefore investigated associations between variants in 22 telomere structure and maintenance gene regions and colorectal, breast, prostate, ovarian, and lung cancer risk. We performed subset-based meta-analyses of 204,993 directly-measured and imputed SNPs among 61,851 cancer cases and 74,457 controls of European descent. Independent associations for SNP minor alleles were identified using sequential conditional analysis (with gene-level p value cutoffs ≤3.08 × 10-5 ). Of the thirteen independent SNPs observed to be associated with cancer risk, novel findings were observed for seven loci. Across the DCLRE1B region, rs974494 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Across the TERC region, rs75316749 was positively associated with colorectal, breast, ovarian, and lung cancers. Across the DCLRE1B region, rs974404 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Near POT1, rs116895242 was inversely associated with colorectal, ovarian, and lung cancers, and RTEL1 rs34978822 was inversely associated with prostate and lung cancers. The complex association patterns in telomere-related genes across cancer types may provide insight into mechanisms through which telomere dysfunction in different tissues influences cancer risk.

Regulatory MiR-148a-ACVR1/BMP circuit defines a cancer stem cell-like aggressive subtype of hepatocellular carcinoma.

UNLABELLED: Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the third most common cancer in Asia. HCC has heterogeneous etiologic and molecular profiles and a varied response to therapeutics. The high recurrence rate and curtailed survival in this cancer are attributed to its resistance to therapy. The ultimate goal is to develop a more effective personalized therapeutic strategy for HCC, but the first step is to develop a system for classifying the disease on the basis of molecular biomarkers. To that end, we performed mRNA and microRNA (miRNA) expression profiling in 100 HCC tissues. Clustering analysis of informative genes identified two robust subtypes, which were validated by an independent dataset. The subtype characterized by a cancer stem cell-like signature was clinically aggressive and associated with poor survival. Integrated analysis of miRNA and mRNA expression in this subtype showed that miR-148a was expressed at a significantly lower level in these tumors than in the other subtype. MiR-148a has been shown to directly suppress the expression of activin A receptor type 1 (ACVR1), a key receptor in the signaling pathway of the bone morphogenetic proteins (BMPs), which regulate many stem cell markers as well as the clinically important cytokine interleukin-8 (IL-8). Increased expression of ACVR1 and its downstream genes EPCAM, CD24, CD90, and IL-8 was associated with shorter survival in a larger cohort of 227 HCC cases. Introduction of miR-148a resulted in suppressed tumor phenotypes both in vitro and in vivo. CONCLUSION: We identified a clinically aggressive stem cell-like subtype of HCC that is characterized by an miR-148a-ACVR1-BMP-Wnt circuit. We propose that miR-148a may serve as a prognostic biomarker and therapeutic target for this subtype of HCC.

Genome-wide association studies identify several new loci associated with pigmentation traits and skin cancer risk in European Americans.

Aiming to identify novel genetic loci for pigmentation and skin cancer, we conducted a series of genome-wide association studies on hair color, eye color, number of sunburns, tanning ability and number of non-melanoma skin cancers (NMSCs) among 10 183 European Americans in the discovery stage and 4504 European Americans in the replication stage (for eye color, 3871 males in the discovery stage and 2496 males in the replication stage). We targeted novel chromosome regions besides the known ones for replication. As a result, we identified a new region downstream of the EDNRB gene on 13q22 associated with hair color and the strongest association was the single-nucleotide polymorphism (SNP) rs975739 (P = 2.4 × 10(-14); P = 5.4 × 10(-9) in the discovery set and P = 1.2 × 10(-6) in the replication set). Using blue, intermediate (including green) and brown eye colors as co-dominant outcomes, we identified the SNP rs3002288 in VASH2 on 1q32.3 associated with brown eye (P = 7.0 × 10(-8); P = 5.3 × 10(-5) in the discovery set and P = 0.02 in the replication set). Additionally, we identified a significant interaction between the SNPs rs7173419 and rs12913832 in the OCA2 gene region on brown eye color (P-value for interaction = 3.8 × 10(-3)). As for the number of NMSCs, we identified two independent SNPs on chr6 and one SNP on chromosome 14: rs12203592 in IRF4 (P = 7.2 × 10(-14); P = 1.8 × 10(-8) in the discovery set and P = 6.7 × 10(-7) in the replication set), rs12202284 between IRF4 and EXOC2 (P = 5.0 × 10(-8); P = 6.6 × 10(-7) in the discovery set and P = 3.0 × 10(-3) in the replication set) and rs8015138 upstream of GNG2 (P = 6.6 × 10(-8); P = 5.3 × 10(-7) in the discovery set and P = 0.01 in the replication set).

Caffeine Intake, Coffee Consumption, and Risk of Cutaneous Malignant Melanoma.

BACKGROUND: Caffeine has been shown to prevent ultraviolet radiation-induced carcinogenesis and to inhibit growth of melanoma cells in experimental studies. We evaluated the association among caffeine intake, coffee consumption, and melanoma risk among three large cohort studies. METHODS: The analysis used data from 89,220 women in the Nurses' Health Study II (1991-2009), 74,666 women in the Nurses' Health Study (1980-2008), and 39,424 men in the Health Professionals Follow-up Study (1986-2008). We used Cox proportional hazards models to estimate the hazard ratios (HR) with 95% confidence intervals (CIs) of melanoma associated with dietary intakes. RESULTS: We documented 2,254 melanoma cases over 4 million person-years of follow-up. After adjustment for other risk factors, higher total caffeine intake was associated with a lower risk of melanoma (≥393 mg/day vs. <60 mg/day: HR = 0.78, 95% CI = 0.64, 0.96; Ptrend = 0.048). The association was more apparent in women (≥393 mg/day vs. <60 mg/day: HR = 0.70, 95% CI = 0.58, 0.85; Ptrend = 0.001) than in men (HR = 0.94, 95% CI = 0.75, 1.2; Ptrend = 0.81), and more apparent for melanomas occurring on body sites with higher continuous sun exposure (head, neck, and extremities; ≥393 mg/day vs. <60 mg/day: HR = 0.71, 95% CI = 0.59, 0.86; Ptrend = 0.001) than for melanomas occurring on body sites with lower continuous sun exposure (trunk including shoulder, back, hip, abdomen, and chest; HR = 0.90, 95% CI = 0.70, 1.2; Ptrend = 0.60). This pattern of association was similar to that for caffeinated coffee consumption, whereas no association was found for decaffeinated coffee consumption and melanoma risk. CONCLUSIONS: Increasing caffeine intake and caffeinated coffee consumption is associated with decreased risk of cutaneous malignant melanomas.

Ambient particulate matter and lung cancer incidence and mortality: a meta-analysis of prospective studies.

BACKGROUND: Chronic exposure to ambient particulate matter (PM) has been suggested to be associated with an increased risk of lung cancer, but the results were inconsistent. We performed a systematic review and meta-analysis of prospective studies to assess the association between exposure to PM and the incidence and mortality of lung cancer in adults. METHODS: We searched PUBMED and EMBASE databases for prospective cohort studies that evaluated the association between PM2.5 (diameter < 2.5 µm), PM10 (diameter < 10 µm) and lung cancer incidence and mortality. Relative risks (RRs) and 95% confidence interval (CI) were calculated using fixed-effect or random-effects models when appropriate. RESULTS: We initially identified 1987 citations, and 19 prospective cohort studies were finally included in our meta-analysis. The pooled adjusted RRs for lung cancer mortality were 1.09 (95% CI: 1.06-1.11; I(2) = 18.3%, P = 0.26) for 10 µg/m(3) increase in the concentration of PM2.5 (12 studies), and 1.05 (95% CI: 1.03-1.07; I(2) = 41.9%, P = 0.11) for 10 µg/m(3) increase in the concentration of PM10 (seven studies). The increased risk of lung cancer mortality associated with PM2.5 and PM10 was consistent across most subgroups. PM10 (three studies) and PM2.5 (two studies) were not found to be significantly associated with lung cancer incidence. CONCLUSIONS: Ambient PM2.5 and PM10 pollutions are prospectively associated with a significantly increased risk of lung cancer mortality. More studies addressing the association between PM and lung cancer incidence are required.

Identification of a melanoma susceptibility locus and somatic mutation in TET2.

Although genetic studies have reported a number of loci associated with melanoma risk, the complex genetic architecture of the disease is not yet fully understood. We sought to identify common genetic variants associated with melanoma risk in a genome-wide association study (GWAS) of 2298 cases and 6654 controls. Thirteen of 15 known loci were replicated with nominal significance. A total of 69 single-nucleotide polymorphisms (SNPs) were selected for in silico replication in two independent melanoma GWAS datasets (a total of 5149 cases and 12 795 controls). Seven novel loci were nominally significantly associated with melanoma risk. These seven SNPs were further genotyped in 234 melanoma cases and 238 controls. The SNP rs4698934 was nominally significantly associated with melanoma risk. The combined odds ratio per T allele = 1.18; 95% confidence interval (1.10-1.25); combined P = 7.70 × 10(-) (7). This SNP is located in the intron of the TET2 gene on chromosome 4q24. In addition, a novel somatic mutation of TET2 was identified by next-generation sequencing in 1 of 22 sporadic melanoma cases. TET2 encodes a member of TET family enzymes that oxidizes 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). It is a putative epigenetic biomarker of melanoma as we previously reported, with observation of reduced TET2 transcriptional expression. This study is the first to implicate TET2 genetic variation and mutation in melanoma.