No abstract

Purpose Promoter hypermethylation has been recently proposed as a mean for HNSCC detection in salivary rinses. In a prospective study of a high-risk population, we showed that EDNRB promoter methylation in salivary rinses is a useful biomarker for oral cancer and premalignancy. Experimental Design Using that cohort, we evaluated EDNRB methylation status and 8 additional genes. Clinical risk assessment by expert clinicians was performed and compared with biomarker performance in the prediction of premalignant and malignant disease. Methylation status of 9 genes was analyzed in salivary rinses of 191 patients by Quantitative methylation-specific PCR. Results HOXA9, EDNRB and DCC methylation were associated (p= 0.012; p<0.0001; p=0.0005) with premalignant or malignant disease. On multivariable modeling, histological diagnosis was only independently associated with EDNRB (p=0.0003) or DCC (p=0.004) methylation. A subset of patients received clinical risk classification (CRC) by expert clinicians based on lesion examination. CRC, DCC and EDNRB were associated with diagnosis of dysplasia/cancer on univariate (p=0.008; p=0.026; p=0.046) and multivariate analysis (p=0.012; p=0.037; p=0.047). CRC identified dysplasia/cancer with56% of sensitivity and 66% of specificity with a similar AUC (0.61, 95%CI=0.60-0.81) when compared to EDNRB and DCC combined AUC (0.60, 95%CI=0.51-0.69), sensitivity of 46% and specificity of 72%. A combination of EDNRB, DCC and CRC was optimal AUC (0.67, 95%CI=0.58-0.76). Conclusion EDNRB and/or DCC methylation in salivary rinses compares well to examination by an expert clinician in CRC of oral lesions. These salivary biomarkers may be particularly useful in oral premalignancy and malignancy screening in clinical care settings in which expert clinicians are not available

Genotype-by-environment (G × E) interactions could play an important role in cattle populations, and it should be considered in breeding programmes to select the best sires for different environments. The objectives of this study were to study G × E interactions for female fertility traits in the Danish Holstein dairy cattle population using a reaction norm model (RNM), and to detect the particular genomic regions contributing to the performance of these traits and the G × E interactions. In total 4534 bulls were genotyped by an Illumina BovineSNP50 BeadChip. An RNM with a pedigree-based relationship matrix and a pedigree-genomic combined relationship matrix was used to explore the existence of G × E interactions. In the RNM, the environmental gradient (EG) was defined as herd effect. Further, the genomic regions affecting interval from calving to first insemination (ICF) and interval from first to last insemination (IFL) were detected using single-step genome-wide association study (ssGWAS). The genetic correlations between extreme EGs indicated that G × E interactions were sizable for ICF and IFL. The genomic RNM (pedigree-genomic combined relationship matrix) had higher prediction accuracy than the conventional RNM (pedigree-based relationship matrix). The top genomic regions affecting the slope of the reaction norm included immunity-related genes (IL17, IL17F and LIF), and growth-related genes (MC4R and LEP), while the top regions influencing the intercept of the reaction norm included fertility-related genes such as EREG, AREG and SMAD4. In conclusion, our findings validated the G × E interactions for fertility traits across different herds and were helpful in understanding the genetic background of G × E interactions for these traits.

Jinhua pig, a well-known Chinese indigenous breed, has evolved as a pig breed with excellent meat quality, greater disease resistance, and higher prolificacy. The reduction in the number of Jinhua pigs over the past years has raised concerns about inbreeding. Runs of homozygosity (ROH) along the genome have been applied to quantify individual autozygosity to improve the understanding of inbreeding depression and identify genes associated with traits of interest. Here, we investigated the occurrence and distribution of ROH using next-generation sequencing data to characterize autozygosity in 202 Jinhua pigs, as well as to identify the genomic regions with high ROH frequencies within individuals. The average inbreeding coefficient, based on ROH longer than 1 Mb, was 0.168 ± 0.052. In total, 18,690 ROH were identified in all individuals, among which shorter segments (1–5 Mb) predominated. Individual ROH autosome coverage ranged from 5.32 to 29.14% in the Jinhua population. On average, approximately 16.8% of the whole genome was covered by ROH segments, with the lowest coverage on SSC11 and the highest coverage on SSC17. A total of 824 SNPs (about 0.5%) and 11 ROH island regions were identified (occurring in over 45% of the samples). Genes associated with reproduction ( HOXA3, HOXA7, HOXA10 , and HOXA11 ), meat quality ( MYOD1, LPIN3 , and CTNNBL1 ), appetite ( NUCB2 ) and disease resistance traits ( MUC4, MUC13, MUC20, LMLN, ITGB5, HEG1, SLC12A8 , and MYLK ) were identified in ROH islands. Moreover, several quantitative trait loci for ham weight and ham fat thickness were detected. Genes in ROH islands suggested, at least partially, a selection for economic traits and environmental adaptation, and should be subject of future investigation. These findings contribute to the understanding of the effects of environmental and artificial selection in shaping the distribution of functional variants in the pig genome.

Serological detection of Epstein-Barr virus (EBV) antibodies is frequently used in nasopharyngeal carcinoma (NPC) mass screening. However, the large number of seropositive subjects who require close follow-up is still a big burden. The present study aimed to detect the nasopharyngeal EBV load in a high-risk population seropositive for antibodies against EBV, as well as to examine whether assay for nasopharyngeal EBV DNA load might reduce the number of high-risk subjects for follow-up and improve early detection of NPC. A prospective and population-based cohort study was conducted in southern China from 2006 through 2013. Among 22,186 participants, 1045 subjects with serum immunoglobulin A (IgA) antibodies against viral capsid antigen (VCA) titers ≥ 1:5 were defined as high-risk group, and were then followed-up for NPC occurrence. Qualified nasopharyngeal swab specimens were available from 905 participants and used for quantitative PCR assay. Our study revealed that 89% (802/905) subjects showed positive EBV DNA in nasopharyngeal swab. The nasopharyngeal EBV load in females was higher than that in males. The nasopharyngeal EBV load increased with increasing serum VCA/IgA titers. Eight cases of newly diagnosed NPC showed an extremely elevated EBV load, and 87.5% (7 of 8 patients) were early-stage NPCs. The EBV loads of 8 NPCs were significantly higher than those of 897 NPC-free subjects (mean, 2.8×106 copies/swab [range 4.8×104-1.1×108] vs. 5.6×103 [range 0-3.8×106]). Using mean EBV load in NPC-free population plus two standard deviations as cut-off value, a higher diagnostic performance was obtained for EBV load test than serum VCA/IgA test (area under ROC, 0.980 vs 0.895). In conclusion, in a prospective and population-based study we demonstrated that an additional assay of EBV load in the nasopharynx among high-risk individuals may reduce the number of subjects needed to be closely followed up and could serve as part of a NPC screening program in high-risk populations.

Polygenic risk scores (PRS) have the potential to identify individuals at risk of diseases, optimizing treatment, and predicting survival outcomes. Here, we construct and validate a genome-wide association study (GWAS) derived PRS for nasopharyngeal carcinoma (NPC), using a multi-center study of six populations (6 059 NPC cases and 7 582 controls), and evaluate its utility in a nested case-control study. We show that the PRS enables effective identification of NPC high-risk individuals (AUC = 0.65) and improves the risk prediction with the PRS incremental deciles in each population (Ptrend ranging from 2.79 × 10−7 to 4.79 × 10−44). By incorporating the PRS into EBV-serology-based NPC screening, the test’s positive predictive value (PPV) is increased from an average of 4.84% to 8.38% and 11.91% in the top 10% and 5% PRS, respectively. In summary, the GWAS-derived PRS, together with the EBV test, significantly improves NPC risk stratification and informs personalized screening.

ABSTRACT Oral health and changes in the oral microbiome have been associated with both local and systemic cancer. Poor oral hygiene is a known risk factor for nasopharyngeal carcinoma (NPC), a virally associated head and neck cancer endemic to southern China. We explored the relationship between NPC and the oral microbiome using 16S rRNA sequencing in a study of 499 NPC patients and 495 population-based age and sex frequency-matched controls from an area of endemicity of Southern China. We found a significant reduction in community richness in cases compared to that in controls. Differences in the overall microbial community structure between cases and controls could not be explained by other potential confounders; disease status explained 5 times more variation in the unweighted UniFrac distance than the next most explanatory variable. In feature-based analyses, we identified a pair of coexcluding Granulicatella adiacens amplicon sequence variants (ASVs) which were strongly associated with NPC status and differed by a single nucleotide. The G. adiacens variant an individual carried was also associated with the overall microbial community based on beta diversity. Co-occurrence analysis suggested the two G. adiacens ASVs sit at the center of two coexcluding clusters of closely related organisms. Our results suggest there are differences in the oral microbiomes between NPC patients and healthy controls, and these may be associated with both a loss of microbial diversity and niche specialization among closely related commensals. IMPORTANCE The relationship between oral health and the risk of nasopharyngeal carcinoma (NPC) was previously established. However, the role of oral microbiome has not been evaluated in the disease in a large epidemiological study. This paper clearly establishes a difference in the oral microbiomes between NPC patients and healthy controls which cannot be explained by other confounding factors. It furthermore identifies a pair of closely related coexcluding organisms associated with the disease, highlighting the importance of modern methods for single-nucleotide resolution in 16S rRNA sequence characterization. To the best of our knowledge, this is one of the first examples of cancer-associated niche specialization of the oral microbiome.

Chinese indigenous pigs in the Taihu Lake region are well known for their high fecundity and other excellent characteristics. To better understand the characteristics of these breeds in this area as well as to provide the government and breeders the molecular basis for formulating a reasonable conservation policy, we explored the structure of haplotype blocks and genetic diversity of the 7 populations which is relevant for the management and conservation of these important genetic resources using next-generation sequencing data. In this study, a total of 131 300 single-nucleotide polymorphisms with minor allele frequencies ⩾0.05 were obtained for further analysis. In general, there are similar within-breed genetic diversities (He, Ho, Pn, Ar) among these 7 pig populations in the Taihu Lake region. Average values for the inbreeding coefficients estimates in the 7 populations are 0.110 (F1), 0.056 (F2), and 0.078 (F3). All the breeds have seen a continuous decline in Ne estimates over time with FJ and SW populations having a very similar curve. Moreover, the Ne of SMS pig breeds were smaller than other Chinese pig breeds, indicating that SMS pig breeds underwent stronger selection pressure than other Chinese pig breeds. The average genetic distances among the 7 populations in the Taihu Lake region were 0.235 (MMS), 0.240 (SMS), 0.269 (EH), 0.248 (MI), 0.221 (FJ), 0.254 (JX), and 0.212 (SW). A summary of the number of haplotype blocks and haplotype diversity was also presented. This study provide a deep understanding of the current situation of conservation in this region, thereby uncovering the pertinent insight to better formulate more reasonable preservation policies for the government departments and breeding planners to follow-up.