Integrative genomics analysis of genes with biallelic loss and its relation to the expression of mRNA and micro-RNA in esophageal squamous cell carcinoma.

BACKGROUND: Genomic instability plays an important role in human cancers. We previously characterized genomic instability in esophageal squamous cell carcinomas (ESCC) in terms of loss of heterozygosity (LOH) and copy number (CN) changes in tumors. In the current study we focus on biallelic loss and its relation to expression of mRNA and miRNA in ESCC using results from 500 K SNP, mRNA, and miRNA arrays in 30 cases from a high-risk region of China. RESULTS: (i) Biallelic loss was uncommon but when it occurred it exhibited a consistent pattern: only 77 genes (<0.5%) showed biallelic loss in at least 10% of ESCC samples, but nearly all of these genes were concentrated on just four chromosomal arms (i.e., 42 genes on 3p, 14 genes on 9p, 10 genes on 5q, and seven genes on 4p). (ii) Biallelic loss was associated with lower mRNA expression: 52 of the 77 genes also had RNA expression data, and 41 (79%) showed lower expression levels in cases with biallelic loss compared to those without. (iii) The relation of biallelic loss to miRNA expression was less clear but appeared to favor higher miRNA levels: of 60 miRNA-target gene pairs, 34 pairs (57%) had higher miRNA expression with biallelic loss than without, while 26 pairs (43%) had lower miRNA expression. (iv) Finally, the effect of biallelic loss on the relation between miRNA and mRNA expression was complex. Biallelic loss was most commonly associated with a pattern of elevated miRNA and reduced mRNA (43%), but a pattern of both reduced miRNA and mRNA was also common (35%). CONCLUSION: Our results indicate that biallelic loss in ESCC is uncommon, but when it occurs it is localized to a few specific chromosome regions and is associated with reduced mRNA expression of affected genes. The effect of biallelic loss on miRNA expression and on the relation between miRNA and mRNA expressions was complex.

Genetic variants in fas signaling pathway genes and risk of gastric cancer.

Populations in north central China are at high risk for gastric cancers (GC), and altered FAS-mediated cell signaling and/or apoptosis may contribute to this risk. We examined the association of 554 single nucleotide polymorphisms (SNPs) in 53 Fas signaling-related genes using a pathway-based approach in 1758 GC cases (1126 gastric cardia adenocarcinomas (GCA) and 632 gastric noncardia adenocarcinomas (GNCA)), and 2111 controls from a genome-wide association study (GWAS) of GC in ethnic Chinese. SNP associations with risk of overall GC, GCA and GNCA were evaluated using unconditional logistic regressions controlling for age, sex and study. Gene- and pathway-based associations were tested using the adaptive rank-truncated product (ARTP) method. Statistical significance was evaluated empirically by permutation. Significant pathway-based associations were observed for Fas signaling with risk of overall GC (p = 5.5E-04) and GCA (p = 6.3E-03), but not GNCA (p= 8.1E-02). Among examined genes in the Fas signaling pathway, MAP2K4, FAF1, MAPK8, CASP10, CASP8, CFLAR, MAP2K1, CAP8AP2, PAK2 and IKBKB were associated with risk of GC (nominal p < 0.05), and FAF1 and MAPK8 were significantly associated with risk of both GCA and GNCA (nominal p< 0.05). Our examination of genetic variation in the Fas signaling pathway is consistent with an association of altered Fas signaling and/or apoptosis with risk of GC. As one of the first attempts to investigate a pathway-level association, our results suggest that these genes and the Fas signaling pathway warrant further evaluation in relation to GC risk in other populations.

Genotypic variants at 2q33 and risk of esophageal squamous cell carcinoma in China: a meta-analysis of genome-wide association studies.

Genome-wide association studies have identified susceptibility loci for esophageal squamous cell carcinoma (ESCC). We conducted a meta-analysis of all single-nucleotide polymorphisms (SNPs) that showed nominally significant P-values in two previously published genome-wide scans that included a total of 2961 ESCC cases and 3400 controls. The meta-analysis revealed five SNPs at 2q33 with P< 5 × 10(-8), and the strongest signal was rs13016963, with a combined odds ratio (95% confidence interval) of 1.29 (1.19-1.40) and P= 7.63 × 10(-10). An imputation analysis of 4304 SNPs at 2q33 suggested a single association signal, and the strongest imputed SNP associations were similar to those from the genotyped SNPs. We conducted an ancestral recombination graph analysis with 53 SNPs to identify one or more haplotypes that harbor the variants directly responsible for the detected association signal. This showed that the five SNPs exist in a single haplotype along with 45 imputed SNPs in strong linkage disequilibrium, and the strongest candidate was rs10201587, one of the genotyped SNPs. Our meta-analysis found genome-wide significant SNPs at 2q33 that map to the CASP8/ALS2CR12/TRAK2 gene region. Variants in CASP8 have been extensively studied across a spectrum of cancers with mixed results. The locus we identified appears to be distinct from the widely studied rs3834129 and rs1045485 SNPs in CASP8. Future studies of esophageal and other cancers should focus on comprehensive sequencing of this 2q33 locus and functional analysis of rs13016963 and rs10201587 and other strongly correlated variants.

[STXBP1 gene mutation in newborns with refractory seizures].

OBJECTIVE: To study the relationship between STXBP1 gene mutations and refractory seizures with unknown causes in newborns. METHODS: The coding region of STXBP1 gene was detected using direct Sanger sequencing in 11 newborns with refractory seizures of unknown causes. RESULTS: STXBP1 gene mutation was found in 1 out of 11 patients. It was a missense mutation: c.1439C>T (p.P480L). CONCLUSIONS: STXBP1 gene mutation can be found in neonatal refractory seizures of unknown causes, suggesting a new approach of further research of this disease.

Genetic variants in sex hormone metabolic pathway genes and risk of esophageal squamous cell carcinoma.

In China, esophageal cancer is the fourth leading cause of cancer death where essentially all cases are histologically esophageal squamous cell carcinoma (ESCC), in contrast to esophageal adenocarcinoma in the West. Globally, ESCC is 2.4 times more common among men than women and recently it has been suggested that sex hormones may be associated with the risk of ESCC. We examined the association between genetic variants in sex hormone metabolic genes and ESCC risk in a population from north central China with high-incidence rates. A total of 1026 ESCC cases and 1452 controls were genotyped for 797 unique tag single-nucleotide polymorphisms (SNPs) in 51 sex hormone metabolic genes. SNP-, gene- and pathway-based associations with ESCC risk were evaluated using unconditional logistic regression adjusted for age, sex and geographical location and the adaptive rank truncated product (ARTP) method. Statistical significance was determined through use of permutation for pathway- and gene-based associations. No associations were observed for the overall sex hormone metabolic pathway (P = 0.14) or subpathways (androgen synthesis: P = 0.30, estrogen synthesis: P = 0.15 and estrogen removal: P = 0.19) with risk of ESCC. However, six individual genes (including SULT2B1, CYP1B1, CYP3A7, CYP3A5, SHBG and CYP11A1) were significantly associated with ESCC risk (P < 0.05). Our examination of genetic variation in the sex hormone metabolic pathway is consistent with a potential association with risk of ESCC. These positive findings warrant further evaluation in relation to ESCC risk and replication in other populations.

Replication of a genome-wide case-control study of esophageal squamous cell carcinoma.

In a previous pilot case-control study of individuals diagnosed with esophageal squamous cell carcinoma (ESCC) and matched controls from a high-risk area in China, we identified 38 single nucleotide polymorphisms (SNPs) associated with ESCC located in or near one of 33 genes. In our study, we attempted to replicate the results of these 38 gene-related SNPs in a new sample of 300 ESCC cases and 300 matched controls from the same study conducted in Shanxi Province, China. Among 36 evaluable SNPs, 4 were significant in one or more analyses, including SNPs located in EPHB1, PGLYRP2, PIK3C3 and SLC9A9, although the odds ratios (ORs) for these genotypes were modest. Associations were found with EPHB1/rs1515366 (OR 0.92, 95% CI 0.86-0.99; p = 0.019), PIK3C3/rs52911 (OR 0.93, 95% CI 0.88-0.99; p = 0.02) and PGLYRP2/rs959117 (OR 0.93, 95% CI, 0.86-1.01; p = 0.061) in general linear models (additive mode); and the genotype distribution differed between cases and controls for SLC9A9/rs956062 (p = 0.024). To examine these 4 genes in more detail, 40 HapMap-based tag SNPs from these 4 genes were evaluated in the same subjects and 7 additional SNPs associated with ESCC were identified. Further confirmation of these findings in other populations and other studies are needed to determine if the signals from these SNPs are indirectly associated due to linkage disequilibrium, or are directly related to biologic function and the development of ESCC.

Genome-wide association study in esophageal cancer using GeneChip mapping 10K array.

Whole genome association studies of complex human diseases represent a new paradigm in the postgenomic era. In this study, we report application of the Affymetrix, Inc. (Santa Clara, CA) high-density single nucleotide polymorphism (SNP) array containing 11,555 SNPs in a pilot case-control study of esophageal squamous cell carcinoma (ESCC) that included the analysis of germ line samples from 50 ESCC patients and 50 matched controls. The average genotyping call rate for the 100 samples analyzed was 96%. Using the generalized linear model (GLM) with adjustment for potential confounders and multiple comparisons, we identified 37 SNPs associated with disease, assuming a recessive mode of transmission; similarly, 48 SNPs were identified assuming a dominant mode and 53 SNPs in a continuous mode. When the 37 SNPs identified from the GLM recessive mode were used in a principal components analysis, the first principal component correctly predicted 46 of 50 cases and 47 of 50 controls. Among all the SNPs selected from GLMs for the three modes of transmission, 39 could be mapped to 1 of 33 genes. Many of these genes are involved in various cancers, including GASC1, shown previously to be amplified in ESCCs, and EPHB1 and PIK3C3. In conclusion, we have shown the feasibility of the Affymetrix 10K SNP array in genome-wide association studies of common cancers and identified new candidate loci to study in ESCC.

Clinical Manifestations and Amplitude-integrated Encephalogram in Neonates with Early-onset Epileptic Encephalopathy.

BACKGROUND: The patients with early-onset epileptic encephalopathy (EOEE) suffer from neurodevelopmental delay. The aim of this study was to analyze the clinical manifestations and amplitude-integrated encephalogram (aEEG) characteristics of infants with EOEE with onset within the neonatal period, to make early diagnosis to improve the prognosis. METHODS: One-hundred and twenty-eight patients with neonatal seizure were enrolled and followed up till 1 year old. Sixty-six neonates evolved into EOEE were as the EOEE group, the other 62 were as the non-EOEE (nEOEE) group. Then we compared the clinical and aEEG characteristics between the two groups to analyze the manifestations in neonates with EOEE. RESULTS: Compared to the nEOEE group, the incidence of daily seizure attacks, more than two types of convulsions, more than two antiepileptic drugs (AEDs) application, severely abnormal aEEG background, absence of cyclicity, and more than two seizures detection were significantly higher in the EOEE group (P < 0.05) (97% vs. 54.8%; 30.3% vs. 14.5%; 97.0% vs. 25.4%; 39.4% vs. 3.2%; 57.6% vs. 9.7%; and 56% vs. 3.2%, respectively). Severely abnormal background pattern (odds ratio [OR] = 0.081, 95% confidence interval [CI]: 0.009-0.729, P = 0.025) and more than two seizures detection by aEEG (OR = 0.158, 95% CI: 0.043-0.576, P = 0.005) were the independent risk factors for the evolvement into EOEE. The upper and lower margins of active sleep (AS) and quiet sleep (QS) were significantly higher in EOEE group than those of the control group (P < 0.05) (34.3 ± 13.6 vs. 21.3 ± 6.4; 9.9 ± 3.7 vs. 6.7 ± 2.2; 41.2 ± 15.1 vs. 30.4 ± 11.4; and 11.9 ± 4.4 vs. 9.4 ± 4.0; unit: µV, respectively). AS upper margin was demonstrated a higher diagnostic specificity and sensitivity for EOEE than another three parameters according to the receiver operating characteristic curves; the area under the curve was 0.827. CONCLUSIONS: The clinical characteristics of the neonatal seizure which will evolve into EOEE were more than two AEDs application, high seizure frequency (daily attack), and more than two types of the seizure. Significant high voltage, severely abnormal background, absence of cyclicity, and more than two seizures detected on aEEG were the meaningful indicators to the prediction of EOEE.

[Evaluation of early cognitive ability of infants born preterm by near-infrared spectroscopy].

OBJECTIVE: To compare the differences in cerebral oxygenation responses between the infants born preterm and full-term infants and to evaluate the early cognitive ability of infants born preterm. METHODS: Cerebral oxygenation after light stimulation was detected by near infrared spectroscopy (NIRS) in preterm infants at 3 or 6 months corrected gestational age (GA). The results were compared with those of age-matched infants born at term. RESULTS: The start and peak response time of cerebral oxygenation occurring after light stimulation in preterm infants at 3 months corrected GA was 17.2 +/- 5.2 and 38.4 +/- 9.6 seconds respectively, which were significantly longer than in age-matched term infants (13.1 +/- 2.7 and 28.9 +/- 5.0 seconds respectively) (P < 0.05). The maximum response value of hemoglobin, oxyhemoglobin and regional oxygen saturation of the preterm infants at 3 months corrected GA was (1.2 +/- 0.5)%, (1.5 +/- 0.6)%, and (1.3 +/- 0.4)% respectively , which were significantly lower than that of the term infants [(2.3 +/- 0.3)%, (2.8 +/- 0.3)% and (2.4 +/- 0.5)% respectively] (P < 0.05). Cerebral oxygenation responses to light stimulation in preterm infants examined at 6 months corrected GA were not significantly different from age-matched term infants. CONCLUSIONS: Cerebral oxygenation responses to light stimulation in infants born preterm at 3 months corrected GA are not as good as age-matched term infants, but were close to the level of age-matched term infants at 6 months corrected GA. This suggests that the early cognitive ability of preterm infants before 3 months corrected GA might fall behind age-matched term infants.

Evaluation of BRCA2 in the genetic susceptibility of familial esophageal cancer.

Previous studies of esophageal squamous cell carcinoma (ESCC) have shown a high frequency of allelic loss on chromosome 13q, infrequent somatic mutations in BRCA2, and a suggested association between a positive family history (FH+) of upper gastrointestinal cancer and germline BRCA2 mutations. In all, 70 ESCC patients (44 FH+ and 26 FH-) were examined by direct full sequencing of germline DNA for BRCA2 mutations. In addition, 28 family members of three of these patients and 232 unrelated healthy blood bank donor controls were examined for the mutations identified in the 70 ESCC patients. Five BRCA2 germline mutations, including three not previously reported (N1600del, A2054P, and V2109I), were identified in six of 44 FH+ patients, but none of 26 FH- patients (14 vs 0%, P=0.078), consistent with our previous findings (3/34 or 9% FH+ vs 0/22 or 0% FH-, P=0.27). The cumulative frequency of BRCA2 germline mutations in ESCC patients in this and our previous study combined is 12%, with all mutations found in FH+ as opposed to FH- cases (9/78 or 12% FH+ vs 0/48 or 0% FH-, P=0.013). We conclude that germline mutations in BRCA2 in ESCC patients from this high-risk area of China are more frequent in FH+ than FH- cases, suggesting that BRCA2 may play a role in genetic susceptibility to familial ESCC.

Decision forest analysis of 61 single nucleotide polymorphisms in a case-control study of esophageal cancer; a novel method.

BACKGROUND: Systematic evaluation and study of single nucleotide polymorphisms (SNPs) made possible by high throughput genotyping technologies and bioinformatics promises to provide breakthroughs in the understanding of complex diseases. Understanding how the millions of SNPs in the human genome are involved in conferring susceptibility or resistance to disease, or in rendering a drug efficacious or toxic in the individual is a major goal of the relatively new fields of pharmacogenomics. Esophageal squamous cell carcinoma is a high-mortality cancer with complex etiology and progression involving both genetic and environmental factors. We examined the association between esophageal cancer risk and patterns of 61 SNPs in a case-control study for a population from Shanxi Province in North Central China that has among the highest rates of esophageal squamous cell carcinoma in the world. METHODS: High-throughput Masscode mass spectrometry genotyping was done on genomic DNA from 574 individuals (394 cases and 180 age-frequency matched controls). SNPs were chosen from among genes involving DNA repair enzymes, and Phase I and Phase II enzymes. We developed a novel adaptation of the Decision Forest pattern recognition method named Decision Forest for SNPs (DF-SNPs). The method was designated to analyze the SNP data. RESULTS: The classifier in separating the cases from the controls developed with DF-SNPs gave concordance, sensitivity and specificity, of 94.7%, 99.0% and 85.1%, respectively; suggesting its usefulness for hypothesizing what SNPs or combinations of SNPs could be involved in susceptibility to esophageal cancer. Importantly, the DF-SNPs algorithm incorporated a randomization test for assessing the relevance (or importance) of individual SNPs, SNP types (Homozygous common, heterozygous and homozygous variant) and patterns of SNP types (SNP patterns) that differentiate cases from controls. For example, we found that the different genotypes of SNP GADD45B E1122 are all associated with cancer risk. CONCLUSION: The DF-SNPs method can be used to differentiate esophageal squamous cell carcinoma cases from controls based on individual SNPs, SNP types and SNP patterns. The method could be useful to identify potential biomarkers from the SNP data and complement existing methods for genotype analyses.

Infrequent mutation in the BRCA2 gene in esophageal squamous cell carcinoma.

PURPOSE: Previous studies have shown a high rate of allelic loss in esophageal squamous cell carcinoma (ESCC) in the vicinity of the BRCA2 gene. We aimed to assess whether the tumor suppressor gene BRCA2 was the inactivation target for allelic loss observed on chromosome 13q in ESCC. EXPERIMENTAL DESIGN: We examined the entire coding sequence of the BRCA2 gene for mutations using single-strand conformation polymorphism analysis and DNA sequencing in 56 ESCC patients from Shanxi, China. RESULTS: Eight mutations were identified in 5 patients (9%), including 3 with germ-line mutations and 2 with only somatic mutations. However, all but 1 of the mutations were missense or silent changes and of unknown significance. Evidence for potential biallelic inactivation was seen in only 4 (7%) cases. CONCLUSIONS: BRCA2 mutations occur in ESCC but are infrequent and of unknown consequence. The putative target tumor suppressor gene corresponding to the high rate of chromosome 13q allelic loss remains unknown.

Common genetic variants related to vitamin D status are not associated with esophageal squamous cell carcinoma risk in China.

BACKGROUND: Few studies have examined the association of common genetic variants related to vitamin D metabolism and signaling to esophageal squamous cell carcinoma (ESCC). METHODS: We evaluated the association between 12 single nucleotide polymorphisms (SNPs) in four genes related to vitamin D levels and ESCC risk using data from a genome-wide association study. Participants were recruited from the Shanxi Upper Gastrointestinal Cancer Genetics Project and the Linxian Nutrition Intervention Trials, and included 1942 ESCC cases and 2111 controls. We used logistic models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the SNP associations, after controlling for age and gender. RESULTS: None of the 12 evaluated SNPs in the four vitamin D-related genes were significantly associated with risk of ESCC. The strongest associations were for rs3794060 (P=0.07) and rs12800438 (P=0.08) in the DHCR7/NADSYN1 gene. No association between vitamin D-related SNPs and risk of ESCC was observed in a genotype score analysis that included all 12 SNPs. ORs for quartiles 2, 3 and 4 of the genotype scores were 0.83 (95% CI: 0.68, 1.01), 1.02 (0.85, 1.21), and 1.08 (0.89, 1.30), respectively, with no evidence for a significant monotonic trend (P=0.120). CONCLUSIONS: Our results suggested that common genetic variants related to vitamin D levels are not associated with risk of ESCC in this Chinese population.

Common genetic variants in epigenetic machinery genes and risk of upper gastrointestinal cancers.

BACKGROUND: Populations in north central China are at high risk for oesophageal squamous cell carcinoma (ESCC) and gastric cancer (GC), and genetic variation in epigenetic machinery genes and pathways may contribute to this risk. METHODS: We used the adaptive multilocus joint test to analyse 192 epigenetic genes involved in chromatin remodelling, DNA methylation and microRNA biosynthesis in 1942 ESCC and 1758 GC cases [1126 cardia (GCA) and 632 non-cardia adenocarcinoma (GNCA)] and 2111 controls with Chinese ancestry. We examined potential function of risk alleles using in silico and expression quantitative trait loci (eQTLs) analyses. RESULTS: Suggestive pathway-based associations were observed for the overall epigenetic (P-value(PATH) = 0.034) and chromatin remodelling (P-value(PATH) = 0.039) pathways with risk of GCA, but not GC, GNCA or ESCC. Overall, 37 different epigenetic machinery genes were associated with risk of one or more upper gastrointestinal (UGI) cancer sites (P-value(GENE )< 0.05), including 14 chromatin remodelling genes whose products are involved in the regulation of HOX genes. We identified a gastric eQTL (rs12724079; rho = 0.37; P = 0.0006) which regulates mRNA expression of ASH1L. Several suggestive eQTLs were also found in oesophageal (rs10898459 in EED), gastric cardia (rs7157322 in DICER1; rs8179271 in ASH1L), and gastric non-cardia (rs1790733 in PPP1CA) tissues. CONCLUSIONS: Results of our analyses provide limited but suggestive evidence for a role of epigenetic gene variation in the aetiology of UGI cancer.

Evidence for a familial esophageal cancer susceptibility gene on chromosome 13.

Previous segregation analyses of pedigrees from areas of China where esophageal squamous cell carcinoma (ESCC) rates are extraordinarily high suggested a Mendelian mode of transmission. We initiated a search for a major ESCC gene by conducting a genome-wide scan in ESCC tumors. Chromosome 13 showed loss of heterozygosity (LOH) in 95% of microsatellite markers, the highest frequency of LOH on any chromosome. In the current study, we established a high-resolution deletion map using 107 markers on 13q and compared LOH frequency by family history of upper gastrointestinal cancer. Overall allelic loss was significantly higher in those with a positive (versus negative) family history, suggesting the presence of an inherited tumor suppressor gene on 13q in ESCC.

Oesophageal squamous cell carcinoma in high-risk Chinese populations: Possible role for vascular epithelial growth factor A.

BACKGROUND: Mechanisms involved in wound healing play some role in carcinogenesis in multiple organs, likely by creating a chronic inflammatory milieu. This study sought to assess the role of genetic markers in selected inflammation-related genes involved in wound healing (interleukin (IL)-1a, IL-1b, IL-1 Receptor type I (IL-1Ra), IL-1 Receptor type II (IL-1Rb), tumour necrosis factor (TNF)-α, tumour necrosis factor receptor superfamily member (TNFRSF)1A, nuclear factor kappa beta (NF-kB)1, NF-kB2, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, hypoxia induced factor (HIF)-1α, vascular endothelial growth factor (VEGF)A and P-53) in risk to oesophageal squamous cell carcinoma (OSCC). METHODS: We genotyped 125 tag single nucleotide polymorphism (SNP)s in 410 cases and 377 age and sex matched disease-free individuals from Nutritional Intervention Trial (NIT) cohort, and 546 cases and 556 controls individually matched for age, sex and neighbourhood from Shanxi case-control study, both conducted in high-risk areas of north-central China (1985-2007). Cox proportional-hazard models and conditional logistic regression models were used for SNPs analyses for NIT and Shanxi, respectively. Fisher's inverse test statistics were used to obtain gene-level significance. RESULTS: Multiple SNPs were significantly associated with OSCC in both studies, however, none retained their significance after a conservative Bonferroni adjustment. Empiric p-values for tag SNPs in VEGFA in NIT were highly concentrated in the lower tail of the distribution, suggesting this gene may be influencing risk. Permutation tests confirmed the significance of this pattern. At the gene level, VEGFA yielded an empiric significance (P=0.027) in NIT. We also observed some evidence for interaction between environmental factors and some VEGFA tag SNPs. CONCLUSION: Our finding adds further evidence for a potential role for markers in the VEGFA gene in the development and progression of early precancerous lesions of oesophagus.

Joint analysis of three genome-wide association studies of esophageal squamous cell carcinoma in Chinese populations.

We conducted a joint (pooled) analysis of three genome-wide association studies (GWAS) of esophageal squamous cell carcinoma (ESCC) in individuals of Chinese ancestry (5,337 ESCC cases and 5,787 controls) with 9,654 ESCC cases and 10,058 controls for follow-up. In a logistic regression model adjusted for age, sex, study and two eigenvectors, two new loci achieved genome-wide significance, marked by rs7447927 at 5q31.2 (per-allele odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.82-0.88; P = 7.72 × 10(-20)) and rs1642764 at 17p13.1 (per-allele OR = 0.88, 95% CI = 0.85-0.91; P = 3.10 × 10(-13)). rs7447927 is a synonymous SNP in TMEM173, and rs1642764 is an intronic SNP in ATP1B2, near TP53. Furthermore, a locus in the HLA class II region at 6p21.32 (rs35597309) achieved genome-wide significance in the two populations at highest risk for ESSC (OR = 1.33, 95% CI = 1.22-1.46; P = 1.99 × 10(-10)). Our joint analysis identifies new ESCC susceptibility loci overall as well as a new locus unique to the population in the Taihang Mountain region at high risk of ESCC.

Detectable clonal mosaicism and its relationship to aging and cancer.

In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.

[Studies on hereditary epidemiology of cardia cancer in Shanxi province.].

OBJECTIVE: Studies on cardia-cancer caused by hereditary factors. METHODS: Case-control method was adopted, with information including name, sex, date of birth, date of death of all the I, II, III relatives of the patients, diagnosis and the treatment collected. The hereditary probability of cardia cancer and the separation degree were calculated by Falconer and Li-Mentel-Gart. RESULTS: (1) Prevalence rates of cardia-cancer on relative I, relative II, relative III of cardia-cancer patients appeared to be 0.54%, 0.04%, and 0.05% respectively. Prevalence rates of upper-digestive-tract-cancer of relative I, relative II, relative III of cardia-cancer patients showed as: 2.50%, 0.36% and 0.13% respectively. Data showed that relative I > relative II > relative III and family cluster existed in both males and females. (2) Cardia-cancer hereditary probability of the relative I cardia-cancer probands was 11.71%, with males as 14.01% and females as 14.72%. The upper-digestive-tract-cancer hereditary probability of the relative I cardia-cancer probands was 13.87%, with males as 11.49% and females as 23.08%, both below 25%, indicating this was a low hereditary cancer. (3) The upper-digestive-tract-cancer separation of the blood compatriots of cardia-cancer patients was 0.0452, with males as 0.0441 and females as 0.0507, both below 0.25, indicating the nature of a multi-gene but not single-gene hereditary way. CONCLUSION: Hereditary factor is recognized as one of the high risk cardia cancer, but not the most risky factor causing the high morbidity of cardia cancer in Shanxi province.