Showing papers by "Alisa M. Goldstein published in 2015"

Analysis of heritability and shared heritability based on genome-wide association studies for thirteen cancer types

Abstract: Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the add ...

Characterization of large structural genetic mosaicism in human autosomes

Abstract: Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.

Nested PCR Biases in Interpreting Microbial Community Structure in 16S rRNA Gene Sequence Datasets

Abstract: Background Sequencing of the PCR-amplified 16S rRNA gene has become a common approach to microbial community investigations in the fields of human health and environmental sciences. This approach, however, is difficult when the amount of DNA is too low to be amplified by standard PCR. Nested PCR can be employed as it can amplify samples with DNA concentration several-fold lower than standard PCR. However, potential biases with nested PCRs that could affect measurement of community structure have received little attention. Results In this study, we used 17 DNAs extracted from vaginal swabs and 12 DNAs extracted from stool samples to study the influence of nested PCR amplification of the 16S rRNA gene on the estimation of microbial community structure using Illumina MiSeq sequencing. Nested and standard PCR methods were compared on alpha- and beta-diversity metrics and relative abundances of bacterial genera. The effects of number of cycles in the first round of PCR (10 vs. 20) and microbial diversity (relatively low in vagina vs. high in stool) were also investigated. Vaginal swab samples showed no significant difference in alpha diversity or community structure between nested PCR and standard PCR (one round of 40 cycles). Stool samples showed significant differences in alpha diversity (except Shannon’s index) and relative abundance of 13 genera between nested PCR with 20 cycles in the first round and standard PCR (P 27% of total OTUs in stool). Conclusions Nested PCR introduced bias in estimated diversity and community structure. The bias was more significant for communities with relatively higher diversity and when more cycles were applied in the first round of PCR. We conclude that nested PCR could be used when standard PCR does not work. However, rare taxa detected by nested PCR should be validated by other technologies.

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

Abstract: 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 500K SNP, mRNA, and miRNA arrays in 30 cases from a high-risk region of China. (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 (ie, 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 %). 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.

Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types

Abstract: Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl 2, on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation. Studies of related individuals have consistently demonstrated that there is notable familial aggregation of cancer. The three largest studies, based on the Swedish Family-Cancer Database (1–3), the Utah Population and Cancer Registry Database (4,5), and the Icelandic Cancer Registry (6), have shown familial aggregation for cancer at nearly every anatomical site. For common cancers such as prostate, breast, and lung, the familial relative risk (FRR), defined as the increase in risk associated with each affected first-degree relative of an individual, is generally estimated to be below or around 2.0. In contrast, for some rare cancers occurring early in life, such as those of testes and bone, estimates of FRR can exceed 5. Although shared environmental factors contribute to this aggregation, studies of twins (7,8) and extended family members (6,9,10) have clearly identified a substantial genetic contribution, commonly known as heritability. Genome-wide association studies (GWAS) have provided an opportunity to study the contribution of common single-nucleotide polymorphisms (SNPs) to the heritability of complex traits, including cancers. In addition to identifying specific susceptibility SNPs, novel mixed-effect modeling methods (11–13) can utilize GWAS data to quantify the additive heritability attributable to all common susceptibility SNPs captured by genotyping arrays, regardless of whether those SNPs individually have reached the stringent level of genome-wide statistical significance. Understanding the total contribution of common SNPs will be instrumental for evaluating the potential clinical applications of genetics in risk stratification and for guiding future genetic studies of cancer(14,15). Evidence also suggests that there is overlap between cancers with respect to their genetic architectures. Previous family studies have observed familial co-aggregation of cancers among certain sites (5,6), including pairs of cancers at neighboring sites, such as the colon and rectum, as well as for more distant and seemingly unrelated sites such as the cervix and esophagus (6). GWAS have also directly identified shared regions such as 8q24.1 and 5p15.33 (TERT-CLPTM1L) containing SNPs affecting cancer at multiple sites, while earlier studies have identified major genes such as TP53 (16) and BRCA (17) containing highly penetrant rare variants affecting multiple cancers. Sites with overlapping genetic architectures may be studied together to understand shared biology and to increase power to detect susceptibility loci. In this study, we performed an analysis of heritability and shared heritability for cancer at 13 different sites using data from case/control GWAS of more than 80 000 individuals carried out or reported to the US National Cancer Institute. We expand upon recent GWAS estimates of heritability (13) by nearly doubling the number of cases evaluated, exploring six new cancer (sub)types, and considering populations of nonEuropean ancestry. We use detailed information on multiple D ow naded rom http/academ ic.p.com /jnci/article-ab07/12/djv279/2457731 by U niersity of Vrona user on 19 Feruary 2020 7 of 11 | JNCI J Natl Cancer Inst, 2015, Vol. 107, No. 12 a r t ic le a r t ic le smoking characteristics to assess the proportion of heritability in smoking-related cancers that can be attributed to the genetic determinants of cigarette smoking. Furthermore, we use genetic correlation analysis to assess shared heritability across cancer sites and for lung cancer across two distinct ethnic populations to assess the evidence of gene-environment interactions for this complex malignancy. These analyses provide insights into the contribution of common SNPs to cancer heritability, coheritability and their relationships to a major environmental risk-factor, smoking.

Histologic features of melanoma associated with CDKN2A genotype.

Abstract: Background Inherited susceptibility genes have been associated with histopathologic characteristics of tumors. Objective We sought to identify associations between histology of melanomas and CDKN2A genotype. Methods This was a case-control study design comparing 28 histopathologic tumor features among individuals with sporadic melanomas (N = 81) and cases from melanoma families with (N = 123) and without (N = 120) CDKN2A germline mutations. Results Compared with CDKN2A − cases, mutation carriers tended to have histologic features of superficial spreading melanoma subtype including higher pigmentation ( P trend = .02) and increased pagetoid scatter ( P trend = .07) after adjusting for age at diagnosis, sex, and American Joint Committee on Cancer thickness category. Similar associations were observed when comparing mutation carriers with a combined group of CDKN2A − (wild type) and sporadic melanomas. The presence of spindle cell morphology in the vertical growth phase was also an important predictor of genotype. Of the 15 cases with this phenotype, none were observed to harbor a CDKN2A mutation. Limitations Our study examined rare mutations and may have been underpowered to detect small, but biologically significant associations between histology and genotype. Conclusion Familial melanomas with CDKN2A mutations preferentially express a histologic phenotype of dense pigmentation, high pagetoid scatter, and a non-spindle cell morphology in the vertical growth phase.

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

Abstract: 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 ¼0.034) and chromatin remodelling (P-value PATH ¼0.039) 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 ¼0.37; P ¼0.0006) which regulates mRNA expression of ASH1L. Several suggestive