Jeanette E. Eckel-Passow

Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors

BACKGROUND The prediction of clinical behavior, response to therapy, and outcome of infiltrative glioma is challenging. On the basis of previous studies of tumor biology, we defined five glioma molecular groups with the use of three alterations: mutations in the TERT promoter, mutations in IDH, and codeletion of chromosome arms 1p and 19q (1p/19q codeletion). We tested the hypothesis that within groups based on these features, tumors would have similar clinical variables, acquired somatic alterations, and germline variants. METHODS We scored tumors as negative or positive for each of these markers in 1087 gliomas and compared acquired alterations and patient characteristics among the five primary molecular groups. Using 11,590 controls, we assessed associations between these groups and known glioma germline variants. RESULTS Among 615 grade II or III gliomas, 29% had all three alterations (i.e., were triple-positive), 5% had TERT and IDH mutations, 45% had only IDH mutations, 7% were triple-negative, and 10% had only TERT mutations; 5% had other combinations. Among 472 grade IV gliomas, less than 1% were triple-positive, 2% had TERT and IDH mutations, 7% had only IDH mutations, 17% were triple-negative, and 74% had only TERT mutations. The mean age at diagnosis was lowest (37 years) among patients who had gliomas with only IDH mutations and was highest (59 years) among patients who had gliomas with only TERT mutations. The molecular groups were independently associated with overall survival among patients with grade II or III gliomas but not among patients with grade IV gliomas. The molecular groups were associated with specific germline variants. CONCLUSIONS Gliomas were classified into five principal groups on the basis of three tumor markers. The groups had different ages at onset, overall survival, and associations with germline variants, which implies that they are characterized by distinct mechanisms of pathogenesis. (Funded by the National Institutes of Health and others.).

Integrated Analysis of Gene Expression, CpG Island Methylation, and Gene Copy Number in Breast Cancer Cells by Deep Sequencing

We used deep sequencing technology to profile the transcriptome, gene copy number, and CpG island methylation status simultaneously in eight commonly used breast cell lines to develop a model for how these genomic features are integrated in estrogen receptor positive (ER+) and negative breast cancer. Total mRNA sequence, gene copy number, and genomic CpG island methylation were carried out using the Illumina Genome Analyzer. Sequences were mapped to the human genome to obtain digitized gene expression data, DNA copy number in reference to the non-tumor cell line (MCF10A), and methylation status of 21,570 CpG islands to identify differentially expressed genes that were correlated with methylation or copy number changes. These were evaluated in a dataset from 129 primary breast tumors. Gene expression in cell lines was dominated by ER-associated genes. ER+ and ER− cell lines formed two distinct, stable clusters, and 1,873 genes were differentially expressed in the two groups. Part of chromosome 8 was deleted in all ER− cells and part of chromosome 17 amplified in all ER+ cells. These loci encoded 30 genes that were overexpressed in ER+ cells; 9 of these genes were overexpressed in ER+ tumors. We identified 149 differentially expressed genes that exhibited differential methylation of one or more CpG islands within 5 kb of the 5′ end of the gene and for which mRNA abundance was inversely correlated with CpG island methylation status. In primary tumors we identified 84 genes that appear to be robust components of the methylation signature that we identified in ER+ cell lines. Our analyses reveal a global pattern of differential CpG island methylation that contributes to the transcriptome landscape of ER+ and ER− breast cancer cells and tumors. The role of gene amplification/deletion appears to more modest, although several potentially significant genes appear to be regulated by copy number aberrations.

Genomic Analysis Reveals That Immune Function Genes Are Strongly Linked to Clinical Outcome in the North Central Cancer Treatment Group N9831 Adjuvant Trastuzumab Trial

PURPOSE To develop a genomic signature that predicts benefit from trastuzumab in human epidermal growth factor receptor 2-positive breast cancer. PATIENTS AND METHODS DASL technology was used to quantify mRNA in samples from 1,282 patients enrolled onto the Combination Chemotherapy With or Without Trastuzumab in Treating Women With Breast Cancer (North Central Cancer Treatment Group N9831 [NCCTG-N9831]) adjuvant trastuzumab trial. Cox proportional hazard ratios (HRs), adjusted for significant clinicopathologic risk factors, were used to determine the association of each gene with relapse-free survival (RFS) for 433 patients who received chemotherapy alone (arm A) and 849 patients who received chemotherapy plus trastuzumab (arms B and C). Network and pathway analyses were used to identify key biologic processes linked to RFS. The signature was built by using a voting scheme. RESULTS Network and functional ontology analyses suggested that increased RFS was linked to a subset of immune function genes. A voting scheme model was used to define immune gene enrichment based on the expression of any nine or more of 14 immune function genes at or above the 0.40 quantile for the population. This model was used to identify immune gene-enriched tumors in arm A and arms B and C. Immune gene enrichment was linked to increased RFS in arms B and C (HR, 0.35; 95% CI, 0.22 to 0.55; P < .001), whereas arm B and C patients who did not exhibit immune gene enrichment did not benefit from trastuzumab (HR, 0.89; 95% CI, 0.62 to 1.28; P = .53). Enriched immune function gene expression as defined by our predictive signature was not associated with increased RFS in arm A (HR, 0.90; 95% CI, 0.60 to 1.37; P = .64). CONCLUSION Increased expression of a subset of immune function genes may provide a means of predicting benefit from adjuvant trastuzumab.

Development and evaluation of BioScore: a biomarker panel to enhance prognostic algorithms for clear cell renal cell carcinoma.

The authors previously showed that increased tumor expression levels of B7‐H1, survivin, and Ki‐67 are independent predictors of poor outcome for patients with clear cell renal cell carcinoma (ccRCC). In the current study, they described the creation of a scoring system based on this panel of biomarkers that can be used in tandem with existing clinicopathologic features and algorithms to improve ccRCC outcome prediction.

Statistical analysis of relative labeled mass spectrometry data from complex samples using ANOVA

Statistical tools enable unified analysis of data from multiple global proteomic experiments, producing unbiased estimates of normalization terms despite the missing data problem inherent in these studies. The modeling approach, implementation, and useful visualization tools are demonstrated via a case study of complex biological samples assessed using the iTRAQ relative labeling protocol.

Variants near TERT and TERC influencing telomere length are associated with high-grade glioma risk

Glioma, the most common central nervous system cancer in adults, has poor prognosis. Here we identify a new SNP associated with glioma risk, rs1920116 (near TERC), that reached genome-wide significance (Pcombined = 8.3 × 10−9) in a meta-analysis of genome-wide association studies (GWAS) of high-grade glioma and replication data (1,644 cases and 7,736 controls). This region has previously been associated with mean leukocyte telomere length (LTL). We therefore examined the relationship between LTL and both this new risk locus and other previously established risk loci for glioma using data from a recent GWAS of LTL (n = 37,684 individuals). Alleles associated with glioma risk near TERC and TERT were strongly associated with longer LTL (P = 5.5 × 10−20 and 4.4 × 10−19, respectively). In contrast, risk-associated alleles near RTEL1 were inconsistently associated with LTL, suggesting the presence of distinct causal alleles. No other risk loci for glioma were associated with LTL. The identification of risk alleles for glioma near TERC and TERT that also associate with telomere length implicates telomerase in gliomagenesis.

The Mayo prosthetic joint infection risk score: implication for surgical site infection reporting and risk stratification.

OBJECTIVE The goal of this study was to develop a prognostic scoring system for the development of prosthetic joint infection (PJI) that could risk-stratify patients undergoing total hip (THA) or total knee (TKA) arthroplasties. DESIGN Previously reported case-control study. SETTING Tertiary referral care setting from 2001 through 2006. METHODS A derivation data set of 339 cases and 339 controls was used to develop 2 scores. A baseline score and a 1-month-postsurgery risk score were computed as a function of the relative contributions of risk factors for each model. Points were assigned for the presence of each factor and then summed to get a subjects risk score. RESULTS The following risk factors were detected from multivariable modeling and incorporated into the baseline Mayo PJI risk score: body mass index, prior other operation on the index joint, prior arthroplasty, immunosuppression, ASA score, and procedure duration (c index, 0.722). The 1-month-postsurgery risk score contained the same variables in addition to postoperative wound drainage (c index, 0.716). CONCLUSION The baseline score might help with risk stratification in relation to public reporting and reimbursement as well as targeted prevention strategies in patients undergoing THA or TKA. The application of the 1-month-postsurgery PJI risk score to patients undergoing THA or TKA might benefit those undergoing workup for PJI.

LEF-1 is a prosurvival factor in chronic lymphocytic leukemia and is expressed in the preleukemic state of monoclonal B-cell lymphocytosis

The canonical Wnt signaling pathway is pathogenic in a variety of cancers. We previously identified aberrant expression of the Wnt pathway transcription factor and target gene lymphoid enhancer binding factor-1 (LEF1) in chronic lymphocytic leukemia (CLL). This suggested that the Wnt signaling pathway has a role in the biology of CLL. In this study, we performed a Wnt pathway analysis using gene expression profiling and identified aberrant regulation of Wnt pathway target genes, ligands, and signaling members in CLL cells. Furthermore, we identified aberrant protein expression of LEF-1 specifically in CLL but not in normal mature B-cell subsets or after B-cell activation. Using the T cell-specific transcription factor/LEF (TCF/LEF) dual luciferase reporter assay, we demonstrated constitutive Wnt pathway activation in CLL, although the pathway was inactive in normal peripheral B cells. Importantly, LEF-1 knockdown decreased CLL B-cell survival. We also identified LEF-1 expression in CD19(+)/CD5(+) cells obtained from patients with monoclonal B-cell lymphocytosis, suggesting a role for LEF-1 early in CLL leukemogenesis. This study has identified the constitutive activation and prosurvival function of LEF-1 and the Wnt pathway in CLL and uncovered a possible role for these factors in the preleukemic state of monoclonal B-cell lymphocytosis.

Antimicrobial resistance trends of Escherichia coli bloodstream isolates: a population-based study, 1998―2007

BACKGROUND There have been contradictory results regarding temporal changes in the antimicrobial resistance of Escherichia coli from tertiary care centres. Therefore, we performed a population-based investigation to examine in vitro antimicrobial resistance trends of E. coli bloodstream isolates. METHODS In this retrospective population-based incidence study, we identified 461 unique patients with first episodes of E. coli bloodstream infection (BSI) from 1 January 1998 to 31 December 2007 through microbiology records at the two laboratories in Olmsted County, Minnesota. Logistic regression was used to examine temporal changes in antimicrobial resistance and Poisson regression for changes in incidence rates. RESULTS The median age of patients with E. coli BSI was 69 years; 306 (66.4%) were female. The age-adjusted incidence rate of E. coli BSI per 100 000 person-years was 48.0 (95% CI: 42.5-53.4) in females and 34.0 (95% CI: 28.6-39.6) in males. The urinary tract was the most common primary source of infection (79.8%). During the study period, resistance rates of E. coli bloodstream isolates increased from 32% to 53% for ampicillin, from 23% to 45% for ampicillin/sulbactam, from 9% to 28% for trimethoprim/sulfamethoxazole and from 0% to 12% for ciprofloxacin. Resistance rates to carbapenems, cephalosporins and piperacillin/tazobactam remained low and stable. CONCLUSIONS To our knowledge, this is the first population-based study on antimicrobial resistance trends of E. coli bloodstream isolates in the USA. We demonstrated linear trends of increasing resistance among these isolates to three different classes of antimicrobial over the past decade.

Incidence Rate and Outcome of Gram‐Negative Bloodstream Infection in Solid Organ Transplant Recipients

Bacterial infections are common complications of solid organ transplantation (SOT). In this study, we defined the incidence, mortality and in vitro antimicrobial resistance rates of Gram‐negative bloodstream infection (BSI) in SOT recipients. We identified 223 patients who developed Gram‐negative BSI among a cohort of 3367 SOT recipients who were prospectively followed at the Mayo Clinic (Rochester, MN) from January 1, 1996 to December 31, 2007. The highest incidence rate (IR) of Gram‐negative BSI was observed within the first month following SOT (210.3/1000 person‐years [95% confidence interval (CI): 159.3–268.3]), with a sharp decline to 25.7 (95% CI: 20.1–32.1) and 8.2 (95% CI: 6.7–10.0) per 1000 person‐years between 2 and 12 months and more than 12 months following SOT, respectively. Kidney recipients were more likely to develop Gram‐negative BSI after 12 months following transplantation than were liver recipients (10.3 [95% CI: 7.9–13.1] vs. 5.2 [95% CI: 3.1–7.8] per 1000 person‐years). The overall unadjusted 28‐day all‐cause mortality of Gram‐negative BSI was 4.9% and was lower in kidney than in liver recipients (1.6% vs. 13.2%, p < 0.001). We observed a linear trend of increasing resistance among Escherichia coli isolates to fluoroquinolone antibiotics from 0% to 44% (p = 0.002) throughout the study period. This increase in antimicrobial resistance may influence the choice of empiric therapy.