Thrombocytosis portends adverse prognostic significance in patients with stage II colorectal carcinoma

Thrombocytosis portends adverse prognostic significance in many types of cancers including ovarian and lung carcinoma. In this study, we determined the prevalence and prognostic significance of thrombocytosis (defined as platelet count in excess of 400 × 10 3/μl) in patients with colorectal cancer. We performed a retrospective analysis of 310 consecutive patients diagnosed at our Institution between 2004 and 2013. The patients (48.7% male and 51.3% female) had a mean age of 69.9 years (+/- 12.7 years) at diagnosis. Thrombocytosis was found in a total of 25 patients, with a higher incidence in those with stage III and IV disease (14.4% of patients). Although the mean platelet count increased with the depth of tumor invasion (pT), its values remained within normal limits in the whole patient cohort. No patient with stage I cancer (n=57) had elevated platelet count at diagnosis. By contrast, five of the 78 patients (6.4%) with stage II cancer showed thrombocytosis, and four of these patients showed early recurrence and/or metastatic disease, resulting in shortened survival (they died within one year after surgery). The incidence of thrombocytosis increased to 12.2% and 20.6%, respectively, in patients with stage III and IV disease. The overall survival rate of patients with thrombocytosis was lower than those without thrombocytosis in the stage II and III disease groups, but this difference disappeared in patients with stage IV cancer who did poorly regardless of their platelet count. We concluded that thrombocytosis at diagnosis indicates adverse clinical outcome in colorectal cancer patients with stage II or III disease. This observation is especially intriguing in stage II patients because the clinical management of these patients is controversial. If our data are confirmed in larger studies, stage II colon cancer patients with thrombocytosis may be considered for adjuvant chemotherapy

Enhancement of the stability of genetic switches by overlapping upstream regulatory domains

We study genetic switches formed from pairs of mutually repressing operons. The switch stability is characterised by a well defined lifetime which grows sub-exponentially with the number of copies of the most-expressed transcription factor, in the regime accessible by our numerical simulations. The stability can be markedly enhanced by a suitable choice of overlap between the upstream regulatory domains. Our results suggest that robustness against biochemical noise can provide a selection pressure that drives operons, that regulate each other, together in the course of evolution.Comment: 4 pages, 5 figures, RevTeX

In silico prediction of tumor antigens derived from functional missense mutations of the cancer gene census

Antigen-specific immune responses against peptides derived from missense gene mutations have been identified in multiple cancers. The application of personalized peptide vaccines based on the tumor mutation repertoire of each cancer patient is a near-term clinical reality. These peptides can be identified for pre-validation by leveraging the results of massive gene sequencing efforts in cancer. In this study, we utilized NetMHC 3.2 to predict nanomolar peptide binding affinity to 57 human HLA-A and B alleles. All peptides were derived from 5,685 missense mutations in 312 genes annotated as functionally relevant in the Cancer Genome Project. Of the 26,672,189 potential 8–11 mer peptide-HLA pairs evaluated, 0.4% (127,800) display binding affinities < 50 nM, predicting high affinity interactions. These peptides can be segregated into two groups based on the binding affinity to HLA proteins relative to germline-encoded sequences: peptides for which both the mutant and wild-type forms are high affinity binders, and peptides for which only the mutant form is a high affinity binder. Current evidence directs the attention to mutations that increase HLA binding affinity, as compared with cognate wild-type peptide sequences, as these potentially are more relevant for vaccine development from a clinical perspective. Our analysis generated a database including all predicted HLA binding peptides and the corresponding change in binding affinity as a result of point mutations. Our study constitutes a broad foundation for the development of personalized peptide vaccines that hone-in on functionally relevant targets in multiple cancers in individuals with diverse HLA haplotypes

Correction of technical bias in clinical microarray data improves concordance with known biological information

The performance of gene expression microarrays has been well characterized using controlled reference samples, but the performance on clinical samples remains less clear. We identified sources of technical bias affecting many genes in concert, thus causing spurious correlations in clinical data sets and false associations between genes and clinical variables. We developed a method to correct for technical bias in clinical microarray data, which increased concordance with known biological relationships in multiple data sets

Intrinsic limitations of inverse inference in the pairwise Ising spin glass

We analyze the limits inherent to the inverse reconstruction of a pairwise Ising spin glass based on susceptibility propagation. We establish the conditions under which the susceptibility propagation algorithm is able to reconstruct the characteristics of the network given first- and second-order local observables, evaluate eventual errors due to various types of noise in the originally observed data, and discuss the scaling of the problem with the number of degrees of freedom

Modeling of negative autoregulated genetic networks in single cells

We discuss recent developments in the modeling of negative autoregulated genetic networks. In particular, we consider the temporal evolution of the population of mRNA and proteins in simple networks using rate equations. In the limit of low copy numbers, fluctuation effects become significant and more adequate modeling is then achieved using the master equation formalism. The analogy between regulatory gene networks and chemical reaction networks on dust grains in the interstellar medium is discussed. The analysis and simulation of complex reaction networks are also considered.Comment: 15 pages, 4 figures. Published in Gen

A Breast Cancer Meta-Analysis of Two Expression Measures of Chromosomal Instability Reveals a Relationship with Younger Age at Diagnosis and High Risk Histopathological Variables

Breast cancer in younger patients often presents with adverse histopathological features, including increased frequency of estrogen receptor negative and lymph node positive disease status. Chromosomal instability (CIN) is increasingly recognised as an important prognostic variable in solid tumours. In a breast cancer meta-analysis of 2423 patients we examine the relationship between clinicopathological parameters and two distinct chromosomal instability gene expression signatures in order to address whether younger age at diagnosis is associated with increased tumour genome instability. We find that CIN, assessed by the two independently derived CIN expression signatures, is significantly associated with increased tumour size, ER negative or HER2 positive disease, higher tumour grade and younger age at diagnosis in ER negative breast cancer. These data support the hypothesis that chromosomal instability may be a defining feature of breast cancer biology and clinical outcome

The Genome of the Chicken DT40 Bursal Lymphoma Cell Line

The chicken DT40 cell line is a widely used model system in the study of multiple cellular processes due to the efficiency of homologous gene targeting. The cell line was derived from a bursal lymphoma induced by avian leukosis virus infection. In this study we characterized the genome of the cell line using whole genome shotgun sequencing and single nucleotide polymorphism array hybridization. The results indicate that wild-type DT40 has a relatively normal karyotype, except for whole chromosome copy number gains, and no karyotype variability within stocks. In a comparison to two domestic chicken genomes and the Gallus gallus reference genome, we found no unique mutational processes shaping the DT40 genome except for a mild increase in insertion and deletion events, particularly deletions at tandem repeats. We mapped coding sequence mutations that are unique to the DT40 genome; mutations inactivating the PIK3R1 and ATRX genes likely contributed to the oncogenic transformation. In addition to a known avian leukosis virus integration in the MYC gene, we detected further integration sites that are likely to de-regulate gene expression. The new findings support the hypothesis that DT40 is a typical transformed cell line with a relatively intact genome; therefore, it is well-suited to the role of a model system for DNA repair and related processes. The sequence data generated by this study, including a searchable de novo genome assembly and annotated lists of mutated genes, will support future research using this cell line