Clinically relevant biomarkers are useful to determine cancer patients' prognosis and treatments. To discover new putative biomarkers, we performed in silico analysis of a 325-gene panel previously ...associated with breast epithelial cell biology and clinical outcomes. Sixteen public datasets of microarray samples representing 8 cancer types and a total of 3,663 patients' samples were used for the analyses. Feature selection was used to identify the best subsets of the 325 genes for each classification, and linear discriminant analysis was used to quantify the accuracy of the classifications. A subset of 102 of the 325 genes were found to be housekeeping (HK) genes, and the classifications were repeated using only the 102 HK subset. The 325-gene panel and 102 HK subset were able to distinguish colon, gastric, lung, ovarian, pancreatic, and prostate tumors and leukemia from normal adjacent tissue, and classify disease subtypes of breast and lung cancers and leukemia with 70% or higher accuracy. HK genes have been overlooked as potential biomarkers due to their relative stability. This study describes a set of HK genes as putative biomarkers applicable to multiple cancer types worth following in subsequent validation studies.
Summary
Background
Patients with Crohn's disease (CD) have serologic responses to various microbial antigens. Serologic markers are associated with aggressive forms of disease and can be detected ...before onset of symptoms. Their utility in pre‐clinical disease or prediction of complicated disease course before diagnosis is unclear.
Aim
To evaluate the pattern of serologic anti‐microbial antibodies long prior to diagnosis and the subsequent risk of complicated Crohn's disease at diagnosis.
Methods
Sera from 100 US military personnel with Crohn's disease were obtained from the Department of Defense Serum Repository. For each patient, four samples were obtained at different time points before and around diagnosis, and were tested for 6 microbiota‐directed antibodies (ASCA‐IgA, ASCA‐IgG, anti‐OmpC, anti‐CBir1, anti‐A4‐Fla2 and anti‐FlaX). Associations between the presence and accumulation of Crohn's disease anti‐microbial antibodies before diagnosis and with the later development of complications were evaluated.
Results
Overall, 65 patients were positive for at least one Crohn's disease associated anti‐microbial antibody in the earliest available sample, at a median of 6 years before Crohn's disease diagnosis (interquartile range, 5.6–8.2). The number of positive anti‐microbial antibodies increased up to the time of Crohn's disease diagnosis. Complicated disease developed around the time of diagnosis in 24 patients. The proportion of positive antimicrobial antibodies before diagnosis was higher in patients with complicated vs. noncomplicated Crohn's disease. There was an inverse relationship between the time to first complication and the magnitude of serologic response before diagnosis.
Conclusion
The presence and accumulation of circulating anti‐microbial antibodies years before Crohn's disease diagnosis was associated with complicated Crohn's disease at or shortly after diagnosis.
The decision tree method for classification problems has been extended to accommodate multiple dependent properties. When applied to drug discovery efforts this means a separate activity class can be ...predicted for each of several targets with a single tree model. A new tree representation and growth procedure, PUMP-RP, has been developed. The final architecture of the tree allows for easy interpretation as to which independent variables and split values are important for all targets and which are specific to a given target. It should thus be usefully applied to studies of drug specificity. A side benefit of the new method is that it can make use of data with missing (or even sparse) dependent property values. This has the potential to leverage copious data from an older, well-studied target while beginning to study a newer target for which only a small amount of data are available.
We have carried out partially unified multiple property recursive partitioning (PUMP-RP) analyses on a database of cyclooxygenase (COX) inhibitors, using CART methods implemented in Cerius2. Three ...sets of physicochemical descriptors (ISIS public keys, DAYLIGHT Fingerprints, and Cerius2) were computed for the database molecules which were divided into two groups, assigned as training (89%) and test (11%selected using diversity analyses tools in Cerius2) sets. The descriptors which led to the discrimination of active and selective COX-2 inhibitors included ISIS Key #59 (Snot%A%A), Balaban electrotopological index JY, partition coefficient AlogP, and Jurs surface area descriptors (FNSA, FPSA, and PPSA). A strong correlation is obtained between the predicted and experimental COX-2 inhibitory activity and a moderate correlation for selectivity of the COX-2 inhibitors, both in the training and test sets. Application of the RP trees to a validation set of Merck cyclooxygenase inhibitors shows good consistency with the COX-1 and COX-2 activity data, albeit moderate consistency with the selectivity data. Compared to the independent RP models (obtained by considering each activity separately), the PUMP-RP decision trees provide easier identification and interpretation of those descriptors that are common to both COX-1 and COX-2 activities. Similarly, they are easier to distinguish the descriptors that discriminate the two activities. The study represents a preliminary validation of the PUMP-RP method described in the previous article of this issue.
Multiple large-scale genomic profiling efforts have been undertaken in osteosarcoma to define the genomic drivers of tumorigenesis, therapeutic response, and disease recurrence. The spatial and ...temporal intratumor heterogeneity could also play a role in promoting tumor growth and treatment resistance. We conducted longitudinal whole-genome sequencing of 37 tumor samples from 8 patients with relapsed or refractory osteosarcoma. Each patient had at least one sample from a primary site and a metastatic or relapse site. Subclonal copy-number alterations were identified in all patients except one. In 5 patients, subclones from the primary tumor emerged and dominated at subsequent relapses. MYC gain/amplification was enriched in the treatment-resistant clones in 6 of 7 patients with multiple clones. Amplifications in other potential driver genes, such as CCNE1, RAD21, VEGFA, and IGF1R, were also observed in the resistant copy-number clones. A chromosomal duplication timing analysis revealed that complex genomic rearrangements typically occurred prior to diagnosis, supporting a macroevolutionary model of evolution, where a large number of genomic aberrations are acquired over a short period of time followed by clonal selection, as opposed to ongoing evolution. A mutational signature analysis of recurrent tumors revealed that homologous repair deficiency (HRD)-related SBS3 increases at each time point in patients with recurrent disease, suggesting that HRD continues to be an active mutagenic process after diagnosis. Overall, by examining the clonal relationships between temporally and spatially separated samples from patients with relapsed/refractory osteosarcoma, this study sheds light on the intratumor heterogeneity and potential drivers of treatment resistance in this disease.
The chemoresistant population in recurrent osteosarcoma is subclonal at diagnosis, emerges at the time of primary resection due to selective pressure from neoadjuvant chemotherapy, and is characterized by unique oncogenic amplifications.
PDF
