Efficient Parameter Estimation Enables the Prediction of Drug Response Using a Mechanistic Pan-Cancer Pathway Model.

Mechanistic models are essential to deepen the understanding of complex diseases at the molecular level. Nowadays, high-throughput molecular and phenotypic characterizations are possible, but the integration of such data with prior knowledge on signaling pathways is limited by the availability of scalable computational methods. Here, we present a computational framework for the parameterization of large-scale mechanistic models and its application to the prediction of drug response of cancer cell lines from exome and transcriptome sequencing data.

Genotype-phenotype correlations in patients with retinoblastoma and interstitial 13q deletions.

Patients with an interstitial 13q deletion that contains the RB1 gene show retinoblastoma and variable clinical features. Relationship between phenotypic expression and loss of specific neighboring genes are unresolved, yet. We obtained clinical, cytogenetic and molecular data in 63 patients with an interstitial 13q deletion involving RB1.

AML/MDS with 11q/MLL amplification show characteristic gene expression signature and interplay of DNA copy number changes.

AML/MDS patients carrying 11q amplifications involving the mixed lineage leukemia gene (MLL) locus are characterized by a complex aberrant karyotype (CAK) frequently including deletions within 5q, 17p, and 7q, older age and fast progression of the disease with extremely poor prognosis. MLL has been shown to be overexpressed in cases with 11q amplification. However, in most of the cases, the amplified region is not restricted to the MLL locus.

An integrative approach for analyzing the interplay of genetic and epigenetic changes in tumors.

The accumulation of chromosomal aberrations is a characteristic feature of tumor development. However, an understanding of tumorigenesis that assumes that changes in DNA copy number always cause equivalent changes in the corresponding RNA and protein levels is an oversimplification and completely ignores the individual genetic and epigenetic context in which an aberration has to be evaluated. We present a brief introduction to various techniques dedicated to the genome-wide analysis of genetic and epigenetic changes, and illustrate how complementary information derived from these various DNA array-based technologies can lead to a better understanding of the consequences of chromosomal aberrations.