Unraveling heterogeneous susceptibility and the evolution of breast cancer using a systems biology approach

Abstract

BackgroundAn essential question in cancer is why individuals with the same disease have different clinical outcomes. Progress toward a more personalized medicine in cancer patients requires taking into account the underlying heterogeneity at different molecular levels.ResultsHere, we present a model in which there are complex interactions at different cellular and systemic levels that account for the heterogeneity of susceptibility to and evolution of ERBB2-positive breast cancers. Our model is based on our analyses of a cohort of mice that are characterized by heterogeneous susceptibility to ERBB2-positive breast cancers. Our analysis reveals that there are similarities between ERBB2 tumors in humans and those of backcross mice at clinical, genomic, expression, and signaling levels. We also show that mice that have tumors with intrinsically high levels of active AKT and ERK are more resistant to tumor metastasis. Our findings suggest for the first time that a site-specific phosphorylation at the serine 473 residue of AKT1 modifies the capacity for tumors to disseminate. Finally, we present two predictive models that can explain the heterogeneous behavior of the disease in the mouse population when we consider simultaneously certain genetic markers, liver cell signaling and serum biomarkers that are identified before the onset of the disease.ConclusionsConsidering simultaneously tumor pathophenotypes and several molecular levels, we show the heterogeneous behavior of ERBB2-positive breast cancer in terms of disease progression. This and similar studies should help to better understand disease variability in patient populations.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0599-z) contains supplementary material, which is available to authorized users.

Clinicopathogenomic analysis of mismatch repair proficient colorectal adenocarcinoma uncovers novel prognostic subgroups with differing patterns of genetic evolution

“…Establishing the temporal relationships between mutations has been accomplished in some tumor types by utilizing multiregion sequencing. These studies have yielded compelling phylogenetic trees showing branched evolution of the tumor cell populations . However, these studies use a limited number of specimens making the findings difficult to generalize, especially to other tumor types.…”

Missing heritability of complex diseases: Enlightenment by genetic variants from intermediate phenotypes

“…We identified QTLs associated with the heterogeneous behavior of the different pathophenotypes of the disease, and QTLs associated with the variability of the different intermediate phenotypes studied. After carrying out this study, we observed that most of the tumor QTLs associated with different pathophenotypes did not overlap with the QTLs associated with intermediate phenotypes, even with those that could be expected to be strongly associated with tumor variability, such as those related with tumor cell signaling . Thus, an intermediate phenotype associated with the pathogenesis of a complex trait, in turn presents its own variability along the population, and is also controlled by a number of QTLs that seem to be different.…”

“…such as those related with tumor cell signaling [76]. Thus, an intermediate phenotype associated with the pathogenesis of a complex trait, in turn presents its own variability along the population, and is also controlled by a number of QTLs that seem to be different.…”

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“…Some of the specific signalling molecules from pathways related to metabolism were measured in liver tissue [22] (see material and methods in Data in Brief [20]).…”