Identification of QTL associated with cardiotoxicity due to anthracyclines and taxanes and DNA damage response

Introduction: Anthracyclines are among the most widely used chemotherapeutic agents in the treatment of a variety of tumours. The identification of genetic and molecular factors responsible for the increased risk of CDA (cardiotoxicity due to anthracyclines) will contribute to a better understanding of their pathophysiology. This, in turn, could lead to new approaches to predict, prevent, and treat this serious complication of chemotherapy.

WORKING HYPOTHESIS: Based on two premises: (i) anthracyclines have a pro-genotoxicity effect. Differences in anti-genotoxicity pathways and genetic variants could contribute to different susceptibility to CDA. (ii) Simplified model system to identify genetic determinants involved in the quantitative inheritance of complex traits.

Materials and methods: In this study, a cohort of mice carrying ERBB2 breast cancer are treated with doxorubicin alone (N = 85) or in combination with docetaxel (N = 77). The cohort was generated by a backcross between two genetically homogeneous strains, C57BL / 6 and FVB, with the latter carrying the transgene ErbB2 / Neu, under the mammary mouse tumour virus (MMTV) promoter. Histopathological heart damage was assessed using the Ariol™ system. Measurements were made of the cardiac levels of some key proteins involved in the pathways protecting against genotoxicity: total ATR, pp53 (Ser15), Total P21, Total MDM2, pHistone H2AX (Ser139), pCHK1 (Ser345), and pCHK2 (Thr68).

Results: Identification was made of: (i) differences dependent on the genetic background in both cardiotoxicity and the levels of proteins implicated in the pathways protecting against genotoxicity; (ii) levels of anti-genotoxicity pathways were associated with chemotherapy cardiotoxicity; (iii) quantitative trait loci (QTLs) specific and common to cardiotoxicity, and the levels of the pathways studied.

Conclusion: Genetic determinants associated with anthracycline cardiotoxicity have been identified using components of the anti-genotoxic pathways as sub-phenotypes. Crosses of syngeneic mouse strains are useful in these studies, but require further validation in the human population.