Human Cancer Genetics Programme

Human Genotyping-CEGEN Unit

Head of Unit:  Anna González-Neira
Research highlights
Two novel genes associated with anthracycline-induced cardiotoxicity

Anthracycline chemotherapeutic agents are widely used in the treatment of breast cancer; however, chronic anthracyclineinduced cardiotoxicity (AIC) is a serious long-term complication leading to substantial morbidity. Our aim was to identify new genes influencing the susceptibility to AIC. We studied the association of variants on the Illumina HumanExome BeadChip array in cancer anthracycline-treated patients. Through genebased tests (SKAT-O), which have greater statistical power to detect association with rare variation and that can evaluate the cumulative effect of multiple genetic variants, we identified novel significant associations for 2 genes: the first one, ETFB (electron transfer flavoprotein beta subunit) is involved in mitochondrial β-oxidation and ATP production (Ruiz Pinto et al., Breast Cancer Res Treat 2017), and the second one, GPR35 (G protein-coupled receptor 35), is a gene with potential roles in cardiac physiology and pathology (Ruiz Pinto et al., Pharmacogenet Genomics 2017). Further functional studies are currently being undertaken.

Genetic Factors underlying the risk of alopecia in patients treated with chemotherapy

Alopecia is a common toxicity of anticancer drugs and is considered by patients as being the second worst physical side-effect of chemotherapy, after nausea and vomiting. Alopecia associated with conventional doses of chemotherapy has traditionally been considered to be reversible in all cases upon cessation of therapy. However, the observation of some cases of alopecia that persists several years after the end of adjuvant chemotherapy has prompted us to identify genetic factors associated with the appearance of this toxicity in a cohort of cancer patients. We performed a GWAS (Genome Wide Association Study) involving patients suffering from this adverse drug reaction and patients without the toxicity; both were treated with the same drug and dose. We found several significant loci (P value <10-6) associated with the risk of developing alopecia. Currently we are replicating the most significant hits in an independent cohort of patients.

Identification of genetic variants associated with docetaxel and anthracycline efficacy

Docetaxel and anthracycline are widely used in the treatment of breast cancer, although the benefit is limited to only a small proportion of patients, and preoperative biomarkers predictive of clinical outcome remain lacking. We carried out a pharmacogenetic study in 181 patients with locally advanced breast cancer who were previously enrolled in a phase 2 randomised clinical trial (NCT00123929); a trial in which patients were randomly assigned to receive doxorubicin (anthracycline) or docetaxel (taxane) in neoadjuvant therapy. We assessed whether genetic variants in 15 key transport or metabolism genes relevant to doxorubicin and docetaxel drugs could play a role as predictive biomarkers. We identified a genetic variant located in the promoter of ABCC2, as the strongest association with tumour response observed in patients treated with doxorubicin (P=0.009). We also identified a significant association for an intronic variant located in CYP1B1 associated with docetaxel tumour response (P=2.15x10-4). Our integrated pathway-based approach enables the revealing of promising genetic biomarkers for treatment outcome in breast cancer patients (submitted for publication).