Therapies targeting driver genes alterations in cancer have reduced treatment toxicities and improved patients’ survival. However, cancer cells develop drug resistance over time. This thesis investigates how the combined knowledge of constitutional genetic variation and tumor chromosomal aberrations may serve in the development of novel therapeutic approaches in cancer.

In Paper I we investigated loss of heterozygosity (LOH) at 22q13.2 chromosome which creates the bystander loss of CYP2D6, a polymorphic gene that has frequent inactivating variants. We show that loss of CYP2D6 activity can sensitize tumor cells to talazoparib and validated the finding in patient-derived organoid models.

Papers II, III and IV focused on exploiting chromosome 8p22 loss in the NAT2 locus for a novel therapeutical strategy in cancer.

In Paper II we aimed to quantitate the number of patients that potentially could benefit from NAT2 LOH-based therapy and develop a method for haplotyping and LOH testing. We estimated which heterozygous patients could be candidates for the therapy in case of NAT2*Rapid loss in their tumors. We demonstrated that multiplexed SMRT sequencing may serve as a suitable haplotyping and LOH resolution method.

In Paper III we identified novel compounds for LOH-based treatment where we found 6 novel NAT2 substrates and 43 candidates for validation studies. 

Paper IV assessed clinically approved cytotoxic compounds based on the cellular NAT2 status. We found that anthracycline antibiotics and HDAC inhibitors are more toxic to cells with rapid NAT2. Doxorubicin, daunorubicin, idarubicin and vorinostat were metabolised by NAT2, a metabolic conversion detected for the first time.

We performed target identification to uncover new potential LOH therapy targets in cancer in Paper V. By mining public databases and mapping prevalent alleles, 70 genes with constitutional variants potentially affecting their function, located in commonly lost chromosomal regions, were identified as potential target genes for therapy development.