• Mutational signatures are markers of drug sensitivity of cancer cells. J Levatic, M Salvadores, F Fuster, F Supek (2022) Nature Communications.  

We identify robust associations between certain mutational signatures and drug activity across cancer cell line panels; these are as numerous as associations with driver gene alterations. Signatures of prior exposures to DNA damaging agents associate with resistance, while deficient DNA repair tends to sensitize to therapeutics.

• Loss of the abasic site sensor HMCES is synthetic lethal with the activity of the APOBEC3A cytosine deaminase in cancer cells. J Biayna, I Garcia-Cao, [...] F Supek*, T Stracker* (2021) PLOS Biology.  

We propose HMCES, a protein linked to the protection of abasic sites, as a central protein for the tolerance of A3A expression. HMCES depletion results in synthetic lethality with A3A expression preferentially in a TP53-mutant background. Our results suggest that HMCES is an attractive target for selective treatment of A3A-expressing tumors.

• Copy number losses of oncogenes and gains of tumor suppressor genes generate common driver mutations. E Besedina, F Supek (2024) Nature Communications.  

oncogenes may simultaneously exhibit signatures of positive selection and also negative selection in different gene segments. | We reveal a general trend of increased positive selection on oncogene mutations not only upon CNA gains but also upon CNA deletions. | Similarly, we observe a surprising positive interaction between mutations and CNA gains in tumor suppressor genes. 

• The impact of rare germline variants on human somatic mutation processes. M Vali-Pour, [...], B Lehner*, F Supek* (2022) Nature Communications.  

Rates and types of somatic mutation vary across individuals, but few inherited influences thereon are known. We perform a gene-based rare variant association study with diverse mutational processes, using ~11k cancer genomes, to identify 42 genes causal to 15 somatic mutational phenotypes incl. HR and MMR deficiencies.

• Passenger mutations accurately classify human tumors. M Salvadores, D Mas-Ponte, F Supek (2019) PLOS Comp Biol.  

Density of somatic mutations across chromosomal domains is a mutational phenotype that can differentiate human tissues // Driver mutations are poor classifiers of cancer (sub)type, while passenger mutation-based phenotypes are highly predictive // Trinucleotide signatures and regional mutation density phenotypes are complementary in classifying tumors.

• Whole genome DNA sequencing provides an atlas of somatic mutagenesis in healthy human cells and identifies a tumor-prone cell type. I Franco, H Helgadottir, … D Mas-Ponte, …., F Supek & M Eriksson (2019) Genome Biology.

Multiple cell types from diverse healthy somatic tissues usually display a stereotyped mutation profile. However, the same tissue can sometimes harbor cells with distinct mutation profiles associated to different differentiation states. For example, we identify a cell type in the kidney with unusual mutation rate increase in active chromatin.