[3] mutational signatures

• 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.

• 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.