Mutational processes of tobacco smoking and APOBEC activity generate protein-truncating mutations in cancer genomes.

Mutational signatures represent a genomic footprint of endogenous and exogenous mutational processes through tumor evolution. However, their functional impact on the proteome remains incompletely understood. We analyzed the protein-coding impact of single-base substitution (SBS) signatures in 12,341 cancer genomes from 18 cancer types. Stop-gain mutations (SGMs) (i.e., nonsense mutations) were strongly enriched in SBS signatures of tobacco smoking, APOBEC cytidine deaminases, and reactive oxygen species. These mutational processes alter specific trinucleotide contexts and thereby substitute serines and glutamic acids with stop codons. SGMs frequently affect cancer hallmark pathways and tumor suppressors such as TP53, FAT1, and APC. Tobacco-driven SGMs in lung cancer correlate with smoking history and highlight a preventable determinant of these harmful mutations. APOBEC-driven SGMs are enriched in YTCA motifs and associate with APOBEC3A expression. Our study exposes SGM expansion as a genetic mechanism by which endogenous and carcinogenic mutational processes directly contribute to protein loss of function, oncogenesis, and tumor heterogeneity.

In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer.

How the genetic landscape governs a tumor's response to immunotherapy remains poorly understood. To assess the immune-modulatory capabilities of 573 genes associated with altered cytotoxicity in human cancers, here we perform CRISPR/Cas9 screens directly in mouse lung cancer models. We recover the known immune evasion factors Stat1 and Serpinb9 and identify the cancer testis antigen Adam2 as an immune modulator, whose expression is induced by KrasG12D and further elevated by immunotherapy. Using loss- and gain-of-function experiments, we show that ADAM2 functions as an oncogene by restraining interferon and TNF cytokine signaling causing reduced presentation of tumor-associated antigens. ADAM2 also restricts expression of the immune checkpoint inhibitors PDL1, LAG3, TIGIT and TIM3 in the tumor microenvironment, which might explain why ex vivo expanded and adoptively transferred cytotoxic T-cells show enhanced cytotoxic efficacy in ADAM2 overexpressing tumors. Together, direct in vivo CRISPR/Cas9 screens can uncover genetic alterations that control responses to immunotherapies.

Exome-wide tandem repeats confer large effects on subcortical volumes in UK Biobank participants.

The human subcortex is involved in memory and cognition. Structural and functional changes in subcortical regions is implicated in psychiatric conditions. We performed an association study of subcortical volumes using 15,941 tandem repeats (TRs) derived from whole exome sequencing (WES) data in 16,527 unrelated European ancestry participants. We identified 17 loci, most of which were associated with accumbens volume, and nine of which had fine-mapping probability supporting their causal effect on subcortical volume independent of surrounding variation. The most significant association involved NTN1 -[GCGG] N and increased accumbens volume (ß=5.93, P=8.16x10 -9 ). Three exonic TRs had large effects on thalamus volume ( LAT2 -[CATC] N ß=-949, P=3.84x10 -6 and SLC39A4 -[CAG] N ß=-1599, P=2.42x10 -8 ) and pallidum volume ( MCM2 -[AGG] N ß=-404.9, P=147x10 -7 ). These genetic effects were consistent measurements of per-repeat expansion/contraction effects on organism fitness. With 3-dimensional modeling, we reinforced these effects to show that the expanded and contracted LAT2 -[CATC] N repeat causes a frameshift mutation that prevents appropriate protein folding. These TRs also exhibited independent effects on several psychiatric symptoms, including LAT2 -[CATC] N and the tiredness/low energy symptom of depression (ß=0.340, P=0.003). These findings link genetic variation to tractable biology in the brain and relevant psychiatric symptoms. We also chart one pathway for TR prioritization in future complex trait genetic studies.