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Patient sex influences a wide range of cancer phenotypes, including prevalence, response to therapy and survival endpoints. Molecular sex differences across the central dogma have been identified that may drive these phenotypic differences. Despite a growing catalog of specific genomic, transcriptomic and proteomic sex differences in a range of cancer types, their functional consequences remain unclear. To assess how patient sex impacts cancer cell function, we evaluated 1,209 cell lines subjected to CRISPR knockout, RNAi knockdown or drug exposures. Despite limited statistical power, we identified pan- and per-cancer sex differences in gene essentiality in six sex-linked and fourteen autosomal genes, and in drug sensitivity for two compounds. These data expand our understanding of the propagation of sex-differing molecular features to functional outcomes, and their role in influencing patient phenotypes. They highlight the importance of considering sex-specific effects in mechanistic and functional studies., Competing Interests: Completing Interests P.C.B. sits on the Scientific Advisory Boards of BioSymetrics Inc and Intersect Diagnostics Inc., and formerly sat on that of Sage Bionetworks.

Summary: DNA sequencing continues to get cheaper and faster. In parallel, algorithmic innovations have allowed inference of a wide range of nuclear, mitochondrial, somatic and evolutionary from DNA sequencing data. To make automated, high-quality DNA sequencing more readily available, we created an extensible Nextflow meta-pipeline called metapipeline-DNA. Metapipeline-DNA supports processing raw sequencing reads through alignment, variant detection, quality control and subclonal reconstruction. Each step supports quality-control, data-visualization and multiple algorithms. Metapipeline-DNA is cloud-compatible and highly configurable, with options to subsect, optimize and optimize analyses, including with automated failure-recovery. Metapipeline-DNA enables high-scale, fault-tolerant, comprehensive analysis of genome sequencing., Availability: Metapipeline-DNA is an open-source Nextflow pipeline under the GPLv2 license and is available at https://github.com/uclahs-cds/metapipeline-DNA., Competing Interests: Conflict of Interest Statement PCB sits on the Scientific Advisory Boards of Intersect Diagnostics Inc., BioSymetrics Inc. and previously sat on that of Sage Bionetworks. All other authors have no conflicts of interest to declare.

Reference genomes are foundational to modern genomics. Our growing understanding of genome structure leads to continual improvements in reference genomes and new genome "builds" with incompatible coordinate systems. We quantified the impact of genome build on germline and somatic variant calling by analyzing tumour-normal whole-genome pairs against the two most widely used human genome builds. The average individual had a build-discordance of 3.8% for germline SNPs, 8.6% for germline SVs, 25.9% for somatic SNVs and 49.6% for somatic SVs. Build-discordant variants are not simply false-positives: 47% were verified by targeted resequencing. Build-discordant variants were associated with specific genomic and technical features in variant- and algorithm-specific patterns. We leveraged these patterns to create StableLift, an algorithm that predicts cross-build stability with AUROCs of 0.934 ± 0.029. These results call for significant caution in cross-build analyses and for use of StableLift as a computationally efficient solution to mitigate inter-build artifacts., Competing Interests: Conflicts of Interest PCB sits on the Scientific Advisory Boards of Intersect Diagnostics Inc., BioSymetrics Inc. and previously sat on that of Sage Bionetworks. All other authors declare no conflicts of interest.