We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer.

Multi-omics, variously called integrated omics, pan-omics, and trans-omics, aims to combine two or more omics data sets to aid in data analysis, visualization and interpretation to determine the mechanism of a biological process. Multi-omics efforts have taken center stage in biomedical research leading to the development of new insights into biological events and processes. However, the mushrooming of a myriad of tools, datasets, and approaches tends to inundate the literature and overwhelm researchers new to the field. The aims of this review are to provide an overview of the current state of the field, inform on available reliable resources, discuss the application of statistics and machine/deep learning in multi-omics analyses, discuss findable, accessible, interoperable, reusable (FAIR) research, and point to best practices in benchmarking. Thus, we provide guidance to interested users of the domain by addressing challenges of the underlying biology, giving an overview of the available toolset, addressing common pitfalls, and acknowledging current methods’ limitations. We conclude with practical advice and recommendations on software engineering and reproducibility practices to share a comprehensive awareness with new researchers in multi-omics for end-to-end workflow.

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage III/IV disease, driven by *