edited and revised the manuscript. Tomas Kirchhoff led the project. All authors have read and approved the final version of the manuscript. Ethical approval and ethical standards Written informed consents for the use of the blood specimens and clinical information were obtained at the time of enrollment from all participants and the study was approved by the Institutional Review Board (IRB) at all institutions

An array-based genotyping approach has been the standard practice for genome-wide association studies (GWASs); however, as sequencing costs plummet over the past years, ultra low-coverage whole-genome sequencing (ulcWGS <0.5× coverage) has emerged as a promising alternative that provides superior genomic coverage with substantial reduction of genotyping cost. To evaluate the potential utility of ulcWGS, we performed a whole-genome sequencing (WGS) of 72 European individuals to a target coverage of 0.4× and compared its performance with the widely used Infinium Global Screening Multi-Disease Array (GSA-MD). We showed that the number of variants captured by ulcWGS is comparable with imputed GSA-MD platform, particularly for low-frequency (95.5%) and common variants (99.9%), with high imputation R2 accuracy (mean 0.93 for SNPs and 0.86 for indels). Using deep-coverage 30× WGS as the “truth” genotypes, we found that ulcWGS has higher overall nonreference genotype concordance compared with imputed GSA-MD for both SNPs (0.90 vs. 0.88) and indels (0.86 vs. 0.83). In addition, ulcWGS proved to be as sensitive as the genotyping-based method in sex imputation and ancestry prediction producing similar principal component (PC) scores. Our findings provide important evidence that the cost efficient ulcWGS of <0.5× generates high genotype accuracy, outperforming the standard genotyping arrays, making it an attractive alternative to the array-based method in next-generation GWAS design.

In immuno-oncology (IO), the baseline host factors attract significant clinical interest as promising predictive biomarker candidates. Growing evidence from experimental or population-based studies suggests that the host genetic factors contribute to the immunological status of a patient as it plays out at the multiple rate-limiting steps of the cancer immunity cycle. Recent observations suggest that germline genetics may be associated with tumor microenvironment phenotypes, autoimmune toxicities and/or efficacy of immunotherapy regimens and overall cancer survival. Despite these highly intriguing indications, the potential of germline genetic factors as personalized biomarkers of immune-checkpoint inhibition (ICI) remains vastly unexplored. Here, we review the rationale for exploring the germline genetic factors as novel biomarkers predictive of IO outcomes, including ICI efficacy, toxicity and survival, and discuss the comprehensive approaches for the identification of such germline genetic indicators. In addressing the current limitations, we highlight a need for large collaborative consortia in these efforts. We also outline possible avenues for incorporating germline genetic factors into emerging multifactorial tools for a more personalized prediction of ICI outcomes.