Table 1.

Current challenges and opportunities for further study in understanding how germline variants play a role in shaping the outcome of patients with cancer.

Category	Challenge	Explanation	Possible Solutions
Cancer Risk, Cancer Progression, and General Problems of Germline Variant Cancer Genomics	Cohort Size	Common variants typically have low effect sizes whereas variants with large effect sizes are often rare, thus requiring large cohorts	Building Large Cohorts or Tests Involving Groups of Variants
	Integration with Clinical Phenotypes	Datasets in genomics often have minimal clinical annotation	Building datasets with more detailed clinical annotation
	Effect Sizes	The effect sizes of individual germline variants must be large to motivate clinical use	Building models with combinations of variants and incorporating variants with large effect sizes, such as pathogenic germline variants
	Ethnicity Background	Effects of germline variants may differ based on ethnicity	Perform analyses in ethnically diverse cohorts
Germline-Somatic Interactions	Understanding the molecular basis for the interaction	Associations may be the result of several complex and indirect associations.	Network based computational approaches or experimental perturbation
	Context Dependency	Interactions may be dependent on specific environmental exposures or may occur in certain genetic backgrounds	Building datasets with more detailed clinical annotation of environmental exposures and performing studies in ethnically diverse cohorts
Drug Responsiveness and Toxicity	Differing Treatment Regimens or Differing Dosages	Patients with the same cancer treated with chemotherapy may undergo different treatment regimens or may be treated with different dosages of chemotherapy drugs	Report detailed treatment information when building genomic datasets and experimental perturbation