Impact of tumour heterogeneity and tissue sampling for genetic mutation testing: a systematic review and post-hoc analysis.

Objective To identify guidelines to assist systematic reviewers or clinical researchers in identifying sampling bias due to tumour heterogeneity (TH) in solid cancers assayed for somatic mutations. We assessed current reporting standards to determine the impact of TH on sample bias. Study design We conducted a systematic review searching 13 databases (Jan-2019) to identify guidelines. A post-hoc analysis was performed using 12 prostate tumour somatic mutation datasets from a previous systematic review to assess reporting on TH. Results Searches identified 2085 records. No formal guidelines were identified. Forty publications contained incidental recommendations across five major themes: using multiple tumour samples (n=29), sample purity thresholds (n=14), using specific sequencing methods (n=8), using liquid biopsies (n=4), microdissection (n=4). In post-hoc analyses, 50% (6/12) clearly reported pathology methods. 42% (5/12) did not report pathology results. 42% (5/12) confirmed the pathology of the sample by direct diagnosis rather than inference. 42% (5/12) used multiple samples per patient. 58% (7/12) reported on tumour purity (range: 10% to 100%). Conclusions As precision medicine progresses to the clinic, guidelines are required to help evidence-based decision makers understand how TH may impact sample bias. Authors need to clearly report pathology methods and results, tumour purity methods and results.