Impact of genetic counselling strategy on diagnostic yield and workload for genome sequencing-based tumour diagnostics

Abstract

PurposeGenome sequencing (GS) enables comprehensive molecular analysis of tumours and identification of hereditary cancer predisposition. According to guidelines, directly determining pathogenic germline variants (PGVs) requires pre-test genetic counselling, which is cost-ineffective. Referral for genetic counselling based on tumour variants alone could miss relevant PGVs and/or result in unnecessary referrals. MethodsWe validated GS for detection of germline variants and simulated three strategies using paired tumour-normal genome sequencing data of 937 metastatic patients. In strategy-1 genetic counselling prior to tumour testing allowed direct PGV analysis. In strategy-2 and -3, germline testing and referral for post-test genetic counselling is based on tumour variants using Dutch (strategy-2) or ESMO-PMWG (strategy-3) guidelines. ResultsIn strategy-1, PGVs would be detected in 50 patients (number-needed-to counsel; NTC=18.7). In strategy-2, 86 patients would have been referred for genetic counselling and 43 would have PGVs (NTC=2). In strategy-3, 94 patients would have been referred for genetic counselling and 32 would have PGVs (NTC=2.9). Hence, 43 and 62 patients, respectively, were unnecessarily referred based on a somatic variant. ConclusionBoth post-tumour test counselling strategies (2 and 3) had significantly lower NTC, and strategy-2 had the highest PGV yield. Combining pre-tumour test mainstreaming and post-tumour test counselling may maximize the clinically relevant PGV yield and minimize unnecessary referrals.