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

Whole genome sequencing (WGS) enables comprehensive molecular analysis of tumours and identification of hereditary cancer predisposition. According to the 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. Here we sought to determine the optimal strategy with high PGV yield and a low number-needed-to counsel (NTC). Therefore, we compared the PGV yield and NTC of three simulated strategies, using paired tumour-normal WGS data from 937 metastatic patients. In strategy-1 genetic counselling of all 937 patients prior to the WGS-tumour testing allowed direct PGV analysis using a tumour type-specific gene panel. In strategy-2 and -3, germline testing and referral for post-test genetic counselling is based on tumour variants using adjusted Dutch guidelines (strategy-2) or ESMO-Precision Medicine Working Group recommendations (strategy-3). In strategy-1, clinically relevant PGVs would be detected in 50 patients (NTC=18.7). In strategy-2, 86 patients would have been referred for genetic counselling and 43 would have clinically relevant PGVs (NTC=2). In strategy-3, 94 patients would have been referred for genetic counselling and 32 would have clinically relevant PGVs (NTC=2.9). Hence, in strategy-2 and -3, 43 and 62 patients, respectively, were unnecessarily referred based on a somatic variant, primarily in BRCA1/2, PALB2, MLH1, and MSH2/6 genes. Both post-tumour test counselling strategies (2 and 3) had significantly lower NTC compared to pre tumour test counselling (strategy-1). The adjusted Dutch guidelines had the highest PGV yield per NTC since it was also based on clinical criteria. Both post-tumour test counselling strategies could be improved by using a hybrid approach of directly analysing hereditary predisposition with counselling through mainstreaming for BRCA1/2, PALB2, MLH1, and MSH2/6 genes, along with tumour type specific strategies for other cancer predisposition genes. ### Competing Interest Statement KM reports research grants from AstraZeneca and speakers fees from MSD, Roche, AstraZeneca. and Benecke. KM received consultancy fees from Pfizer, BMS, Roche, MSD, Abbvie, AstraZeneca, Diaceutics, Lilly, Bayer, Boehringer Ingelheim and nonfinancial support from Roche, Takeda, Pfizer, PGDx and DELFi. EC reports consultancy fees and support for attending meetings and traveling from Illumina. EV is member of the supervisory board of Hartwig Medical Foundation. GM is cofounder and a board member (CSO) of CRCbioscreen BV, he has a research collaboration with CZ Health Insurances (cash matching to ZonMW grant) and he has research collaborations with Exact Sciences, Sysmex, Sentinel Ch. SpA, Personal Genome Diagnostics (PGDX), DELFi; these companies provide materials, equipment, and/or sample/genomic analyses. GM is an Advisory Board member of Missie Tumor Onbekend. RK, LS, NG, DB, MM, KS, ER, FH, PR, MB, LB, JB, MR, TW, and LK report no conflicts of interest. ### Funding Statement The Netherlands Organisation for Health Research and Care innovation (ZonMW, Project No. 446002004) and Hartwig Medical Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The WIDE study was performed in concordance with the Declaration of Helsinki, Dutch law, and Good Clinical Practice after approval by the Medical Ethical Committee of the Netherlands Cancer Institute (NKI) (NL68609.031.18). All included patients provided written consent for study participation. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript