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Translational research (agnostic)

1673P - Exploring different strategies to incorporate germline analysis in tumor whole genome sequencing

Presentation Number
  • Roelof Koster (Amsterdam, Netherlands)
Sat, 10.09.2022



Whole genome sequencing of tumors is gaining momentum for patients with advanced cancer. Pathogenic germline variants (PGVs) are detectable in tumor analysis and can be important in guiding therapy selection, cancer type diagnosis and/or for follow-up/surveillance. Here, we discuss different strategies to incorporate germline analyses in WGS-based tumor diagnostics for metastatic cancer patients.


Anonymized analysis of 988 WIDE (WGS Implementation in standard cancer Diagnostics for Every cancer patient) cases was performed to assess the prevalence of PGVs in 49 selected cancer predisposition genes. Three scenarios of integrated germline analysis were analyzed and compared to all PGVs detected in the 49 genes: 1) PGVs are reported based on a tumor type-specific gene panel, 2) and 3) are tumor-based analysis with subsequent referral for germline testing based on: ESMO Precision Medicine Working Group (2) recommendations or Dutch guidelines (3).


92 PGVs in 24 different genes were detected in 90 unique patients (∼10% of all patients) across 20 different tumor types. Consequently, PGVs would also be detected in tumor types that are generally not referred for germline diagnostics. In scenario 1, 61 PGVs were detected with a 66% (59 of 90 pts) yield. The majority of unreported variants were tumor type-unspecific intermediate risk genes (CHEK2, ATM and MITF). Detection yields were lower in the tumor based scenarios 2 and 3. Based on the ESMO recommendation 36 of 92 PGVs would have been detected in 35 of 90 unique patients with a PGV present (39% yield). However, 58 additional patients without a PGV would have been referred for follow-up germline testing based on the presence of a somatic variant. Using national guidelines 44 of 92 PGVs would be detected in 43 patients of 90 unique patients with a PGV (48% yield). An additional 44 patients would be referred for germline analysis having a somatic variant as basis of their referral.


Adequate incorporation of germline DNA analysis holds the potential to identify clinically relevant PGVs. Ideally paired tumor/normal sequencing is performed for advanced cancer patients, enabling genome wide somatic analysis in combination with germline analysis using a tumor type-specific gene panel.

Legal entity responsible for the study

The authors.


The Netherlands Organisation for Health Research and Care innovation (ZonMW) and Hartwig Medical Foundation.


K. Monkhorst: Financial Interests, Institutional, Invited Speaker: AstraZeneca, MSD, Roche, Benecke; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Advisory Board: Pfizer, BMS, AbbVie, Diaceutics, Lilly, Bayer, Boehringer Ingelheim, Roche; Non-Financial Interests, Institutional, Other: Takeda, PGDx, Delfi. All other authors have declared no conflicts of interest.