Whole-Genome Sequencing Finds Actionable Cancer Variants in 15% of Patients Where Standard Testing Failed
In a multi-center prospective study of 195 cancer patients for whom conventional genetic testing was uninformative, germline whole-genome sequencing with virtual gene panel analysis identified pathogenic variants consistent with the presenting cancer in 5.1% and secondary actionable findings in another 9.7%. Health economic modeling showed that upfront WGS was nearly three times more cost-effective per actionable case than sequential standard-then-WGS testing. The results support replacing conventional genetic testing with WGS for hereditary cancer evaluation, though national-scale adoption would require substantial investment.
The original study
The clinical utility and costs of whole-genome sequencing to detect cancer susceptibility variants-a multi-site prospective cohort study.
- Authors
- Davidson AL, Dressel U, Norris S, Canson DM, Glubb DM, Fortuno C, et al.
- Journal
- Genome medicine
- Type
- Multicenter Study, Journal Article, Research Support, Non-U.S. Gov't
- PMID
- 37723522
Original abstract
BACKGROUND: Many families and individuals do not meet criteria for a known hereditary cancer syndrome but display unusual clusters of cancers. These families may carry pathogenic variants in cancer predisposition genes and be at higher risk for developing cancer. METHODS: This multi-centre prospective study recruited 195 cancer-affected participants suspected to have a hereditary cancer syndrome for whom previous clinical targeted genetic testing was either not informative or not available. To identify pathogenic disease-causing variants explaining participant presentation, germline whole-genome sequencing (WGS) and a comprehensive cancer virtual gene panel analysis were undertaken. RESULTS: Pathogenic variants consistent with the presenting cancer(s) were identified in 5.1% (10/195) of participants and pathogenic variants considered secondary findings with potential risk management implications were identified in another 9.7% (19/195) of participants. Health economic analysis estimated the marginal cost per case with an actionable variant was significantly lower for upfront WGS with virtual panel ($8744AUD) compared to standard testing followed by WGS ($24,894AUD). Financial analysis suggests that national adoption of diagnostic WGS testing would require a ninefold increase in government annual expenditure compared to conventional testing. CONCLUSIONS: These findings make a case for replacing conventional testing with WGS to deliver clinically important benefits for cancer patients and families. The uptake of such an approach will depend on the perspectives of different payers on affordability.