The clinical utility and costs of whole-genome sequencing to detect cancer susceptibility variants-a multi-site prospective cohort study

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.

Keywords: Diagnostic testing; Familial cancer; Genetics; Health economics; Variants; Whole-genome sequencing.

Fig. 1

Scenarios used as the basis of the health economic analysis. Scenario 1: Standard testing; Scenario 2: standard testing followed by whole-genome sequencing (WGS); Scenario 3 upfront WGS. FCC—familial cancer centre; MDT—multi-disciplinary team meeting

Fig. 2

Schema of participant recruitment and approach to bioinformatics and curation. A Index case recruitment and enrolment acceptance. B Bioinformatics and variant identification approach. C Curation of prioritised variants. For detailed description of each step, see ‘Methods’. CNV—copy-number variant; indel—small insertions and deletions; LP—likely pathogenic; MDT—multidisciplinary team; P—pathogenic; SNV—single-nucleotide variant; SV—structural variant; VUS—variant of uncertain significance

Fig. 3

Variants identified within index cases. A The number and classification of variants discussed at the MDT meetings and returned to the treating clinician after the MDT meeting. Classifications: LP—likely pathogenic; P—pathogenic; VUS—variant of uncertain significance; VUS:A—available evidence is highly suggestive that the VUS variant is disease-causing; VUS:B—available evidence is insufficient to classify the VUS variant as either disease-causing or benign; and VUS:C—available evidence is highly suggestive that the VUS variant is likely benign. ^Two pathogenic PALB2 variants known to be common within the Australian population were reported directly to the relevant Familial Cancer Centre without a formal MDT meeting. B Post-MDT meeting classification of returned variants. C Type of returned variants. Types: CNV—copy-number variant; DNV—dinucleotide substitution; INDEL—small insertion or deletion; SNV—single-nucleotide variant; SV—structural variant; SV ± —structural variant with somatic origin. D Molecular consequence of returned variants. For panels B through D the number and type of variants (y-axis) is shown for each gene (x-axis)