Clinically actionable cancer and non-cancer risk genes identified by whole genome sequencing (WGS) in early-onset tumours (EOT).

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Background: The global incidence of EOT (≤40 years) is increasing, with no clear explanation. The short interval between environmental or lifestyle exposures and tumour development suggests these factors alone are insufficient. Monogenic germline predisposition is frequently associated with EOT and may influence survivorship and family planning. However, many individuals with EOT do not meet current criteria for germline testing. In Australia, excess mortality among EOT survivors is partly attributable to non-cancer causes, particularly cardiovascular disease. We performed WGS in an unselected Australian EOT cohort to assess the prevalence of clinically actionable cancer predisposition genes (CPGs) and non-cancer genes (NCGs). Methods: Individuals diagnosed with a tumour at ≤40 years were eligible. Family pedigrees were collected. WGS was performed on germline DNA (preferentially blood). Analysis included 70 CPGs and 54 ACMG-designated actionable NCGs. Only autosomal dominant and biallelic recessive deleterious variants were reported. Results: Among 1865 participants (1090 female, 58%), 337 (18%) had multiple primary tumours (MPTs). Compared to those without MPTs, individuals with MPTs were more likely to be female (66% vs 57%, P=0.002), have a first-degree relative (FDR) with cancer (66% vs 38%, P<0.0001), and have MPTs in a FDR (18% vs 5%, P<0.0001). WGS data were available for 1565 participants (905 female, 58%). Deleterious variants in CPGs were identified in 187 (12%; 198 variants) individuals, with a higher detection rate in those with MPTs (20% vs 10%, P<0.0001). Actionable NCG variants were identified in 64 individuals (4%; 65 variants); 53 (3%) harboured 54 variants associated with increased cardiovascular disease risk. Conclusions: Monogenic predisposition does not adequately explain EOTs. Individuals with MPTs are more likely to carry deleterious variants in CPGs. In addition to germline findings, family history may help identify those at increased risk of second malignancies. Identification of actionable NCG variants, including cardiovascular risk genes, may guide integrated longitudinal management during treatment and survivorship.