Dataset Information

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.

SUBMITTER: Davidson AL

PROVIDER: S-EPMC10507925 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Publications

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

Davidson Aimee L AL Dressel Uwe U Norris Sarah S Canson Daffodil M DM Glubb Dylan M DM Fortuno Cristina C Hollway Georgina E GE Parsons Michael T MT Vidgen Miranda E ME Holmes Oliver O Koufariotis Lambros T LT Lakis Vanessa V Leonard Conrad C Wood Scott S Xu Qinying Q McCart Reed Amy E AE Pickett Hilda A HA Al-Shinnag Mohammad K MK Austin Rachel L RL Burke Jo J Cops Elisa J EJ Nichols Cassandra B CB Goodwin Annabel A Harris Marion T MT Higgins Megan J MJ Ip Emilia L EL Kiraly-Borri Catherine C Lau Chiyan C Mansour Julia L JL Millward Michael W MW Monnik Melissa J MJ Pachter Nicholas S NS Ragunathan Abiramy A Susman Rachel D RD Townshend Sharron L SL Trainer Alison H AH Troth Simon L SL Tucker Katherine M KM Wallis Mathew J MJ Walsh Maie M Williams Rachel A RA Winship Ingrid M IM Newell Felicity F Tudini Emma E Pearson John V JV Poplawski Nicola K NK Mar Fan Helen G HG James Paul A PA Spurdle Amanda B AB Waddell Nicola N Ward Robyn L RL

Genome medicine 20230919 1

<h4>Background</h4>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.<h4>Methods</h4>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 av ...[more]

PMID: 37723522

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Project description:Background Dilated cardiomyopathy may be heritable but shows extensive genetic heterogeneity. The utility of whole exome sequencing as a first-line genetic test for patients with dilated cardiomyopathy in a contemporary "real-world" setting has not been specifically established. Using whole exome sequencing with rigorous, evidence-based variant interpretation, we aimed to identify the prevalence of a molecular diagnosis in patients with dilated cardiomyopathy in a clinical setting. Methods and Results Whole exome sequencing was performed in eligible patients (n=83) with idiopathic or familial dilated cardiomyopathy. Variants were prioritized for curation in up to 247 genes and classified using American College of Medical Genetics and Genomics-based criteria. Ten (12%) had a pathogenic or likely pathogenic variant. Eight (10%) participants had truncating TTN variants classified as variants of uncertain significance. Five (6%) participants had variants of unknown significance according to strict American College of Medical Genetics and Genomics criteria but classified as either pathogenic or likely pathogenic by other clinical laboratories. Pathogenic or likely pathogenic variants were found in 8 genes (all within tier 1 genes), 2 (20%) of which are not included in a standard commercially available dilated cardiomyopathy panel. Using our bioinformatics pipeline, there was an average of 0.74 variants of uncertain significance per case with ≈0.75 person-hours needed to interpret each of these variants. Conclusions Whole exome sequencing is an effective diagnostic tool for patients with dilated cardiomyopathy. With stringent classification using American College of Medical Genetics and Genomics criteria, the rate of detection of pathogenic variants is lower than previous reports. Efforts to improve adherence to these guidelines will be important to prevent erroneous misclassification of nonpathogenic variants in dilated cardiomyopathy genetic testing and inappropriate cascade screening.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

Similar Datasets

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