Feasibility and Clinical Utility of Reporting Hereditary Cancer Predisposition Pathogenic Variants Identified in Research Germline Sequencing: A Prospective Interventional Study

Authors

Megan L. Hutchcraft, University of KentuckyFollow
Shulin Zhang, University of KentuckyFollow
Nan Lin, University of Kentucky
Justine C. Pickarski, University of Kentucky
Elizabeth Belcher, University of KentuckyFollow
Sainan Wei, University of KentuckyFollow
Therese J. Bocklage, University of KentuckyFollow
Rachel W. Miller, University of Kentucky
John L. Villano, University of KentuckyFollow
Michael J. Cavnar, University of KentuckyFollow
Joseph Kim, University of Kentucky
Susanne M. Arnold, University of Kentucky
Frederick R. Ueland, University of KentuckyFollow
Jill M. Kolesar, University of KentuckyFollow

Abstract

PURPOSE

Patients with cancer frequently undergo research-grade germline sequencing but clinically actionable results are not routinely disclosed. The objective of this study is to evaluate the feasibility of reporting clinically relevant sec- ondary findings (SF) identified in germline research sequencing using the institutional molecular tumor board (MTB) and the treating oncology physician.

METHODS

This prospective, interventional cohort study enrolled Total Cancer Care par- ticipants with any cancer diagnosis at a single institution. Patients underwent research-grade germline whole-exome sequencing, with bioinformatic anal- ysis in a Clinical Laboratory Improvement Amendments–certified laboratory to verify pathogenic/likely pathogenic germline variants (PGVs) in any American College of Medical Genomics and Genetics SF v2.0 genes. After a protocol modification in consenting patients, the MTB reported PGVs to treating on- cology physicians with recommendations for referral to a licensed genetic counselor and clinical confirmatory testing.

RESULTS

Of the 781 enrolled participants, 32 (4.1%) harbored cancer predisposition PGVs, 24 (3.1%) were heterozygous carriers of an autosomal recessive cancer pre- disposition syndrome, and 14 (1.8%) had other hereditary disease PGVs. Guideline-directed testing would have missed 37.5% (12/32) of the inherited cancer predisposition PGVs, which included BRCA1, BRCA2, MSH6, SDHAF2, SDHB, and TP53 variants. Three hundred fifteen participants consented to reporting results; results for all living patients were reported to the clinical team with half referred to a licensed genetic counselor. There was concordance between all research variants identified in patients (n 5 9) who underwent clinical confirmatory sequencing.

CONCLUSION

MTB reporting of research-grade germline sequencing to the clinical oncology team is feasible. Over a third of PGVs identified using a universal testing strategy would have been missed by guideline-based approach, suggesting a role for expanding germline testing.

Document Type

Article

Publication Date

1-31-2024

Notes/Citation Information

© 2024 by American Society of Clinical Oncology

Digital Object Identifier (DOI)

https://doi.org/10.1200/PO.23.00266

Funding Information

Supported by the Markey Cancer Research Informatics Shared Resource Facility National Cancer Institute Cancer Center Support Grant, grant number P30CA177558. This research was supported by the Biospecimen Procurement and Translational Pathology Shared Resource Facility of the University of Kentucky Markey Comprehensive Cancer Center (MCC; P30CA177558), the Cancer Research Informatics Shared Resource Facilities of the University of Kentucky MCC (P30CA177558), and the Oncogenomics Shared Resource of the University of Kentucky MCC (P30CA177558).

Repository Citation

Hutchcraft, Megan L.; Zhang, Shulin; Lin, Nan; Pickarski, Justine C.; Belcher, Elizabeth; Wei, Sainan; Bocklage, Therese J.; Miller, Rachel W.; Villano, John L.; Cavnar, Michael J.; Kim, Joseph; Arnold, Susanne M.; Ueland, Frederick R.; and Kolesar, Jill M., "Feasibility and Clinical Utility of Reporting Hereditary Cancer Predisposition Pathogenic Variants Identified in Research Germline Sequencing: A Prospective Interventional Study" (2024). Markey Cancer Center Faculty Publications. 185.
https://uknowledge.uky.edu/markey_facpub/185