Rescreening for genetic mutations using multi-gene panel testing in patients who previously underwent non-informative genetic screening☆,☆☆,★
Introduction
Genetic testing for inherited cancer susceptibility syndromes can identify individuals at elevated risk for cancer and reduce morbidity and mortality through targeted screening and risk-reducing surgery [1]. Historically, genetic testing was restricted to only a few well-characterized genes that best fit the patient's clinical history because evaluating multiple genes was laborious and cost prohibitive. In ovarian cancer, this involved BRCA1 and BRCA2 analysis for the majority of patients and additional mismatch repairs genes for a small population of patients with personal and familial histories suggestive of Lynch syndrome. In June 2013 the Supreme Court unanimously ruled against Myriad Genetics, invalidating the exclusive license rights to BRCA1 and BRCA2 genetic testing in the United States. Following this decision, many additional clinical laboratories began offering BRCA1 and BRCA2 testing, both as single gene tests and in the form of comprehensive genetic panels [2].
Over the past two years, there has been rapid integration of panel testing into cancer genetic evaluations. The growing use of panels resulted from the advent of cost effective and time-efficient next-generation sequencing technology coupled with the identification of multiple novel cancer related genes and pathways [3]. Although used for many hereditary cancer syndromes, multi-gene panels have been particularly interesting in ovarian cancer. Recent literature suggests that approximately 23% of ovarian cancers are associated with germline mutations, and of these, 29% have mutations in genes other than BRCA1 or BRCA2 [4]. Furthermore, many patients found to have pathogenic mutations and have no family history of breast or ovarian cancer, suggesting that these mutations would likely be missed with single-gene testing directed by personal and family history [4].
The increasing breadth of genetic information offered and falling prices of next-generation sequencing have led some to suggest that the practice of evaluating single genes is now obsolete [5]. This raises a question regarding management of patients who previously have had negative targeted single gene testing: should these patients be recommended to have repeat screening with multi-gene panels? Multi-gene panel testing has only been available since 2012, and there is limited literature on the question of retesting. Therefore, we sought to investigate the results of multi-gene panel rescreening in individuals with prior non-informative targeted single gene testing.
Section snippets
Methods
This study was approved by the New York University School of Medicine Institutional Review Board. A review was conducted of all patients undergoing multi-gene panel testing between January 1, 2013 (when this technology became available at our institution) and November 1, 2014. Multi-gene panel testing was obtained via one of the three tests available at our institution during the study period (Ambry Genetics, GeneDx, and Myriad Genetics). We refer to prior, non multi-gene panel testing as
Results
Five hundred and sixty patients underwent multi-gene panel testing at our institution during the study period. One hundred and twenty-seven patients were included in our analysis. Four hundred and thirty-three patients were excluded for the following reasons: the patient did not have prior targeted single gene genetic testing (414 patients) or the medical record had incomplete information on prior genetic evaluation and testing (19 patients). The average age at the time of primary testing was 50
Discussion
We evaluated the use of multi-gene panel testing in a population of patients with prior non-informative targeted single gene testing. We found a 7% rate of change in pathogenic mutation characterization and a 42% rate of change in VUS characterization with repeat panel testing. Until recently, hereditary ovarian cancer was explained by germline mutations in the BRCA1 and BRCA2 genes, with an estimated lifetime risk of 30–62% in mutation carriers [7], [8], [9]. However, new data suggest that
Acknowledgments
We acknowledge Ambry Genetics, GeneDx, and Myriad Genetics for sharing their data for use in this project.
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Cited by (0)
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There are no funding sources for this work.
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There are no financial disclosures or other conflicts of interest for any authors.
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The study has been presented as an oral presentation at the Society of Gynecologic Oncology Early Education Summit in December 2014 and was presented as a featured poster at the Society of Gynecologic Oncology Annual Meeting in March 2015 and the American Society of Clinical Oncology Annual Meeting in June 2015.
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Emily Dalton is an employee at Ambry Genetics.