Clinical significance of TP53 variants as possible secondary findings in tumor-only next-generation sequencing

Yoshihiro Yamamoto,Tomohiro Kondo,Tadayuki Kou,Masashi Kanai,Shigemi Matsumoto,Hiromi Murakami,Eijiro Nakamura,Masako Torishima,Shinji Kosugi,Manabu Muto,Masakazu Nishigaki,Aiko Sugiyama,Takahiro Yamada,Hidehiko Miyake

doi:10.1038/s10038-019-0681-6

Yoshihiro Yamamoto, Tomohiro Kondo + Show 12 more

Open Access

https://doi.org/10.1038/s10038-019-0681-6

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Abstract

In tumor-only next-generation sequencing (NGS), identified variants have the potential to be secondary findings (SFs), but they require verification through additional germline testing. In the present study, 194 patients with advanced cancer who underwent tumor-only NGS between April 2015 and March 2018 were enrolled, and the incidences of possible and true SFs were evaluated. Among them, 120 patients (61.9%) harbored at least one possible SF. TP53 was the most frequent gene in which 97 variants were found in 91 patients (49.5%). Nine patients provided informed consent to undergo additional germline testing, and a total of 14 variants (BRCA1, n = 1; BRCA2, n = 2; PTEN, n = 2; RB1, n = 1; SMAD4, n = 1; STK11, n = 1; TP53, n = 6) were analyzed. Three variants (BRCA1, n = 1; BRCA2, n = 2) were confirmed to be SFs, whereas TP53 variants were confirmed to be somatic variants. To confirm the low prevalence of SFs in TP53, we analyzed 24 patients with TP53 variants who underwent a paired tumor–normal NGS assay. As expected, all TP53 variants were confirmed to be somatic variants. A total of 30 patients were tested for germline variants in TP53, but none of them resulted in true SFs, suggesting the low prevalence of SFs in this gene. Therefore, the significance of additional germline testing for TP53 variants appears to be relatively low in daily clinical practice using a tumor-only NGS assay, unless patients have any relevant medical or family history.

Highlights

Supplementary information The online version of this article contains supplementary material, which is available to authorized users.University School of Public Health, Kyoto, Japan 6 Department of Human Health Sciences, School of Medicine, Kyoto University, Kyoto, JapanNext-generation sequencing (NGS)-based multiplex gene assays are utilized to identify variants that predict the response or resistance to a specific drug in patients with cancer, and its use is rapidly increasing in daily clinical practice [1,2,3,4,5,6]
next-generation sequencing (NGS) assays using only tumor DNA are more commonly used in clinical practice to search for somatic mutations in tumor tissues, but they can identify possible germline variants that can lead to secondary findings (SFs) [1, 3, 6, 16]
We evaluated the incidence of possible SFs in ACMG-recommended genes in a tumoronly NGS assay and the clinical significance of additional germline testing to verify true SFs

Summary

Introduction

Next-generation sequencing (NGS)-based multiplex gene assays are utilized to identify variants that predict the response or resistance to a specific drug in patients with cancer, and its use is rapidly increasing in daily clinical practice [1,2,3,4,5,6]. The French Society of Predictive and Personalized Medicine has published guidelines for the reporting of SFs relating to 60 cancer-related genes [9]. NGS assays using only tumor DNA (tumor-only sequencing) are more commonly used in clinical practice to search for somatic mutations in tumor tissues, but they can identify possible germline variants that can lead to SFs [1, 3, 6, 16]. To confirm the presence of true SFs, additional genetic testing using a matched germline DNA is necessary, and this verification process requires additional informed consent, cost, time and effort [16, 17]

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