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

• Published in: Journal of human genetics 2020-01, Vol.65 (2), p.125-132
• Main Authors: Yamamoto, Yoshihiro, Kanai, Masashi, Kou, Tadayuki, Sugiyama, Aiko, Nakamura, Eijiro, Miyake, Hidehiko, Yamada, Takahiro, Nishigaki, Masakazu, Kondo, Tomohiro, Murakami, Hiromi, Torishima, Masako, Matsumoto, Shigemi, Kosugi, Shinji, Muto, Manabu
• Format: Article
• Language: English
• Subjects: Biomarkers, Tumor - genetics; Brain cancer; BRCA1 protein; BRCA1 Protein - genetics; BRCA2 protein; BRCA2 Protein - genetics; Breast cancer; Clinical medicine; Clinical significance; Data analysis; Deoxyribonucleic acid; DNA; Family medical history; Female; Gene Frequency; Genes; Genetic disorders; Genetic Predisposition to Disease; Genetic Variation - genetics; Genetics; Genomics; Germ-Line Mutation; High-Throughput Nucleotide Sequencing; Humans; Laboratories; Male; Medicine; Middle Aged; Mutation; Next-generation sequencing; Ovarian cancer; p53 Protein; Patients; PTEN protein; Sequence Analysis, DNA; Smad4 protein; Tumor Suppressor Protein p53 - genetics; Tumors
• ISSN: 1434-5161; 1435-232X
• DOI: 10.1038/s10038-019-0681-6

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.