Prevalence of Pathogenic Germline Variants in the Circulating Tumor DNA Testing

Overview

Journal Int J Clin Oncol

Specialty Oncology

Date 2022 Jul 23

PMID 35870019

Authors

Yoshihiro Yamamoto

Keita Fukuyama

Masashi Kanai

Tomohiro Kondo

Masahiro Yoshioka

Tadayuki Kou

Pham Nguyen Quy

Reiko Kimura-Tsuchiya

Takahiro Yamada

Shigemi Matsumoto

Shinji Kosugi

Manabu Muto

Affiliations

Soon will be listed here.

Abstract

Background: Somatic and germline variants are not distinguishable by circulating tumor DNA (ctDNA) testing without analyzing non-tumor samples. Although confirmatory germline testing is clinically relevant, the criteria for selecting presumed germline variants have not been established in ctDNA testing. In the present study, we aimed to evaluate the prevalence of pathogenic germline variants in clinical ctDNA testing through their variant allele fractions (VAFs).

Methods: A total of consecutive 106 patients with advanced solid tumors who underwent ctDNA testing (Guardant360) between January 2018 and March 2020 were eligible for this study. To verify the origin of pathogenic variants reported in ctDNA testing, germline sequencing was performed using peripheral blood DNA samples archived in the Clinical Bioresource Center in Kyoto University Hospital (Kyoto, Japan) under clinical research settings.

Results: Among 223 pathogenic variants reported in ctDNA testing, the median VAF was 0.9% (0.02-81.8%), and 88 variants with ≥ 1% VAFs were analyzed in germline sequencing. Among 25 variants with ≥ 30% VAFs, seven were found in peripheral blood DNA (BRCA2: n = 6, JAK2: n = 1). In contrast, among the 63 variants with VAFs ranging from 1 to < 30%, only one variant was found in peripheral blood DNA (TP53: n = 1). Eventually, this variant with 15.6% VAF was defined to be an acquired variant, because its allelic distribution did not completely link to those of neighboring germline polymorphisms.

Conclusion: Our current study demonstrated that VAFs values are helpful for selecting presumed germline variants in clinical ctDNA testing.

Citing Articles

New insights into the biology and development of lung cancer in never smokers-implications for early detection and treatment.

Wang P, Sun S, Lam S, Lockwood W J Transl Med. 2023; 21(1):585.

PMID: 37653450 PMC: 10472682. DOI: 10.1186/s12967-023-04430-x.

Current Clinical Practice of Precision Medicine Using Comprehensive Genomic Profiling Tests in Biliary Tract Cancer in Japan.

Kanai M Curr Oncol. 2022; 29(10):7272-7284.

PMID: 36290850 PMC: 9599999. DOI: 10.3390/curroncol29100573.

References

Hu Y, Alden R, Odegaard J, Fairclough S, Chen R, Heng J . Discrimination of Germline T790M Mutations in Plasma Cell-Free DNA Allows Study of Prevalence Across 31,414 Cancer Patients. Clin Cancer Res. 2017; 23(23):7351-7359. PMC: 5712272. DOI: 10.1158/1078-0432.CCR-17-1745. View

McKerrell T, Park N, Chi J, Collord G, Moreno T, Ponstingl H . V617F hematopoietic clones are present several years prior to MPN diagnosis and follow different expansion kinetics. Blood Adv. 2018; 1(14):968-971. PMC: 5737599. DOI: 10.1182/bloodadvances.2017007047. View

Odegaard J, Vincent J, Mortimer S, Vowles J, Ulrich B, Banks K . Validation of a Plasma-Based Comprehensive Cancer Genotyping Assay Utilizing Orthogonal Tissue- and Plasma-Based Methodologies. Clin Cancer Res. 2018; 24(15):3539-3549. DOI: 10.1158/1078-0432.CCR-17-3831. View

Mayrhofer M, De Laere B, Whitington T, Van Oyen P, Ghysel C, Ampe J . Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis. Genome Med. 2018; 10(1):85. PMC: 6247769. DOI: 10.1186/s13073-018-0595-5. View

Phallen J, Sausen M, Adleff V, Leal A, Hruban C, White J . Direct detection of early-stage cancers using circulating tumor DNA. Sci Transl Med. 2017; 9(403). PMC: 6714979. DOI: 10.1126/scitranslmed.aan2415. View

Suehara Y, Sakata-Yanagimoto M, Hattori K, Kusakabe M, Nanmoku T, Sato T . Mutations found in cell-free DNAs of patients with malignant lymphoma at remission can derive from clonal hematopoiesis. Cancer Sci. 2019; 110(10):3375-3381. PMC: 6778636. DOI: 10.1111/cas.14176. View

Xie M, Lu C, Wang J, McLellan M, Johnson K, Wendl M . Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014; 20(12):1472-8. PMC: 4313872. DOI: 10.1038/nm.3733. View

Chao E, Astbury C, Deignan J, Pronold M, Reddi H, Weitzel J . Incidental detection of acquired variants in germline genetic and genomic testing: a points to consider statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021; 23(7):1179-1184. DOI: 10.1038/s41436-021-01138-5. View

Nakamura Y, Taniguchi H, Ikeda M, Bando H, Kato K, Morizane C . Clinical utility of circulating tumor DNA sequencing in advanced gastrointestinal cancer: SCRUM-Japan GI-SCREEN and GOZILA studies. Nat Med. 2020; 26(12):1859-1864. DOI: 10.1038/s41591-020-1063-5. View

10.

Mack P, Banks K, Espenschied C, Burich R, Zill O, Lee C . Spectrum of driver mutations and clinical impact of circulating tumor DNA analysis in non-small cell lung cancer: Analysis of over 8000 cases. Cancer. 2020; 126(14):3219-3228. PMC: 7383626. DOI: 10.1002/cncr.32876. View

11.

Slavin T, Banks K, Chudova D, Oxnard G, Odegaard J, Nagy R . Identification of Incidental Germline Mutations in Patients With Advanced Solid Tumors Who Underwent Cell-Free Circulating Tumor DNA Sequencing. J Clin Oncol. 2018; :JCO1800328. PMC: 6286162. DOI: 10.1200/JCO.18.00328. View

12.

Baxter E, Scott L, Campbell P, East C, Fourouclas N, Swanton S . Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005; 365(9464):1054-61. DOI: 10.1016/S0140-6736(05)71142-9. View

13.

Green R, Berg J, Grody W, Kalia S, Korf B, Martin C . ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013; 15(7):565-74. PMC: 3727274. DOI: 10.1038/gim.2013.73. View

14.

Pujol P, Vande Perre P, Faivre L, Sanlaville D, Corsini C, Baertschi B . Guidelines for reporting secondary findings of genome sequencing in cancer genes: the SFMPP recommendations. Eur J Hum Genet. 2018; 26(12):1732-1742. PMC: 6244405. DOI: 10.1038/s41431-018-0224-1. View

15.

Chaudhuri A, Chabon J, Lovejoy A, Newman A, Stehr H, Azad T . Early Detection of Molecular Residual Disease in Localized Lung Cancer by Circulating Tumor DNA Profiling. Cancer Discov. 2017; 7(12):1394-1403. PMC: 5895851. DOI: 10.1158/2159-8290.CD-17-0716. View

16.

Miller D, Lee K, Chung W, Gordon A, Herman G, Klein T . ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021; 23(8):1381-1390. DOI: 10.1038/s41436-021-01172-3. View

17.

Derouault P, Chauzeix J, Rizzo D, Miressi F, Magdelaine C, Bourthoumieu S . CovCopCan: An efficient tool to detect Copy Number Variation from amplicon sequencing data in inherited diseases and cancer. PLoS Comput Biol. 2020; 16(2):e1007503. PMC: 7041855. DOI: 10.1371/journal.pcbi.1007503. View

18.

Lanman R, Mortimer S, Zill O, Sebisanovic D, Lopez R, Blau S . Analytical and Clinical Validation of a Digital Sequencing Panel for Quantitative, Highly Accurate Evaluation of Cell-Free Circulating Tumor DNA. PLoS One. 2015; 10(10):e0140712. PMC: 4608804. DOI: 10.1371/journal.pone.0140712. View

19.

Osumi H, Shinozaki E, Takeda Y, Wakatsuki T, Ichimura T, Saiura A . Clinical relevance of circulating tumor DNA assessed through deep sequencing in patients with metastatic colorectal cancer. Cancer Med. 2018; 8(1):408-417. PMC: 6346227. DOI: 10.1002/cam4.1913. View

20.

Stout L, Kassem N, Hunter C, Philips S, Radovich M, Schneider B . Identification of germline cancer predisposition variants during clinical ctDNA testing. Sci Rep. 2021; 11(1):13624. PMC: 8249601. DOI: 10.1038/s41598-021-93084-0. View