TY - JOUR
T1 - Combining variant detection and fragment length analysis improves detection of minimal residual disease in postsurgery circulating tumour DNA of stage II–IIIA NSCLC patients
AU - Vessies, Daan C. L.
AU - Schuurbiers, Milou M. F.
AU - van der Noort, Vincent
AU - Schouten, Irene
AU - Linders, Theodora C.
AU - Lanfermeijer, Mirthe
AU - Ramkisoensing, Kalpana L.
AU - Hartemink, Koen J.
AU - Monkhorst, Kim
AU - van den Heuvel, Michel M.
AU - van den Broek, Daan
N1 - Funding Information: All kits and reagents in this research were funded by Roche Diagnostics, as agreed in OVK-16830. The funder had no influence on the conception and design of the study, on the data analysis or interpretation, or on the writing or decision to publish this manuscript. We thank the Core Facility of Molecular Pathology and Biobanking (CFMPB) of the Netherlands Cancer Institute, and in particular Maartje Alkemade for her help in retrieving materials from the biobank and isolating the tissue DNA. Additionally we thank Robert Schouten for his work in the LEMA study. Ruben Moritz of the NKI pathology IT department was instrumental in collecting the data from the European Genome-phenome Archive (EGA). We thank Pedram Razavi and Jorge Reiss (MSKCC) for allowing us access to their well curated dataset at the EGA. And lastly, we are grateful to the people of EGA and FinaleDB for setting up archives of publicly available data for researchers to use. Funding Information: All kits and reagents in this research were funded by Roche Diagnostics, as agreed in OVK‐16830. The funder had no influence on the conception and design of the study, on the data analysis or interpretation, or on the writing or decision to publish this manuscript. We thank the Core Facility of Molecular Pathology and Biobanking (CFMPB) of the Netherlands Cancer Institute, and in particular Maartje Alkemade for her help in retrieving materials from the biobank and isolating the tissue DNA. Additionally we thank Robert Schouten for his work in the LEMA study. Ruben Moritz of the NKI pathology IT department was instrumental in collecting the data from the European Genome‐phenome Archive (EGA). We thank Pedram Razavi and Jorge Reiss (MSKCC) for allowing us access to their well curated dataset at the EGA. And lastly, we are grateful to the people of EGA and FinaleDB for setting up archives of publicly available data for researchers to use. Publisher Copyright: © 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
PY - 2022/7
Y1 - 2022/7
N2 - Stage II–IIIA nonsmall cell lung cancer (NSCLC) patients receive adjuvant chemotherapy after surgery as standard-of-care treatment, even though only approximately 5.8% of patients will benefit. Identifying patients with minimal residual disease (MRD) after surgery using tissue-informed testing of postoperative plasma circulating cell-free tumour DNA (ctDNA) may allow adjuvant therapy to be withheld from patients without MRD. However, the detection of MRD in the postoperative setting is challenging, and more sensitive methods are urgently needed. We developed a method that combines variant calling and a novel ctDNA fragment length analysis using hybrid capture sequencing data. Among 36 stage II–IIIA NSCLC patients, this method distinguished patients with and without recurrence of disease in a 20 times repeated 10-fold cross validation with 75% accuracy (P = 0.0029). In contrast, using only variant calling or only fragment length analysis, no signification distinction between patients was shown (P = 0.24 and P = 0.074 respectively). In addition, a variant-level fragmentation score was developed that was able to classify variants detected in plasma cfDNA into tumour-derived or white-blood-cell-derived variants with 84% accuracy. The findings in this study may help drive the integration of various types of information from the same data, eventually leading to cheaper and more sensitive techniques to be used in this challenging clinical setting.
AB - Stage II–IIIA nonsmall cell lung cancer (NSCLC) patients receive adjuvant chemotherapy after surgery as standard-of-care treatment, even though only approximately 5.8% of patients will benefit. Identifying patients with minimal residual disease (MRD) after surgery using tissue-informed testing of postoperative plasma circulating cell-free tumour DNA (ctDNA) may allow adjuvant therapy to be withheld from patients without MRD. However, the detection of MRD in the postoperative setting is challenging, and more sensitive methods are urgently needed. We developed a method that combines variant calling and a novel ctDNA fragment length analysis using hybrid capture sequencing data. Among 36 stage II–IIIA NSCLC patients, this method distinguished patients with and without recurrence of disease in a 20 times repeated 10-fold cross validation with 75% accuracy (P = 0.0029). In contrast, using only variant calling or only fragment length analysis, no signification distinction between patients was shown (P = 0.24 and P = 0.074 respectively). In addition, a variant-level fragmentation score was developed that was able to classify variants detected in plasma cfDNA into tumour-derived or white-blood-cell-derived variants with 84% accuracy. The findings in this study may help drive the integration of various types of information from the same data, eventually leading to cheaper and more sensitive techniques to be used in this challenging clinical setting.
KW - MRD
KW - NSCLC
KW - circulating cell-free tumour DNA
KW - ctDNA
KW - fragmentomics
KW - minimal residual disease
UR - http://www.scopus.com/inward/record.url?scp=85132802655&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/1878-0261.13267
DO - https://doi.org/10.1002/1878-0261.13267
M3 - Article
C2 - 35674097
SN - 1574-7891
VL - 16
SP - 2719
EP - 2732
JO - Molecular Oncology
JF - Molecular Oncology
IS - 14
ER -