AUTHOR=Bouzidi Amira , Labreche Karim , Baron Marine , Veyri Marianne , Denis Jérôme Alexandre , Touat Mehdi , Sanson Marc , Davi Frédéric , Guillerm Erell , Jouannet Stéphanie , Charlotte Frédéric , Bielle Franck , Choquet Sylvain , Boëlle Pierre-Yves , Cadranel Jacques , Leblond Véronique , Autran Brigitte , Lacorte Jean-Marc , Spano Jean-Philippe , Coulet Florence , the IDEATION study group , Idbaih Ahmed , Balegroune Noureddine , Guihot Amélie , Theodorou Ioannis , Alentorn Agusti , Brocheriou Isabelle , Anne-Geneviève , Weil Damien Roos , Picca Alberto TITLE=Low-Coverage Whole Genome Sequencing of Cell-Free DNA From Immunosuppressed Cancer Patients Enables Tumor Fraction Determination and Reveals Relevant Copy Number Alterations JOURNAL=Frontiers in Cell and Developmental Biology VOLUME=9 YEAR=2021 URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.661272 DOI=10.3389/fcell.2021.661272 ISSN=2296-634X ABSTRACT=

Cell-free DNA (cfDNA) analysis is a minimally invasive method that can be used to detect genomic abnormalities by directly testing a blood sample. This method is particularly useful for immunosuppressed patients, who are at high risk of complications from tissue biopsy. The cfDNA tumor fraction (TF) varies greatly across cancer type and between patients. Thus, the detection of molecular alterations is highly dependent on the circulating TF. In our study, we aimed to calculate the TF and characterize the copy number aberration (CNA) profile of cfDNA from patients with rare malignancies occurring in immunosuppressed environments or immune-privileged sites. To accomplish this, we recruited 36 patients: 19 patients with non-Hodgkin lymphoma (NHL) who were either human immunodeficiency virus (HIV)-positive or organ transplant recipients, 5 HIV-positive lung cancer patients, and 12 patients with glioma. cfDNA was extracted from the patients’ plasma and sequenced using low-coverage whole genome sequencing (LC-WGS). The cfDNA TF was then calculated using the ichorCNA bioinformatic algorithm, based on the CNA profile. In parallel, we performed whole exome sequencing of patient tumor tissue and cfDNA samples with detectable TFs. We detected a cfDNA TF in 29% of immune-suppressed patients (one patient with lung cancer and six with systemic NHL), with a TF range from 8 to 70%. In these patients, the events detected in the CNA profile of cfDNA are well-known events associated with NHL and lung cancer. Moreover, cfDNA CNA profile correlated with the CNA profile of matched tumor tissue. No tumor-derived cfDNA was detected in the glioma patients. Our study shows that tumor genetic content is detectable in cfDNA from immunosuppressed patients with advanced NHL or lung cancer. LC-WGS is a time- and cost-effective method that can help select an appropriate strategy for performing extensive molecular analysis of cfDNA. This technique also enables characterization of CNAs in cfDNA when sufficient tumor content is available. Hence, this approach can be used to collect useful molecular information that is relevant to patient care.