Cell-free DNA fragmentomics and second malignant neoplasm risk in patients with PTEN hamartoma tumor syndrome

Darren Liu; Lamis Yehia; Andrew Dhawan; Ying Ni; Charis Eng

doi:10.1016/j.xcrm.2023.101384

Cell-free DNA fragmentomics and second malignant neoplasm risk in patients with PTEN hamartoma tumor syndrome

Cell Rep Med. 2024 Feb 20;5(2):101384. doi: 10.1016/j.xcrm.2023.101384. Epub 2024 Jan 18.

Authors

Darren Liu¹, Lamis Yehia², Andrew Dhawan³, Ying Ni⁴, Charis Eng⁵

Affiliations

¹ Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA.
² Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
³ Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH 44195, USA; Center for Personalized Genetic Healthcare, Medical Specialties Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
⁴ Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA; Center for Immunotherapy and Precision Immuno-oncology, Cleveland Clinic, Cleveland, OH 44195, USA.
⁵ Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA; Center for Personalized Genetic Healthcare, Medical Specialties Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Germline High Risk Cancer Focus Group, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address: engc@ccf.org.

Abstract

Individuals with PTEN hamartoma tumor syndrome (PHTS) harbor pathogenic germline PTEN variants that confer a significantly increased lifetime risk of various organ-specific cancers including second primary malignant neoplasms (SMNs). Currently, there are no reliable biomarkers that can predict individual-level cancer risk. Despite the highly promising value of cell-free DNA (cfDNA) as a biomarker for underlying sporadic cancers, the utility of cfDNA in individuals with known cancer-associated germline variants and subclinical cancers remains poorly understood. We perform ultra-low-pass whole-genome sequencing (ULP-WGS) of cfDNA from plasma samples from patients with PHTS and cancer as well as those without cancer. Analysis of cfDNA reveals that patients with PHTS and SMNs have distinct cfDNA size distribution, aberrant genome-wide fragmentation, and differential fragment end motif frequencies. Our work provides evidence that cfDNA profiles may be used as a marker for SMN risk in patients with PHTS.

Keywords: Cowden syndrome; PTEN; PTEN hamartoma tumor syndrome; breast cancer; cell-free DNA; cfDNA; fragmentomics; second primary malignant neoplasm; thyroid cancer.

MeSH terms

Cell-Free Nucleic Acids* / genetics
Germ-Line Mutation
Hamartoma Syndrome, Multiple* / complications
Hamartoma Syndrome, Multiple* / diagnosis
Hamartoma Syndrome, Multiple* / genetics
Humans
Neoplasms*
PTEN Phosphohydrolase / genetics

Substances

PTEN Phosphohydrolase
Cell-Free Nucleic Acids
PTEN protein, human