Cell-free DNA methylation-defined prognostic subgroups in small-cell lung cancer identified by leukocyte methylation subtraction
Sami Ul Haq,
Sabine Schmid,
Mansi K. Aparnathi,
Katrina Hueniken,
Luna Jia Zhan,
Danielle Sacdalan,
Janice J.N. Li,
Nicholas Meti,
Devalben Patel,
Dangxiao Cheng,
Vivek Philip,
Ming S. Tsao,
Michael Cabanero,
Daniel de Carvalho,
Geoffrey Liu,
Scott V. Bratman,
Benjamin H. Lok
Affiliations
Sami Ul Haq
Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, 1 King’s College Circle, Medical Sciences Building, Room 2374, Toronto ON M5S 1A8, Canada; Princess Margaret Cancer Centre, 610 University Ave, Toronto ON M5G 2C1, Canada
Sabine Schmid
Department of Medical Oncology, Cantonal Hospital St.Gallen, Rorschacher Str. 95, 9000 St. Gallen, Switzerland
Mansi K. Aparnathi
Princess Margaret Cancer Centre, 610 University Ave, Toronto ON M5G 2C1, Canada
Katrina Hueniken
Princess Margaret Cancer Centre, 610 University Ave, Toronto ON M5G 2C1, Canada
Luna Jia Zhan
Princess Margaret Cancer Centre, 610 University Ave, Toronto ON M5G 2C1, Canada
Danielle Sacdalan
Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, 1 King’s College Circle, Medical Sciences Building, Room 2374, Toronto ON M5S 1A8, Canada; Princess Margaret Cancer Centre, 610 University Ave, Toronto ON M5G 2C1, Canada
Janice J.N. Li
Princess Margaret Cancer Centre, 610 University Ave, Toronto ON M5G 2C1, Canada
Nicholas Meti
St. Mary’s Hospital Center, 3830 Lacombe Avenue, Montreal, QC H3T 1M5, Canada
Devalben Patel
Princess Margaret Cancer Centre, 610 University Ave, Toronto ON M5G 2C1, Canada
Dangxiao Cheng
Princess Margaret Cancer Centre, 610 University Ave, Toronto ON M5G 2C1, Canada
Vivek Philip
Princess Margaret Cancer Centre, 610 University Ave, Toronto ON M5G 2C1, Canada
Ming S. Tsao
Princess Margaret Cancer Centre, 610 University Ave, Toronto ON M5G 2C1, Canada; Department of Laboratory Medicine & Pathobiology, Temerty Faculty of Medicine, University of Toronto, 1 King’s College Circle, 6th Floor, Toronto ON M5S 1A8, Canada; Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Princess Margaret Cancer Research Tower, 101 College Street, Room 9-309, Toronto, ON M5G 1L7, Canada
Michael Cabanero
Toronto General Hospital, 200 Elizabeth St., Toronto, ON M5G 2C4, Canada; Department of Laboratory Medicine & Pathobiology, Temerty Faculty of Medicine, University of Toronto, 1 King’s College Circle, 6th Floor, Toronto ON M5S 1A8, Canada
Daniel de Carvalho
Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Princess Margaret Cancer Research Tower, 101 College Street, Room 9-309, Toronto, ON M5G 1L7, Canada
Geoffrey Liu
Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, 1 King’s College Circle, Medical Sciences Building, Room 2374, Toronto ON M5S 1A8, Canada; Princess Margaret Cancer Centre, 610 University Ave, Toronto ON M5G 2C1, Canada; Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Princess Margaret Cancer Research Tower, 101 College Street, Room 9-309, Toronto, ON M5G 1L7, Canada
Scott V. Bratman
Radiation Medicine Program, Princess Margaret Cancer Centre, 610 University Ave, Toronto, ON M5G 2C1, Canada; Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Princess Margaret Cancer Research Tower, 101 College Street, Room 9-309, Toronto, ON M5G 1L7, Canada
Benjamin H. Lok
Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, 1 King’s College Circle, Medical Sciences Building, Room 2374, Toronto ON M5S 1A8, Canada; Radiation Medicine Program, Princess Margaret Cancer Centre, 610 University Ave, Toronto, ON M5G 2C1, Canada; Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Princess Margaret Cancer Research Tower, 101 College Street, Room 9-309, Toronto, ON M5G 1L7, Canada; Corresponding author
Summary: Small-cell lung cancer (SCLC) methylome is understudied. Here, we comprehensively profile SCLC using cell-free methylated DNA immunoprecipitation followed by sequencing (cfMeDIP-seq). Cell-free DNA (cfDNA) from plasma of 74 patients with SCLC pre-treatment and from 20 non-cancer participants, genomic DNA (gDNA) from peripheral blood leukocytes from the same 74 patients, and 7 accompanying circulating tumor cell-derived xenografts (CDXs) underwent cfMeDIP-seq. Peripheral blood leukocyte methylation (PRIME) subtraction to improve tumor specificity. SCLC cfDNA methylation is distinct from non-cancer but correlates with CDX tumor methylation. PRIME and k-means consensus identified two methylome clusters with prognostic associations that related to axon guidance, neuroactive ligand−receptor interaction, pluripotency of stem cells, and differentially methylated at long noncoding RNA and other repeats features. We comprehensively profiled the SCLC methylome in a large patient cohort and identified methylome clusters with prognostic associations. Our work demonstrates the potential of liquid biopsies in examining SCLC biology encoded in the methylome.
