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

doi:10.1016/j.isci.2022.105487

Cell-free DNA methylation-defined prognostic subgroups in small-cell lung cancer identified by leukocyte methylation subtraction

iScience. 2022 Nov 4;25(12):105487. doi: 10.1016/j.isci.2022.105487. eCollection 2022 Dec 22.

Authors

Sami Ul Haq^{1

2}, Sabine Schmid³, Mansi K Aparnathi², Katrina Hueniken², Luna Jia Zhan², Danielle Sacdalan^{1

2}, Janice J N Li², Nicholas Meti⁴, Devalben Patel², Dangxiao Cheng², Vivek Philip², Ming S Tsao^{2

5

6}, Michael Cabanero^{7

5}, Daniel de Carvalho⁶, Geoffrey Liu^{1

2

6}, Scott V Bratman^{8

6}, Benjamin H Lok^{1

8

6}

Affiliations

¹ 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.
² Princess Margaret Cancer Centre, 610 University Ave, Toronto ON M5G 2C1, Canada.
³ Department of Medical Oncology, Cantonal Hospital St.Gallen, Rorschacher Str. 95, 9000 St. Gallen, Switzerland.
⁴ St. Mary's Hospital Center, 3830 Lacombe Avenue, Montreal, QC H3T 1M5, Canada.
⁵ Department of Laboratory Medicine & Pathobiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, 6th Floor, Toronto ON M5S 1A8, Canada.
⁶ 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.
⁷ Toronto General Hospital, 200 Elizabeth St., Toronto, ON M5G 2C4, Canada.
⁸ Radiation Medicine Program, Princess Margaret Cancer Centre, 610 University Ave, Toronto, ON M5G 2C1, Canada.

Abstract

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.

Keywords: Cancer; Cancer systems biology; Epigenetics; Genomics.