Molecular subtypes of uterine leiomyosarcoma and correlation with clinical outcome.
The molecular etiology of uterine leiomyosarcoma (ULMS) is poorly understood, which accounts for the wide disparity in outcomes among women with this disease. We examined and compared the molecular profiles of ULMS and normal myometrium (NL) to identify clinically relevant molecular subtypes. Discovery cases included 29 NL and 23 ULMS specimens. RNA was hybridized to Affymetrix U133A 2.0 transcription microarrays. Differentially expressed genes and pathways were identified using standard methods. Fourteen NL and 44 ULMS independent archival samples were used for external validation. Molecular subgroups were correlated with clinical outcome. Pathway analyses of differentially expressed genes between ULMS and NL samples identified overrepresentation of cell cycle regulation, DNA repair, and genomic integrity. External validation confirmed differential expression in 31 genes (P < 4.4 × 10(-4), Bonferroni corrected), with 84% of the overexpressed genes, including CDC7, CDC20, GTSE1, CCNA2, CCNB1, and CCNB2, participating in cell cycle regulation. Unsupervised clustering of ULMS identified two clades that were reproducibly associated with progression-free (median, 4.0 vs 26.0 months; P = .02; HR, 0.33) and overall (median, 18.2 vs 77.2 months; P = .04; HR, 0.33) survival. Cell cycle genes play a key role in ULMS sarcomagenesis, providing opportunities for therapeutic targeting. Reproducible molecular subtypes associated with clinical outcome may permit individualized adjuvant treatment after clinical trial validation.
Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Joyce N
JN
Barlin
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Qin C
QC
Zhou
Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
Mario M
MM
Leitao
Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Maria
M
Bisogna
Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Narciso
N
Olvera
Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Karin K
KK
Shih
Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Anders
A
Jacobsen
Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nikolaus
N
Schultz
Sarcoma Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
William D
WD
Tap
Weill Cornell Medical College, New York, NY, USA; Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Martee L
ML
Hensley
Sarcoma Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Gary K
GK
Schwartz
Division of Molecular Pathology, Fox Chase Cancer Center, Philadelphia, PA, USA.
Jeff
J
Boyd
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Li-Xuan
LX
Qin
Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA. Electronic address: gynbreast@mskcc.org.
Douglas A
DA
Levine
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D020869:Gene Expression Profiling; D018816:Genes, cdc / Q000502:physiology*; D006801:Humans; D007890:Leiomyosarcoma / Q000175:diagnosis / Q000235:genetics*; D046228:Microarray Analysis; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D014594:Uterine Neoplasms / Q000175:diagnosis / Q000235:genetics*
D009363:Neoplasm Proteins