title: Multimerin-1 (MMRN1) as Novel Adverse Marker in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group.
abstract: OBJECTIVE
  Exploratory gene expression array analyses suggested multimerin-1 (MMRN1) to be a predictive biomarker in acute myelogenous leukemia (AML). Following up on these studies, we evaluated the role of MMRN1 expression as outcome predictor in two recent Children's Oncology Group trials.
  
  
  METHODS
  We retrospectively quantified MMRN1 expression in 183 participants of AAML03P1 and 750 participants of AAML0531 by reverse-transcriptase PCR and correlated expression levels with disease characteristics and clinical outcome.
  
  
  RESULTS
  In AAML03P1, the highest quartile of MMRN1 expression (expression ≥0.5 relative to β-glucuronidase; n = 45) was associated with inferior event-free survival (EFS; P < 0.002) and higher relapse risk (P < 0.004). In AAML0531, in which we quantified MMRN1 mRNA for validation, patients with relative MMRN1 expression ≥0.5 (n = 160) less likely achieved remission (67% vs. 77%, P = 0.006), and more frequently had minimal residual disease (43% vs. 24%, P = 0.001) after one induction course. They had inferior overall survival (OS; 44% ± 9% vs. 69% ± 4% at 5 years; P < 0.001) and EFS (32% ± 8% vs. 54% ± 4% at 5 years; P < 0.001) and higher relapse risk (57% ± 10% vs. 35% ± 5% at 5 years; P < 0.001). These differences were partly attributable to the fact that patients with high MMRN1 expression less likely had cytogenetic/molecular low-risk disease (P < 0.001) than those with low MMRN1 expression. Nevertheless, after multivariable adjustment, high MMRN1 expression remained statistically significantly associated with shorter OS (HR, 1.57; 95% confidence interval, 1.17-2.12; P = 0.003) and EFS (HR, 1.34; 1.04-1.73; P = 0.025), and higher relapse risk (HR, 1.40; 1.01-1.94; P = 0.044).
  
  
  CONCLUSIONS
  Together, our studies identify MMRN1 expression as a novel biomarker that may refine AML risk stratification.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: George S
authors.initials: GS
authors.lastname: Laszlo
authors.affiliation: Department of Biostatistics, University of Southern California, Los Angeles, California. Children's Oncology Group, Monrovia, California.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Alonzo
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Chelsea J
authors.initials: CJ
authors.lastname: Gudgeon
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Kimberly H
authors.initials: KH
authors.lastname: Harrington
authors.affiliation: Children's Oncology Group, Monrovia, California.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Gerbing
authors.affiliation: Children's Oncology Group, Monrovia, California.
authors.forename: Yi-Cheng
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Rhonda E
authors.initials: RE
authors.lastname: Ries
authors.affiliation: Children's Oncology Group, Monrovia, California. Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Susana C
authors.initials: SC
authors.lastname: Raimondi
authors.affiliation: Children's Oncology Group, Monrovia, California. Department of Laboratory Medicine and Pathology, University of Minnesota Cancer Center, Minneapolis, Minnesota.
authors.forename: Betsy A
authors.initials: BA
authors.lastname: Hirsch
authors.affiliation: Children's Oncology Group, Monrovia, California. Division of Hematology-Oncology, Children's Mercy Hospitals and Clinics, Kansas City, Missouri.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Gamis
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. Children's Oncology Group, Monrovia, California. Department of Pediatrics, University of Washington, Seattle, Washington.
authors.forename: Soheil
authors.initials: S
authors.lastname: Meshinchi
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Hematology, Department of Medicine, University of Washington, Seattle, Washington. Department of Epidemiology, University of Washington, Seattle, Washington. rwalter@fredhutch.org.
authors.forename: Roland B
authors.initials: RB
authors.lastname: Walter
mesh_terms: D000293:Adolescent; D014408:Biomarkers, Tumor / Q000032:analysis*; D001798:Blood Proteins / Q000032:analysis / Q000096:biosynthesis*; D002648:Child; D002675:Child, Preschool; D017326:Clinical Trials, Phase III as Topic; D018572:Disease-Free Survival; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000401:mortality / Q000473:pathology*; D008297:Male; D015337:Multicenter Studies as Topic; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D001798:Blood Proteins; C069282:multimerin
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