A pharmacogenomic approach to the treatment of children with GH deficiency or Turner syndrome

ObjectiveIndividual sensitivity to recombinant human GH (r-hGH) is variable. Identification of genetic factors contributing to this variability has potential use for individualization of treatment. The objective of this study was to identify genetic markers and gene expression profiles associated with growth response on r-hGH therapy in treatment-naïve, prepubertal children with GH deficiency (GHD) or Turner syndrome (TS).DesignA prospective, multicenter, international, open-label pharmacogenomic study.MethodsThe associations of genotypes in 103 growth- and metabolism-related genes and baseline gene expression profiles with growth response to r-hGH (cm/year) over the first year were evaluated. Genotype associations were assessed with growth response as a continuous variable and as a categorical variable divided into quartiles.ResultsEleven genes in GHD and ten in TS, with two overlapping between conditions, were significantly associated with growth response either as a continuous variable (seven in GHD, two in TS) or as a categorical variable (four more in GHD, eight more in TS). For example, in GHD, GRB10 was associated with high response (≥Q3; P=0.0012), while SOS2 was associated with low response (≤Q1; P=0.006), while in TS, LHX4 was associated with high response (P=0.0003) and PTPN1 with low response (P=0.0037). Differences in expression were identified for one of the growth response-associated genes in GHD (AKT1) and for two in TS (KRAS and MYOD1).ConclusionsCarriage of specific growth-related genetic markers is associated with growth response in GHD and TS. These findings indicate that pharmacogenomics could have a role in individualized management of childhood growth disorders.

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A pilot study to evaluate gene expression profiles in peripheral blood mononuclear cells (PBMCs) from children with GH deficiency and Turner syndrome in response to GH treatment

Clinical Endocrinology ◽

10.1111/j.1365-2265.2008.03477.x ◽

2009 ◽

Vol 70 (3) ◽

pp. 429-434 ◽

Cited By ~ 18

Author(s):

Andrew J. Whatmore ◽

Leena Patel ◽

Peter E. Clayton

Keyword(s):

Gene Expression ◽

Pilot Study ◽

Peripheral Blood Mononuclear Cells ◽

Mononuclear Cells ◽

Gh Deficiency ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Gh Treatment ◽

Peripheral Blood Mononuclear ◽

Blood Mononuclear Cells

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Gene expression profiles predictive of outcome and age in infant acute lymphoblastic leukemia: a Children's Oncology Group study

Blood ◽

10.1182/blood-2011-10-382861 ◽

2012 ◽

Vol 119 (8) ◽

pp. 1872-1881 ◽

Cited By ~ 75

Author(s):

Huining Kang ◽

Carla S. Wilson ◽

Richard C. Harvey ◽

I.-Ming Chen ◽

Maurice H. Murphy ◽

...

Keyword(s):

Gene Expression ◽

Expression Profiles ◽

Lymphoblastic Leukemia ◽

Age Groups ◽

Gene Expression Profiles ◽

Continuous Variable ◽

Oncology Group ◽

Excellent Outcome ◽

Differential Outcomes ◽

Age Related

Abstract Gene expression profiling was performed on 97 cases of infant ALL from Children's Oncology Group Trial P9407. Statistical modeling of an outcome predictor revealed 3 genes highly predictive of event-free survival (EFS), beyond age and MLL status: FLT3, IRX2, and TACC2. Low FLT3 expression was found in a group of infants with excellent outcome (n = 11; 5-year EFS of 100%), whereas differential expression of IRX2 and TACC2 partitioned the remaining infants into 2 groups with significantly different survivals (5-year EFS of 16% vs 64%; P < .001). When infants with MLL-AFF1 were analyzed separately, a 7-gene classifier was developed that split them into 2 distinct groups with significantly different outcomes (5-year EFS of 20% vs 65%; P < .001). In this classifier, elevated expression of NEGR1 was associated with better EFS, whereas IRX2, EPS8, and TPD52 expression were correlated with worse outcome. This classifier also predicted EFS in an independent infant ALL cohort from the Interfant-99 trial. When evaluating expression profiles as a continuous variable relative to patient age, we further identified striking differences in profiles in infants less than or equal to 90 days of age and those more than 90 days of age. These age-related patterns suggest different mechanisms of leukemogenesis and may underlie the differential outcomes historically seen in these age groups.

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