Genetic susceptibility and body mass index in childhood cancer survivors:

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Genetic susceptibility and body mass index in
childhood cancer survivors Where to next?
Julie A. Ross, Ph.D. Department of Pediatrics
and the University of Minnesota Cancer Center
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Overview

• Childhood cancer and abnormal body mass index
• Pathways and genes to explore
• Overweight/Obesity LEPR polymorphism
• Challenges Limitations
• Childhood Cancer Research Network

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Childhood Cancer and Abnormal Body Mass Index
Definitions

• Overweight (BMI 25-30 kg/m2)
• Obese (BMI 30 kg/m2)
• Underweight (BMI

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Overweight/Obesity in survivors of childhood ALL

• Survivors of childhood acute lymphoblastic
  leukemia (ALL) are at higher risk of becoming
  overweight or obese as adults compared to the
  general population.
• Increased risk has been associated with female
  sex and cranial radiation.

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Overweight/obesity in survivors of childhood
brain tumors

• Gurney et al (J Clin Endo Metab 2003 884731-39)
  explored associations in the CCSS between
  treatment for childhood brain tumors and risk of
  either short stature or increased obesity. Of 921
  adults (20-45 years of age), nearly 40 were
  below the 10th percentile for height.
• Further, this association was modified by cranial
  radiation. As with ALL, females treated at a
  young age with high CRT doses were at the highest
  risk of obesity.

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Underweight in childhood cancer survivors

• Meacham et al (Cancer 2005 1031730-9) explored
  the risk of underweight among childhood cancer
  survivors in the CCSS compared to population
  norms (adjusted for age).

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Mechanisms

• Cranial radiation via leptin insensitivity and/or
  growth hormone insufficiency resulting in
  overweight/obesity
• Inadequate nutrition
• Functional changes in nutrient metabolism
• Genetic susceptibility?

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Possible Candidate Genes
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Possible Candidate Genes
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Background ALL and Obesity in CCSS
(Oeffinger et al J Clin Oncol 2003 211359-65)

• A total of 1765 ALL survivors
• Compared with 2565 adult siblings of the
  childhood cancer survivors
• Age- and race- adjusted odds ratio of obesity in
  survivors treated with 20 Gy cranial radiation
  was 2.59 (95 CI1.88-3.55) for females and 1.86
  (95 CI1.33-2.57) for males.
• Risk of overweight and obesity was highest in
  young females treated with 20 Gy radiation no
  pattern observed in males.

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Obesity in survivors of childhood ALL
Leptin Insufficiency?

• Leptin is a hormone primarily secreted by adipose
  tissue.
• Leptin binds to receptors in the hypothalmus
  creating a decrease in appetite and an increase
  in energy expenditure.
• Polymorphisms exist in the leptin-receptor (LEPR)
  gene, which have been implicated in obesity. The
  Gln223Arg polymorphism results in a change in
  charge that likely has functional significance.

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Obesity in survivors of childhood ALL
Study Objective

• To compare LEPR Gln223Arg genotype frequencies in
  survivors of childhood ALL who are overweight or
  obese to those who are normal weight.

- Hypothesis I Survivors with at least two
copies of the 223 Arg allele have increased
susceptibility to being overweight or obese. -
Hypothesis II Survivors with at least two copies
of the 223 Arg allele who are treated with high
levels of cranial radiation will be most at risk
of being overweight or obese.
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Obesity in survivors of childhood ALL
Methods
Baseline questionnaire
Self-report of weight and height -
Body mass index (kg/m2) Chemotherapeutic
agents only Radiation ( 20 Gy)
Cancer Treatment
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Obesity in survivors of childhood ALL
Lab Methods
Buccal cell collection

• CCSS participant at institution with IRB approval
  
• Buccal cell mouthwash collection kit sent
  
• through mail
• DNA extracted, quantified, stored
• Genotyping performed using TaqMan PCR

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Obesity in survivors of childhood ALL
Study Population
1765 ALL survivors (Oeffinger et al analysis)
711 (40) returned sample before




7/15/02
38 missing race 54 non-white 19 samples did not
amplify
600 non-Hispanic white cases
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Obesity in survivors of childhood ALL
Study Population
Buccal cell available Yes No
p value Age, mean 24.7
23.8 7.7 7.3 0.02 Sex
(N, female) 49 48
0.80 Weight BMI 56 0.18 BMI 25-29.9
27 28 BMI 30
19 16 Treatment
Chemo only 24 23
0.14 CRT 1-19 Gy 26
30 CRT 20 Gy 50 47
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Obesity in survivors of childhood ALL
Gln223Arg analysis comparison to controls
CCSS Healthy
ALL Controls
(n600) (n200) Gln/Gln 191
(32) 58 (29) Gln/Arg 288 (48) 99 (49.5)
Arg/Arg 121 (20) 43 (21.5)

?2 0.59, p 0.75
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Obesity in survivors of childhood ALL
(Ross et al J Clin Oncol 2004 223358-3362)
Gln223Arg analysis cases by sex and BMI
FEMALE
MALE BMI
BMI 25 25 Genotype (n174)
(n120) (n148) (n158) Gln/Gln
Gln/Arg 88 76 79
75 Arg/Arg 12
24 21 25

p 0.007 p 0.37
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Obesity in survivors of childhood ALL
Risk of BMI 25 for Arg/Arg in Gln223Arg
Female
Male Gln/Gln
Gln/Gln Arg/Arg Arg/Gln
Arg/Arg Arg/Gln 50 244
71 235 OR
2.5 OR 1.3 95
CI 1.3 4.8 95 CI 0.7 2.2
p 0.004 p
0.39
Adjusted for age at baseline questionnaire,
CRT, age at diagnosis
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Obesity in survivors of childhood ALL
Risk of BMI 25 for Arg/Arg in Gln223Arg Among
Females
CRT 0-19.9 Gy CRT 20
Gy Gln/Gln
Gln/Gln Arg/Arg Arg/Gln
Arg/Arg Arg/Gln 28 117
22 127 OR
1.4 OR 6.1 95
CI 0.6 3.3 95 CI 2.1
22.0 p 0.44
p 0.002
Pinteraction 0.04
Adjusted for age at baseline questionnaire, age
at diagnosis
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Obesity in survivors of childhood ALL
Risk of BMI 25 for Arg/Arg in Gln223Arg Among
Males
CRT 0-19.9 Gy CRT 20
Gy Gln/Gln
Gln/Gln Arg/Arg Arg/Gln
Arg/Arg Arg/Gln 35 119
36 116 OR
0.9 OR 1.8 95
CI 0.4 2.0 95 CI 0.8 4.0
p 0.88 p
0.16
Pinteraction 0.44
Adjusted for age at baseline questionnaire, age
at diagnosis
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Obesity in survivors of childhood ALL
Conclusions

• This study found that the LEPR 223 Arg/Arg
  genotype is significantly associated with risk of
  overweight and obesity in female survivors of
  childhood ALL.
• There was little evidence that the LEPR 223
  Arg/Arg genotype is associated with BMI in male
  survivors of childhood ALL.
• Importantly, there appeared to be a statistically
  significant interaction between high levels of
  cranial radiation and the Arg/Arg genotype among
  females only.

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Obesity in survivors of childhood ALL
Future Considerations

• Identification of children at high risk of
  obesity following therapy might allow for early
  targeted interventions to reduce subsequent
  obesity-related morbidity and mortality.
• Additional study of LEPR and other genes is
  needed to confirm whether there is a gender
  effect and whether certain genotypes result in
  lower leptin receptor binding affinity.
• Challenges

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Even if childhood cancer survivors might be an
informative population to study genetic
susceptibility to overweight and obesity, we need
to consider what is happening to this outcome
in the general population
25
Trends in Overweight Prevalence (), Adults 18
and Older, US, 1992-2002
1992
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Trends in Overweight Prevalence (), Adults 18
and Older, US, 1992-2002
1995
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Trends in Overweight Prevalence (), Adults 18
and Older, US, 1992-2002
1998
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Trends in Overweight Prevalence (), Adults 18
and Older, US, 1992-2002
2002
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Other Overall Challenges

• Relatively small numbers
• Follow-up of patients
• Homogeneity of populations
• Rapidly changing therapies

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Childrens Oncology Group (COG)
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Pediatric Oncology Group (Blue)
Childrens Cancer Group (Red)
COG
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COG Epidemiology Research Program
(Ross JA, Olshan AF. Cancer Epi Biom Prev 2004
131552-54)

• Formation of a national pediatric cancer research
  registry
• Gene-environment interactions
• Methodological issues
• Education

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Childhood Cancer Research Network
A proposal for the establishment of a North
American research registry for childhood cancer
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Why a Childhood Cancer Registry?

• Facilitate enrollment on epidemiology, late
  effects, and cancer control protocols
• More precise estimates of incidence, trends, etc.
• GIS methods for ecological studies providing a
  systematic means to address cancer clustering

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Consent Protocol (COG-AADM01P1)

• COG will form the basis of the CCRN
• Will eventually include record linkage with
  existing cancer registries
• Simplify the IRB review process

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Consent Protocol (COG-AADM01P1)
May 2001 June 2006 Piloted at
23 C.O.G. institutions

• Obtain consent near diagnosis to provide personal
  identifiers at registration
• Obtain consent for possible future contact for
  non-therapeutic studies
• Future studies would then be separately consented
  by the investigator(s) conducting the study.

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Consent Protocol (COG-AADM01P1)June 2006

• All institutions obtained IRB approval
• 2035 parents/patients approached
• 1941 (95) agreed to both consent levels
• 68 ( 3) agreed to name only
• 26 ( 1) refused both

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CCRN Group Wide Opening Registration Procedure

• Reviewed by NCI pediatric central IRB approved
  Feb 2006
• Calls for authorization of parent/patient to CCRN
  rather than consent
• Expected to be open late 2006

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CCRN Group Wide Opening
Steele JR, et al. Cancer Epi Biom Prev, in press

• No to participation in CCRN will request HIPAA
  compliant information only. Yes will allow for
  registration with identifers and ability to
  participate in COG sponsored studies
• Allows portal for non-COG institutions
• Includes reconsideration of authorization and
  recontact at majority

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Acknowledgments
CCRN Steering Committee Alan Gamis, M.D.
Anita Khayat, Ph.D. Mark Krailo, Ph.D.
Louis Leone, Parent Advocate Kim Nagel, RN,
CRA Andrew Olshan, Ph.D. Greg Reaman,
MD, Chairman COG Les Robison, Ph.D., CCSS PI

FUNDING National Childhood Cancer
Foundation Centers for Disease Control NIH U24-
CA55727 (CCSS) NIH U10- CA98543 (COG Parent
Grant) University of Minnesota Childrens Cancer
Research Fund