4. Racial Variation in Incidence of Wilms Tumor:
Relationship to Congenital Anomalies
Greater Delaware Valley Pediatric Tumor Registry: 1970-79
Kramer, Meadows, Jarrett. Med Pediatr Onc 12:401-5, 1984
40 black
* per million children < 14 years
5. International variations
in the incidence of
childhood renal tumors
International
Agency for
Research on
Cancer
Stiller, Parkin:
Br. J. Cancer (1990) 62:1026-1030
6. Presenting features
In Kenyan Wilms tumor
Patients
quite ill
when compared
with Wilms patients
in developed countries
Kyambi et al.
East African Medical Journal, June
1981
9. “Wilms tumor appears to vary more
as a function of ETHNIC GROUP
across different countries than it
does with country for a given ethnic
group.”
Breslow N et al. Epidemiology of Wilms Tumor. Med Pediatr Onc 21:172-181
(1993)
10. What’s the biological basis
for these observed differences
in Wilms tumor
incidence and outcomes
between ethnic groups?
12. To identify markers that classify ethnicity
and correlate with:
stage of
disease aggressive
cancer
progression
histology
survival
ethnic specific therapies
disease
relapse
13. Identify ethnic-specific therapeutic targets
MODIFY existing
therapies according to
ethnicity
NOVEL
ethnic-specific
therapies
Photos courtesy of Dr. Russ White, Tenwek Mission Hospital, Kenya
14. Kenyan Wilms Tumor Study
To assign a molecular signature according to ethnicity for Wilms tumors:
a comparison between North American and Kenyan tissues
15. Quality assurance of Kenyan Wilms tissues
proper fixation poor fixation or treatment effect?
16. Preliminary analysis of Kenyan Wilms tissues
70 tissue blocks
from 21 patients
(67 blocks required re-embedding)
6 patient blocks show
treatment effect (ie, necrosis)
15 patient specimens
evaluable
1. MALDI-TOF imaging mass spec
2. Immunohistochemistry
3. Gene sequencing
17. High-throughput proteomic analysis of formalin-fixed paraffin-embedded
tissue microarrays using MALDI imaging mass spectrometry
histology-
Matrix specific
Assisted
Laser
Desorption
Ionization
Time
Of
Flight
on-tissue
tryptic
digestion
Groseclose et al. Proteomics 2008
18. Molecular analysis of ethnic variations in Wilms tumor
(Vanderbilt patients)
primary tumor tissue
21. Clustering or “classification” according to race group:
~npro data filesblastema857 2A blastema
~npro data filesblastema857 1B blastema
~ro data filesblastema19527 2B blastema
~ro data filesblastema19527 2A blastema
~pro data filesblastema1630 1D blastema
~pro data filesblastema1630 1C blastema
~ro data filesblastema11364 1D blastema
~pro data filesblastema3466 1K blastema
~pro data filesblastema3521 1F blastema
~pro data filesblastema3521 1B blastema
~pro data filesblastema3466 1C blastema
~linpro data filesblastema21-7 blastema
~linpro data filesblastema21-3 blastema
~pro data filesblastema2871 1B blastema
~pro data filesblastema2871 1C blastema
~pro data filesblastema4839 1D blastema
~pro data filesblastema4839 1B blastema
18
19
21
20
22
23
24
25
26
27
28
29
30
31
32
35 30 25 20 15 10 5 0
33
B B B
B B B
B
W
B
B
W
B
B
W W
W
W
blastema only
Axt, Murphy: J Surg Res, 2011
23. Peaks that classify race with greater than 85% accuracy:
blastema
rreedd == bbllaacckk ppaattiieennttss
ggrreeeenn == wwhhiittee ppaattiieennttss
24. Clustering or “classification” according to ethnicity:
26
30 25 20 15 10 5
~clinpro data filesstroma4839 1D stroma
~clinpro data filesstroma2871 1B stroma
~clinpro data filesstroma2871 1C stroma
~clinpro data filesstroma857 2A stroma
~clinpro data filesstroma4839 1B stroma
~clinpro data filesstroma904 1E stroma
~clinpro data filesstroma3466 1C stroma
~clinpro data filesstroma904 1F stroma
~orclinpro data filesstroma21-7 stroma
~orclinpro data filesstroma21-3 stroma
~clinpro data filesstroma3521 1F stroma
~ta filesstroma3521 1B stroma0_R01_085
~linpro data filesstroma11364 1D stroma
~clinpro data filesstroma1630 1D stroma
~clinpro data filesstroma1630 1C stroma
16
17
18
19
20
21
22
23
24
25
27
28
29
W
W
W
B
WWW
W
BBBBBBB
stroma only
Axt, Murphy: J Surg Res, 2011
25. Principal component analysis classification from
944 Da
2191 Da
Intensity (U)
BBllaacckk WWTT
Intensity (U)
WWhhiittee WWTT
stroma
bblluuee == bbllaacckk : oorraannggee == wwhhiittee
Axt, Murphy: J Surg Res, 2011
26. Peaks that classify with greater than 85% accuracy: stroma
bblluuee == bbllaacckk
oorraannggee ==
wwhhiittee
33. CONCLUSION
• WT specimens arising among different race
• groups show unique molecular fingerprints
• that could explain disparate incidences and
• biological behavior and that could reveal
• novel therapeutic targets.
Approximately 500 cases per year in the US. WT is diagnosed in 1/10,000 children under 15 yrs. Peak age at presentation is 2-3 years
Davidoff, A. M. (2009). Wilmsʼ tumor. Current opinion in pediatrics, 21(3), 357-364. doi:10.1097/MOP.0b013e32832b323a
Green, D. M., Breslow, N. E., Beckwith, J. B., Finklestein, J. Z., Grundy, P. E., Thomas, P. R., Kim, T., et al. (1998). Comparison between single-dose and divided-dose administration of dactinomycin and doxorubicin for patients with Wilms“ tumor: a report from the National Wilms” Tumor Study Group Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 16(1), 237-245.
Abdallah, F. K., & Macharia, W. M. (2001). Clinical presentation and treatment outcome in children with nephroblastoma in Kenya East African medical journal, 78(7 Suppl), S43-7.
