Ethnic disparities in wilms tumor by fatma abdalla

ETHNIC DISPARITIES IN WILMS TUMOR

Dr F. K. Abdallah

Wilms Tumor (WT)Wilms Tumor (WT)

Most Common Pediatric Renal MalignancyMost Common Pediatric Renal Malignancy

~ 500 cases per year ~ 500 cases per year USAUSA

1/10,000 children 1/10,000 children < 15 years< 15 years

>90% Survival at 5 >90% Survival at 5 years in developed years in developed nationsnations

Davidoff 2009

9%

65%

56%56% More Children Relapse!

Racial Variation in Incidence of Wilms Tumor:Relationship to Congenital Anomalies

Racial Variation in Incidence of Wilms Tumor:Relationship to Congenital Anomalies

Kramer, Meadows, Jarrett. Med Pediatr Onc 12:401-5, 1984Kramer, Meadows, Jarrett. Med Pediatr Onc 12:401-5, 1984

Greater Delaware Valley Pediatric Tumor Registry: 1970-79Greater Delaware Valley Pediatric Tumor Registry: 1970-79

40 black40 black

* per million children < 14 years* per million children < 14 years

Stiller, Parkin:Br. J. Cancer (1990) 62:1026-1030Stiller, Parkin:Br. J. Cancer (1990) 62:1026-1030

International variationsin the incidence of

childhood renal tumors

International variationsin the incidence of

childhood renal tumors

InternationalAgency forResearch onCancer

InternationalAgency forResearch onCancer

Presenting featuresIn Kenyan Wilms tumor

Patients

Presenting featuresIn Kenyan Wilms tumor

Patients

Kyambi et al.East African Medical Journal, June

1981

Kyambi et al.East African Medical Journal, June

1981

quite illwhen compared

with Wilms patientsin developed countries

quite illwhen compared

with Wilms patientsin developed countries

Photo courtesy of Dr. Mark Newton, Kijabe Mission Hospital, KenyaPhoto courtesy of Dr. Mark Newton, Kijabe Mission Hospital, Kenya

“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.”

“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)Breslow N et al. Epidemiology of Wilms Tumor. Med Pediatr Onc 21:172-181 (1993)

What’s the biological basisfor these observed differences

in Wilms tumorincidence and outcomesbetween ethnic groups?

What’s the biological basisfor these observed differences

in Wilms tumorincidence and outcomesbetween ethnic groups?

But could different biology But could different biology also contribute toalso contribute topoor outcomes?poor outcomes?

But could different biology But could different biology also contribute toalso contribute topoor outcomes?poor outcomes?

To identify markers that classify ethnicityand correlate with:

To identify markers that classify ethnicityand correlate with:

cancerprogression

stage ofdisease aggressive

histology

survival

ethnic specific therapies

diseaserelapse

Photos courtesy of Dr. Russ White, Tenwek Mission Hospital, KenyaPhotos courtesy of Dr. Russ White, Tenwek Mission Hospital, Kenya

Identify ethnic-specific therapeutic targetsIdentify ethnic-specific therapeutic targets

MODIFY existingtherapies according to

ethnicity

MODIFY existingtherapies according to

ethnicity

NOVELethnic-specific

therapies

NOVELethnic-specific

therapies

Kenyan Wilms Tumor StudyKenyan Wilms Tumor Study

To assign a molecular signature according to ethnicity for Wilms tumors:a comparison between North American and Kenyan tissues

To assign a molecular signature according to ethnicity for Wilms tumors:a comparison between North American and Kenyan tissues

Quality assurance of Kenyan Wilms tissuesQuality assurance of Kenyan Wilms tissues

proper fixationproper fixation poor fixation or treatment effect?poor fixation or treatment effect?

Preliminary analysis of Kenyan Wilms tissuesPreliminary analysis of Kenyan Wilms tissues

70 tissue blocksfrom 21 patients

(67 blocks required re-embedding)

70 tissue blocksfrom 21 patients

(67 blocks required re-embedding)

6 patient blocks showtreatment effect (ie, necrosis)

6 patient blocks showtreatment effect (ie, necrosis)

1. MALDI-TOF imaging mass spec2. Immunohistochemistry3. Gene sequencing

1. MALDI-TOF imaging mass spec2. Immunohistochemistry3. Gene sequencing

15 patient specimensevaluable

15 patient specimensevaluable

Groseclose et al. Proteomics 2008

High-throughput proteomic analysis of formalin-fixed paraffin-embedded

tissue microarrays using MALDI imaging mass spectrometry

High-throughput proteomic analysis of formalin-fixed paraffin-embedded

tissue microarrays using MALDI imaging mass spectrometry

on-tissuetryptic

digestion

histology-specificMatrix

AssistedLaserDesorptionIonizationTimeOfFlight

Molecular analysis of ethnic variations in Wilms tumor(Vanderbilt patients)

Molecular analysis of ethnic variations in Wilms tumor(Vanderbilt patients)

primary tumor tissueprimary tumor tissue

mucinous stroma

triphasic

mixoid stroma

BWT1-21-3BWT1-21-3BWT1-21-7BWT1-21-7

skeletal muscle stroma

CWT1-3466-1CCWT1-3466-1C CWT1-3466-1KCWT1-3466-1K

W

B

B

BBB

BBB

WW

WW

W

B

B

B

Clustering or “classification” according to race group:blastema only

Clustering or “classification” according to race group:blastema only

Axt, Murphy: J Surg Res, 2011

Inte

nsity

(U

)

Intensity (U)

644 Da

843 Da

Black WTBlack WT

White WTWhite WT

Principal component analysis classification from Principal component analysis classification from blastemablastema

red = black patientsred = black patients : green = white patientsgreen = white patients

Axt, Murphy: J Surg Res, 2011

Peaks that classify race with greater than 85% accuracy: blastemaPeaks that classify race with greater than 85% accuracy: blastema

red = black patientsred = black patientsgreen = white patientsgreen = white patients

W

B

BBBBBBB

WW

WWW

W

Clustering or “classification” according to ethnicity:stroma only

Clustering or “classification” according to ethnicity:stroma only

Axt, Murphy: J Surg Res, 2011

944 Da

2191 Da

Inte

nsity

(U

)

Intensity (U)

Black WTBlack WT

White WTWhite WT

Principal component analysis classification from stroma

blue = blackblue = black : orange = whiteorange = white

Axt, Murphy: J Surg Res, 2011

Peaks that classify with greater than 85% accuracy: stromaPeaks that classify with greater than 85% accuracy: stroma

blue = blackblue = blackorange = orange = whitewhite

Murphy, Axt:Int J Canc, 2012Murphy, Axt:

Int J Canc, 2012

FavorableHistology

FavorableHistology

FavorableHistology,

Nuclear Unrest

FavorableHistology,

Nuclear Unrest

UnfavorableHistology

UnfavorableHistology

FavorableHistology,

p53

FavorableHistology,

p53

UnfavorableHistology,

p53

UnfavorableHistology,

p53

Murphy, Axt: Int J Canc, 2012Murphy, Axt: Int J Canc, 2012

Murphy, Axt:Int J Canc, 2012Murphy, Axt:

Int J Canc, 2012

β-Cateninactivation:

nucleardetection

β-Cateninactivation:

nucleardetection

FavorableHistology

FavorableHistology

UnfavorableHistology

UnfavorableHistology

FavorableHistology

FavorableHistology

Murphy, Axt: Int J Canc, 2012Murphy, Axt: Int J Canc, 2012

Preliminary analysis of Kenyan Wilms tissuesPreliminary analysis of Kenyan Wilms tissues

Murphy, Axt:Int J Canc, 2012Murphy, Axt:

Int J Canc, 2012

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.

ACKNOWLEDMENTS

• Axt, Jason; Axt, Meridith; Githanga, Jessie; Hansen, Erik; Lessan, Joel; Li, Ming; Musimbi, Joyce; Mwachiro, Michael; Newton, Mark; Ndung’u, James; Njuguna, Festis; Nzioka, Ancent, ; Oruko, Oliver; Patel, Kirtika; Tenge, Robert; Ukoli, Flora; White, Russel; O’Neill, James; Lovvorn, Harold

AcknowledgementsAcknowledgements• National Cancer Institute grant: 1R21National Cancer Institute grant: 1R21CA155946-01• Vanderbilt CTSA grant: UL1 RR024975Vanderbilt CTSA grant: UL1 RR024975• National Cancer Institute grant: 5T32CA106183-National Cancer Institute grant: 5T32CA106183-

06A106A1• National Cancer Institute grant: 4R00CA135695-03National Cancer Institute grant: 4R00CA135695-03• Mass spectrometry:Mass spectrometry:

– Vanderbilt Ingram Cancer Center Core Support GrantVanderbilt Ingram Cancer Center Core Support GrantP30-CA68485P30-CA68485

– Department of Defense Grant DOD W81XWH-05-1- 0179Department of Defense Grant DOD W81XWH-05-1- 0179

THANK YOU!!!