Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors.
OBJECTIVE
To provide a comprehensive, thorough analysis of somatic mutation and promoter hypermethylation of the von Hippel-Lindau (VHL) gene in the cancer genome, unique to clear cell renal cancer (ccRCC). Identify relationships between the prevalence of VHL gene alterations and alteration subtypes with patient and tumor characteristics.


METHODS
As part of a large kidney cancer case-control study conducted in Central Europe, we analyzed VHL mutations and promoter methylation in 205 well-characterized, histologically confirmed patient tumor biopsies using a combination of sensitive, high-throughput methods (endonuclease scanning and Sanger sequencing) and analysis of 11 CpG sites in the VHL promoter.


RESULTS
We identified mutations in 82.4% of cases, the highest VHL gene mutation prevalence reported to date. Analysis of 11 VHL promoter CpG sites revealed that 8.3% of tumors were hypermethylated and all were mutation negative. In total, 91% of ccRCCs exhibited alteration of the gene through genetic or epigenetic mechanisms. Analysis of patient and tumor characteristics revealed that certain mutation subtypes were significantly associated with Fuhrman nuclear grade, metastasis, node positivity, and self-reported family history of RCC.


CONCLUSIONS
Detection of VHL gene alterations using these accurate, sensitive, and practical methods provides evidence that the vast majority of histologically confirmed ccRCC tumors possess genetic or epigenetic alteration of the VHL gene and support the hypothesis that VHL alteration is an early event in ccRCC carcinogenesis. These findings also indicate that VHL molecular subtypes can provide a sensitive marker of tumor heterogeneity among histologically similar ccRCC cases for etiologic, prognostic, and translational studies.
Nickerson
Michael L
ML
Transgenomic, Gaithersburg, Maryland, USA.
Jaeger
Erich
E
Shi
Yangu
Y
Durocher
Jeffrey A
JA
Mahurkar
Sunil
S
Zaridze
David
D
Matveev
Vsevolod
V
Janout
Vladimir
V
Kollarova
Hellena
H
Bencko
Vladimir
V
Navratilova
Marie
M
Szeszenia-Dabrowska
Neonilia
N
Mates
Dana
D
Mukeria
Anush
A
Holcatova
Ivana
I
Schmidt
Laura S
LS
Toro
Jorge R
JR
Karami
Sara
S
Hung
Rayjean
R
Gerard
Gary F
GF
Linehan
W Marston
WM
Merino
Maria
M
Zbar
Berton
B
Boffetta
Paolo
P
Brennan
Paul
P
Rothman
Nathaniel
N
Chow
Wong-Ho
WH
Waldman
Frederic M
FM
Moore
Lee E
LE
D018262:Adenocarcinoma, Clear Cell / Q000235:genetics* / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism*; D008297:Male; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics* / Q000378:metabolism
D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human