Transcript Identification of genes that cause the papillary type of

Identification of genes that cause
the papillary type of kidney cancer
Ian Tomlinson
Wellcome Trust Centre for Human Genetics
Morphological types of kidney cancer
The pathogenesis of papillary renal
cell cancer
• Histologically divided into Types I and II
• Type I = layers of single cells with scanty pale
cytoplasm, single layer on the basement
membrane. Psammoma bodies and foamy
macrophages frequently seen, often CK7+
• Type II = Pseudostratified nuclei and
voluminous eosinophilic cytoplasm
• Type I lower grade and higher stage
• Type II have poorer survival
The pathogenesis of papillary renal
cell cancer
• Histologically divided into Types I and II
• Type I = layers of single cells with scanty pale
cytoplasm, single layer on the basement
membrane. Psammoma bodies and foamy
macrophages frequently seen, often CK7+
• Type II = Pseudostratified nuclei and
voluminous eosinophilic cytoplasm
• Type I lower grade and higher stage
• Type II have poorer survival
MET (HGFR) and type I PRCC
• MET is an oncogene
• Over-expression activates the cell’s pathways
that cause it to grow
• If you inherit an activated, mutant copy of
MET, you also need an extra copy of
chromosome 7 to get a type I papillary cancer
Fumarate hydratase and type II PRCC
• “HLRCC”: multiple skin smooth muscle
tumours, fibroids of the uterus, aggressive
kidney cancers
• Fumarase mutations inactivate protein and
cause failure of energy production
• It may inactivate enzymes that cause genes to
be active in the cell
b.i
Active Site Residues
MCUL missense mutations
I186, both missense and deletion
Frameshift mutations
N318K, missense mutation associated
with renal cell carcionma
R300X and E181fsX205 nonsense
mutations associated with renal cell
carcionoma
Not shown: Q4X, L464P, whole gene deletion
R58X nonsense mutation
But we know very little about the non-inherited
genetic changes that PRCCs need to grow
• Sequenced 23 sporadic type II PRCC genomes
or “exomes” (regions that code for proteins)
• One FH mutation (inherited), p.Gly397Arg
• No mutations in major cancer genes p53, KRAS,
BRAF
• No VHL mutations (found in almost all clear-cell
kidney cancers)
• Some mutations in interesting genes
Major findings of driver mutations in
type II papillary kidney cancer
• SETD2: expected to silence gene expression,
also mutated in clear-cell kidney cancer
• BAP1: Interacts with breast cancer protein
BRCA1, also mutated in clear-cell kidney
cancer
• ARID2: expected to cause gene silencing, also
mutated in liver cancer
• KDM6B: expected to cause gene silencing, low
frequency of mutations in other cancers
ARID2: c.131505delCG, p.G1605fs
BAP1: p. Y546X
Chromosome-scale changes in type II
papillary kidney cancer
• Two groups of type II papillary cancers
• Group 1: Extra copies of chromosome 7
(MET), 16, 17 (KDM6B) + loss of X
chromosome
• Group 2: Very few chromosome changes
• No loss of chromosome 3, c.f. clear cell kidney
cancers
Future
• Find the frequency of mutations
• Extend work to type I papillary kidney cancer
• Consider screening tests to pick up cancer
cells from urine
• Work with groups who are designing therapies
against the new target genes
Acknowledgements
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Chiara Bardella
Michal Kovac
Karl Heinimann
Jen Williams
Mona El Bahrawy
Julie Adam
Paddy Pollard
Eamonn Maher
Stewart Fleming
Peter Ratcliffe
Funded by UCare and University of Oxford