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Identification of genes that cause the papillary type of kidney cancer

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

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Identification of genes that cause the papillary type of kidney cancer

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  1. Identification of genes that cause the papillary type of kidney cancer Ian Tomlinson Wellcome Trust Centre for Human Genetics

  2. Morphological types of kidney cancer

  3. 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

  4. 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

  5. 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

  6. Fumaratehydratase 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

  7. b.i Active Site Residues I186, both missense and deletion MCUL missense mutations N318K, missense mutation associated with renal cell carcionma Frameshift mutations R300X and E181fsX205 nonsense mutations associated with renal cell carcionoma R58X nonsense mutation Not shown: Q4X, L464P, whole gene deletion

  8. 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

  9. 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

  10. ARID2: c.131505delCG, p.G1605fs BAP1: p. Y546X

  11. 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

  12. 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

  13. Acknowledgements • 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

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