Ian Tomlinson

Understanding genetic pathways of colorectal carcinogenesis using mouse models and mitochondrial tumour suppressor genes

There are two project from which the graduate student can pick from - project details below.

Project 1. Understanding genetic pathways of colorectal carcinogenesis using mouse models
One of the many puzzling things about human cancers is why their development tends to follow specific genetic pathways. In colorectal cancer, for example, the K-ras oncogene is usually activated in cancers with an aneuploid/karyotype and p53 mutations; BRAF, on the other hand, is mutated in diploid cancers that rarely have mutant p53, despite BRAF and K-ras acting in the same signalling pathway. Addressing these issues using human cancers is difficult, because exceptions to the pathway rules are too few and such cancers may be exceptional in some unknown respect.

We are therefore setting up mouse models of colorectal cancer in which two or more components of each of the basic human genetic pathways are mutated. In this way, we can examine the functional consequences of combinations of mutations, including combinations that are rarely seen - and hence appear to be selectively non-advantageous - in humans.

Project 2. Mitochondrial tumour suppressor genes: how does energy deficiency cause cancer?
Inherited mutations in the Krebs cycle components, succinate dehydrogenase (SDH) and fumarate hydratase (FH), predispose to a variety of tumours, including respectively phaeochromocytomas and papillary renal cell cancers. These mutations cause defects in energy production, but nevertheless cause tumours to grow.

Although paradoxical, a key consequence of SDH or FH mutations may be activation of the hypoxia pathway through stabilisation of HIF1-alpha and/or HIF2-alpha; this effect is also seen in another cancer syndrome, von Hippel-Lindau disease, and in many sporadic cancers. In SDH- and FH-mutant tumours, the mechanism of HIF stabilisation is thought to be accumulation of the Krebs intermediate, alpha-ketoglutarate, which thereby inhibits the tagging of HIF for proteasomal destruction. Evidence suggests, however, that HIF stabilisation on its own is unlikely to be sufficient for full malignancy.

This project will investigate effects of FH mutation other than on HIF degradation, and examine whether these contribute to cancer growth. It will also search for the genetic changes that are important in sporadic papillary renal cancers and compare their functional effects with the changes in cancers from patients with germline FH mutations.

References

Project 1:

1. Johnson V, Volikos E, Halford SE, Eftekhar Sadat ET, Popat S, Talbot I, Truninger K, Martin J, Jass J, Houlston R, Atkin W, Tomlinson IPM, Silver AR. Exon 3 beta-catenin mutations are specifically associated with colorectal carcinomas in hereditary non-polyposis colorectal cancer syndrome. Gut 2005; 54(2): 264-267.
   
   
2. Lipton L, Halford SE, Johnson V, Novelli MR, Jones A, Cummings C, Barclay E, Sieber O, Sadat A, Bisgaard ML, Hodgson SV, Aaltonen LA, Thomas HJ, Tomlinson IPM. Carcinogenesis in MYH-associated polyposis follows a distinct genetic pathway. Cancer Res 2003; 63(22): 7595-7599.
   
   
3. Rowan A, Halford S, Gaasenbeek M, Kemp Z, Sieber O, Volikos E, Douglas E, Fiegler H, Carter N, Talbot I, Silver A, Tomlinson I. Refining molecular analysis in the pathways of colorectal carcinogenesis. Clin Gastroenterol Hepatol 2005; 3(11): 1115-1123.

Project 2:

1. Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D, Leigh I, Gorman P, Lamlum H, Rahman S, Roylance RR, Olpin S, Bevan S, Barker K, Hearle N, Houlston RS, Kiuru M, Lehtonen R, Karhu A, Vilkki S, Laiho P, Eklund C, Vierimaa O, Aittomaki K, Hietala M, Sistonen P, Paetau A, Salovaara R, Herva R, Launonen V, Aaltonen LA. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 2002; 30(4): 406-410.
   
   
2. Alam NA, Rowan AJ, Wortham NC, Pollard PJ, Mitchell M, Tyrer JP, Barclay E, Calonje E, Manek S, Adams SJ, Bowers PW, Burrows NP, Charles-Holmes R, Cook LJ, Daly BM, Ford GP, Fuller LC, Hadfield-Jones SE, Hardwick N, Highet AS, Keefe M, MacDonald-Hull SP, Potts ED, Crone M, Wilkinson S, Camacho-Martinez F, Jablonska S, Ratnavel R, MacDonald A, Mann RJ, Grice K, Guillet G, Lewis-Jones MS, McGrath H, Seukeran DC, Morrison PJ, Fleming S, Rahman S, Kelsell D, Leigh I, Olpin S, Tomlinson IPM. Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. Hum Mol Genet 2003; 12(11): 1241-1252.
   
   
3. Pollard PJ, Spencer-Dene B, Shukla D, Howarth K, Nye E, El-Bahrawy M, Deheragoda M, Joannou M, McDonald S, Martin A, Igarashi P, Varsani-Brown S, Rosewell I, Poulsom R, Maxwell P, Stamp GW, Tomlinson IPM. Targeted inactivation of fh1 causes proliferative renal cyst development and activation of the hypoxia pathway. Cancer Cell 2007; 11(4):311-319.