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Investigation of the Atypical FBXW7 Mutation Spectrum in Human

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Investigation of the Atypical FBXW7 Mutation Spectrum in Human Gut Online First, published on May 15, 2013 as 10.1136/gutjnl-2013-304719 Colorectal cancer ORIGINAL ARTICLE Gut: first published as 10.1136/gutjnl-2013-304719 on 15 May 2013. Downloaded from Investigation of the atypical FBXW7 mutation spectrum in human tumours by conditional expression of a heterozygous propellor tip missense allele in the mouse intestines Hayley Davis,1 Annabelle Lewis,1 Axel Behrens,2 Ian Tomlinson1 ▸ Additional material is ABSTRACT published online only. To view Objective FBXW7 encodes the substrate recognition Significance of this study please visit the journal online (http://dx.doi.org/10.1136/ component of a ubiquitin ligase that degrades targets gutjnl-2013-304719). such as Notch1, c-Jun, c-Myc and cyclin E. FBXW7 mutations occur in several tumour types, including 1Molecular and Population What is already known about this subject? Genetics Laboratory, Wellcome colorectal cancers. The FBXW7 mutation spectrum in ▸ FBXW7 is commonly mutated in tumours of Trust Centre for Human cancers is unusual. Some tumours have biallelic loss of diverse origins, including colorectal cancer. Genetics, Oxford University, function mutations but most have monoallelic missense ▸ FBXW7 is classed as a tumour suppressor, but Oxford, UK fi 2 mutations involving speci c arginine residues at has an unusual mutation spectrum whereby Mammalian Genetics β Laboratory, London Research -propellor tips involved in substrate recognition. biallelic, simple loss-of-function mutations are Institute, Cancer Research UK, Design FBXW7 functional studies have generally rare; instead, most mutations are monoallelic London, UK used null systems. In order to analyse the most missense changes involving specific arginine common mutations in human tumours, we created a residues at β-sheet propellor tips that allow the Correspondence to Fbxw7fl(R482Q)/+ mouse and conditionally expressed this Professor I Tomlinson, FBXW7 protein to recognise its substrates. Molecular and Population mutation in the intestines using Vill-Cre. We compared ▸ To date, mouse models carry Fbxw7 null +/− Genetics Laboratory, Wellcome these mice with heterozygous null (Fbxw7 ) mutants. alleles, but these do not faithfully recapitulate Trust Centre for Human Results A few sizeable intestinal adenomas occurred in the mutations most commonly present in − Genetics, Oxford University, approximately 30% of R482Q/+ and Fbxw7+/ mice at human cancers. Roosevelt Drive, Oxford age >300 days. Breeding the R482Q allele onto Apc OX3 7BN, UK; fi What are the new ndings? http://gut.bmj.com/ [email protected] mutant backgrounds led to accelerated morbidity and increased polyp numbers and size. Within the small ▸ Conditional expression of a heterozygous Received 15 February 2013 bowel, polyp distribution was shifted proximally. Elevated propellor tip missense Fbxw7 allele in the Revised 5 April 2013 levels of two particular Fbxw7 substrates, Klf5 and Tgif1, mouse intestines causes tumorigenesis. Accepted 20 April 2013 were found in normal intestine and adenomas of ▸ The mutation causes elevated levels not of R482Q/+, R482Q/R482Q and Fbxw7−/− mice, but not classical Fbxw7 substrates such as c-Jun, but of Fbxw7+/− animals. On the Apc mutant background, Klf5 and Tgif1, in both normal intestines and Fbxw7+/− mutants had a phenotype intermediate adenomas. on September 28, 2021 by guest. Protected copyright. between Fbxw7 wild-type and R482Q/+ mice. ▸ On an Apc mutant background, heterozygous Conclusions Heterozygous Fbxw7 propellor tip null Fbxw7 mutations promote tumour growth, (R482Q) mutations promote intestinal tumorigenesis on but have a much weaker effect than an Apc mutant background. Klf5 and Tgif1 are strong heterozygous propellor tip mutants. candidates for mediating this effect. Although ▸ Propellor tip mutations most likely act as heterozygous null Fbxw7 mutations also promote tumour dominant negative, loss-of-function alleles that growth, these have a weaker effect than R482Q. These provide sufficient derangement for findings explain the FBXW7 mutation spectrum found in tumorigenesis and they are found commonly human cancers, and emphasise the need for animal because they require only a single ‘hit’. fl models faithfully to re ect human disease. How might it impact on clinical practice in the foreseeable future? ▸ Use of specific animal models can explain the in vivo mutation spectrum of cancer genes. OBJECTIVE ▸ Genetically targeted therapies need to take into FBXW7 (F-box and WD40 repeat domain contain- account the specific mutations in cancer and ing 7, also known as FBW7, hCDC4), a tumour how they act. suppressor gene, is mutated in many human malig- ▸ FBXW7 substrates exhibit tissue specificity; 1 nancies. FBXW7 encodes the substrate recognition here, TGIF1 and KLF5 have been identified as To cite: Davis H, Lewis A, component of a Skp, Cullin, F-box-containing the strongest candidate substrates for Behrens A, et al. Gut (SCF)-E3 ubiquitin ligase complex and negatively therapeutic intervention. Published Online First: regulates multiple proteins with established roles in [please include Day Month Year] doi:10.1136/gutjnl- 2013-304719 CopyrightDavis H, et alArticle. Gut 2013; author0:1–8. doi:10.1136/gutjnl-2013-304719 (or their employer) 2013. Produced by BMJ Publishing Group Ltd (& BSG) under licence.1 Colorectal cancer the control of cell division and growth, including cyclin E, the crypt compared with the villus.22 Homozygous Fbxw7 c-Jun, c-Myc, mTor and Notch. There are several excellent knockout resulted in impaired intestinal cell differentiation, Gut: first published as 10.1136/gutjnl-2013-304719 on 15 May 2013. Downloaded from – reviews of the growing knowledge of FBXW7.2 5 with a reduction in the number of goblet and Paneth cells. As it became apparent that FBXW7 regulates many oncopro- There was an accumulation of intracellular domain of Notch1 teins, it was hypothesised that mutations in FBXW7 may cause (Nicd1) and phosphorylated c-Jun. Heterozygous Fbxw7 knock- tumorigenesis. FBXW7 mutations were initially identified by out resulted in an accumulation of Nicd1, but not Spruck et al in ovarian and breast cancer cell lines.67Since then phospho-c-Jun. Notch is a key regulator in the binary decision many studies have assessed FBXW7 mutation status in a range of of transit amplifying cells to differentiate into secretory or cancer types, including both solid tumours and haematological absorptive cells and therefore elevated Nicd1 protein levels in neoplasms. A study by Akhoondi et al8 significantly contributed Fbxw7 null cells were reported as the likely cause of the differ- to this collection, as extensive genetic screening of over 500 entiation phenotype observed. Despite the accumulation of primary tumours of diverse tissue origins was carried out, iden- actively proliferating progenitor cells in the guts of homozygous tifying mutations in FBXW7 in 6% of tumours. Variations in null mice, no intestinal tumours were reported up to 11 months mutation frequencies among these tissues were seen, with the of age. Another group23 subsequently studied the same condi- highest frequencies found in lesions from the bile duct, endo- tional Fbxw7 null mouse, finding a small number of adenomas metrium, blood and colorectrum. in the large intestines of homozygous knockout animals at 9– FBXW7 has several important domains, including WD409 10 months of age. Increased crypt budding and fission, but no repeats that form an eight-bladed, barrel-shaped β-propellor (see polyps, were observed in the small intestine. online supplementary figure S1A) which provides a binding As the Fbxw7 null mutant mice do not faithfully recapitulate pocket for substrates.10 11 Critical arginine residues at the apex the mutations most commonly present in human cancers, we of the propellors directly interact with ‘destruction recognition’ have generated a conditional Fbxw7 mutant mouse which (CDC4 phosphodegron, CPD) sequences in substrates.10 11 The carries one of the most commonly occurring propellor tip mis- Catalogue of Somatic Mutations in Cancer (COSMIC) database sense mutations. We have used this to determine the conse- reports 496 mutations in FBXW7 across all tissue types; 53% of quences of propellor tip mutations, and compared the these are missense changes affecting arginine residues 465, 479 phenotypic effects of this mutation with those of heterozygous and 505 that lie at the β-propellor tips which interact with null alleles, both in the normal intestine and in intestinal polyps. FBXW7 substrates, with the majority of these propellor tip mutations being monoallelic. DESIGN FBXW7 mutations have been investigated thoroughly in colo- Generation and genotyping of R482Q mice – fl rectal tumours.12 14 In colorectal cancer, 189 mutations have Generation and genotyping of Fbxw7 (R482Q)/+ mice were been reported, of which 44% are missense mutations at amino described previously24 (see online supplementary figure S1B). fl acids 465, 479 and 505. We have analysed The Cancer Genome Fbxw7 (R482Q)/+ mice were crossed with Vill-Cre mice25 in Atlas (TCGA) set of 226 colorectal cancers and find no evidence order to knock-in the R482Q mutation (equivalent of human http://gut.bmj.com/ that arginine propellor tip missense mutations are associated R479Q) in the intestine. These mice shall be referred to as with clinicopathological variables, including gender, age of pres- R482Q/+ in the heterozygous state. Conditional Fbxw7 null entation and cancer stage (details not shown). Non-propellor tip animals22 were crossed with Vill-Cre animals;
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